Pharmaceutical composition and methods of treating cancer and its metastases
FIELD: medicine, pharmaceutics.
SUBSTANCE: claimed group of inventions relates to medicine, namely to oncology, and can be used for treatment of metastatic neoplastic disease. Claimed is treatment method which includes introduction of therapeutically efficient quantity of sodium meta-arsenite. Additionally introduction of other chemotherapeutical substance is carried out. Claimed is composition, containing sodium meta-arsenite. Claimed is set for inhibition of abnormal cell growth, which includes therapeutically efficient quantity of pharmaceutical composition, containing sodium meta-arsenite, and other chemotherapeutical substance.
EFFECT: group of inventions ensures possibility of metastatic neoplastic disease treatment with alternative compound with anticancer activity, as well as treatment safety.
2 tbl, 6 ex
Cancer is an important health problem in the world. Although made progress in detection and treatment of cancer, currently there is no vaccine or other generally accepted universal successful prophylactic or therapeutic agent. The elimination of the disease is currently based on a combination of early diagnosis and intensive therapy, which may include one or more of a variety of treatments, such as surgery, radiation therapy, chemotherapy and hormonal therapy. Despite the fact that such kinds of treatment benefit many patients for many types of cancer continues to remain high mortality. Advanced anti-cancer drugs will help in the prevention and treatment of cancer.
Unfortunately, cancer is the leading cause of death, second only to heart disease, and for men and women. In the fight against cancer created numerous methods, and they remain the subject of modern research aimed at understanding the nature and causes of the disease, providing ways to control or cure.
Although appreciated by thousands of potential anti-cancer substances, treatment of human remains full of difficulties, which often represent a set of suboptimal alternatives of treatment. what about the fact, a welcome addition to methods of therapeutic treatment available to the oncologist at the present time, could be therapeutic agents with low toxicity or no, which is inexpensive to obtain or manufacture, which is well-tolerated by the patient and easy to apply. Also desirable are substances that will selectively enhance the sensitivity of malignant tissue in order to allow the use of lower doses of irradiation or therapy to achieve the same therapeutic effect with less damage to healthy tissue. Similarly, desirable are also substances that prevent cancer or its recurrence. The present invention compensates these needs by providing such chemotherapeutic and sensitizing substances.
Therefore, the technical task underlying the present invention is the provision of alternative or additional compounds with anticancer activity and methods for clinical application.
This problem is solved by the provision of the embodiments as defined in the claims.
The compounds of this invention are suitable in the treatment of cancer. They are effective in the inhibition of survival and/or growth rakovi the cells and/or for inhibiting undesirable cell growth in General.
Then, the invention provides pharmaceutical and therapeutic compositions that contain pharmaceutically or therapeutically effective amount of these compounds, and therapeutic agents and methods of treatment using such compounds. More specifically, this invention relates to methods of treating cancer using oral (oral intake) sodium salt arsenic acid, disclosed in this specification.
The role of arsenic trioxide in the treatment of cancer, as described by some of the inventors, differs from the present invention, while the role of arsenic (WO 800245; Komipharm International) in the treatment of malignant tumors was limited to the primary tumor.
Also claimed is a kit for inhibiting abnormal cell growth, containing the sodium salt of arsenic acid and/or synthetic analogues, modifications and pharmacologically active fragments.
Before the present compounds, compositions, formulations and methods are described, it must be borne in mind that this invention is not limited to specific compounds, methods, compositions and therapeutic indications described herein, as such methods, compositions and therapeutic indications, of course, vary. You must also bear in mind that the terminology used here with what exists only for the purpose of describing specific options description of the invention and is not intended to limit the scope of the present invention, which is defined only by the attached claims.
When used in this specification including the accompanying claims, the singular forms of the number of words, such as "a," "an" and "the"include their respective references in the plural unless the context clearly dictates otherwise. Thus, for example, reference to "organism" includes one or more different organisms, the reference to "a cell" includes one or more of such cells and reference to "the method" includes reference to equivalent steps and methods known to the average expert in the art, and so forth.
Unless otherwise specified, all used here is the technical and scientific terms have the same meaning as commonly understood, the average expert in the art to which this invention relates. Although in the implementation or testing of the present invention can be used in the methods and materials similar or equivalent to those described herein, suitable methods and materials are described below. All publications, patent applications and other references discussed earlier, provided only for their disclosure prior to the filing date of this application. Nothing in this description is not construed as an admission that the invention is not entitled to anticipate such disclosure is based on the previous invention. All publications, patent applications, patents, and other references mentioned herein are hereby incorporated by reference as a whole, including all drawings.
Before placing next invention may be useful for understanding put forward wording of certain terms used in the future.
"Patient" for purposes of the present invention includes humans and other animals, particularly mammals, and other organisms. Thus, the methods are useful in treatment of a person and use in veterinary medicine. In a preferred embodiment, the patient is a mammal, and in the most preferred embodiment is the man.
The term "animal" refers to an organism with a closed circulatory system blood vessels and includes birds, mammals and crocodiles. The term "animal"used in this description, also includes human subjects.
The term "angiogenesis" refers to the generation of new blood vessels into the cells, tissues, organs or tumors.
The term "metastasis" refers to the process by which tumor cells spread to distant parts of the body. This term is also used here to refer to cancer that develops due to the metastatic process.
The term "associated" uses what I'm here interchangeably with the following: combined with, added to, mixed with, pasirayi on, incubated with originating etc. in Addition, the compounds of the present invention can be implemented in any conventional manner such as, for example, parenteral, oral and local ways and by inhalation, as described herein.
When used in this specification, the term "safe and effective amount" refers to the quantity of a component which is sufficient to cause the desired therapeutic response without undue adverse side effects (such as toxicity, irritation or allergic response) commensurate with a reasonable relation to the benefit/risk in the application of the method of the present invention. What is meant by the term "therapeutically effective amount"is the quantity of the compounds of the present invention, effective to provide the desired therapeutic response. This number, for example, can be effective in stunted growth, delayed metastasis, inhibition of angiogenesis and/or telomeres and/or cause the reduction of cancer, or sarcoma, or lymphoma. The specific safe and effective amount or therapeutically effective amount will vary with such factors as the particular condition to be treated, the physical condition is the patient, type mammal undergoing treatment, duration of treatment, the nature of concurrent therapy (if it occurs) and some of the language used and the structure of the compounds or their derivatives.
"Anti-angiogenic" amount refers to the amount of the compound or composition effective to weaken, to suppress or inhibit angiogenesis or to lead to improved symptoms associated with the angiogenic disease. The desired result may be either a subjective relief of a symptom(s)or an objectively identifiable improvement to the recipient of the dose, reduced vascularization of endothelial cells or decrease in the speed of angiogenesis, as noted by the Clinician or other qualified expert.
The terms "cancer treatment", "therapy" and the like refer generally to any improvement in a mammal having a cancer in which the improvement can be attributed to treatment with the compounds of the present invention. The improvement may be either subjective or objective. For example, if the mammal is a human, the patient may notice an improvement in power or energy or the reduction of pain as a subjective symptom improvement or response to therapy. Alternatively, the Clinician may notice a decrease in size or severity of the tumor, based on medicines is whom the inspection, laboratory parameters, tumor markers, or radiographic data. Some labs say that the Clinician can observe in response to therapy for normalization of tests, including blood cell counts, the number of red blood cells, platelet count, erythrocyte sedimentation rate and levels of various enzymes. In addition, the Clinician can observe the reduction of detectable tumor marker. Alternatively, it may be possible to use other tests to assess objective improvement, such as echo, a study by the method of nuclear magnetic resonance and study by means of positron emission tomography.
"Inhibition of growth of tumor cells can be assessed by any generally accepted method of measuring whether the growth of tumor cells delayed or reduced. This includes direct observation and indirect assessment, such as subjective symptoms or objective evidence, as discussed above.
Thus, compositions of the invention is introduced into cells. By "introduced" here refers to the maintenance of therapeutically effective doses of the substances in the candidate of the invention in a cell or a cell culture or patient. By "therapeutically effective dose" refers to the dose that causes of action for which it is entered. The exact dose will be for the Iset from the goals of treatment, will be installed by a specialist in the art using known techniques. As is well known in this field, devices for the system against (versus) localized delivery, age, body weight, General health, sex, diet, time of administration, the interaction of substances and the severity of the condition may be needed and can be installed by an expert in the field of conventional experimentation. Under the "cells" here refers to almost any cell in which mitosis or meiosis can be changed.
Therefore, the present invention relates to anticancer pharmaceutical compositions containing a therapeutically effective amount of sodium salt of arsenic acid of the following formula (I):
2. The technical field
The present invention relates to compounds, methods and compositions for the treatment of primary and metastatic neoplastic diseases, including, but without limitation, urogenital carcinoma.
More specifically, the present invention relates to new chemotherapeutic compositions of sodium salt of arsenic acid and methods of the new application of oral arsenic compounds for the treatment of prostate cancer, primary and metastatic tumors of the genitourinary system; and bladder, kidneys, testicles, and metastatic cancer to the property.
3. Prior art
The majority of chemotherapeutic substances currently designed for intravenous administration. Oral treatment of antitumor substances at the present time, however, is of interest due to the advantages of easy application, the best endorsement of the patient and reduction in cost and increase the quality of life of patients. For example, patients can be exposed to oral treatment as outpatients.
Therefore, it is clear that oral drugs for the treatment of cancer has a future, and they will play a more important role than they have played in the past. Appear considerations about the preferences of patients and quality of life, which have become major considerations in palliative treatment regimens, prior to the creation of the substances used orally. Intravenous (in/in) is a major source of inconvenience and stress for cancer patients, and approximately 90% of patients expressed a preference against oral/chemotherapy, mainly due to ease of use outside of a clinical situation or previous problems associated with intravenous access.
One of the key objectives of the present invention is to provide a chemotherapeutic product for the treatment of cancer that exhibits high bioavailability, velicanu anticancer activity and a high level of security after oral administration.
3.1. Genitourinary cancer
Among genitourinary malignancies include (among other) cancers of the prostate, bladder, kidney and testis. The problems represented by these malignant formations, similar to those faced by researchers and practitioners in the treatment of all other types of cancer. Smoking, which is strongly connected with the development of lung cancer, causes one third of cancers of the bladder, and some studies have linked obesity with an increased risk for cancers of the colon, breast and kidney.
3.2. Bladder cancer
Carcinoma of the urinary tract are found in 90% of cases directly in the bladder, 8% in the renal pelvis and 2% in the ureter or urethra. Bladder cancer is the fourth most common cancer among men and the eighth in women. There are assumptions that 25% of cancers of the bladder in men are associated with occupational exposure and 50% with Smoking cigarettes. Smoking is a key determinant of risk that persists for up to 10 years after Smoking cessation. The choice of treatment is based on the degree of disease: superficial, invasive or metastatic. Combination chemotherapy is used to treat metastatic disease. Urothelial tumors are homeocysteine, and some of the which a number of individual drugs leads to short-term regressions in 20 to 30 percent of cases. One mode is called MVAC mode. It consists of combination treatment with methotrexate, vinblastine, adriamycin (doxorubicin and cisplatin. Some drugs are within a few days of medication, then repeat every few weeks for several months.
3.3. Kidney cancer
Renal cell cancer causes 90-95% of malignant neoplasms arising from the kidney. Renal cell carcinoma affects more than 30,000 Americans each year and accounts for over 12,000 deaths in the United States each year. Kidney cancer usually appears in adults aged between 50 and 70 years, although it is described in children under 3 years. Kidney cancer causes approximately 3% of the tumors in adults, and the attitudes of men and women is 1.5:1. There is a strong correlation between cigarette Smoking and the development of renal cell cancer. Unproven factors that may increase the risk of kidney cancer include polycystic kidney disease, diabetes and chronic dialysis. Up to 85% of kidney cancers are clear type; from 5% to 15% of kidney cancers are papillary histological type. The main type of kidney cancer is surgery, although it can also be recommended radiation therapy. For some people, it can be used hormonal the ing treatment or biological treatment or after surgery or in the case when the cancer cannot be removed surgically. Sometimes kidney cancer spontaneously corrected without any treatment, but this rarely happens. Still not shown that chemotherapy is useful in the treatment of kidney cancer.
3.4. Testicular cancer
Testicular cancer mainly affects young men in the age group 20 to 44 years of age, where it is the most common cancer. In General, testicular cancer is not very common. Testicular cancer is very well treatable, and more than 9 out of 10 patients can be cured. Primary tumors of germ cells (GCTs) of the testis, resulting from the malignant transformation of primordial primary germ cells, 95 percent of testicular tumors. This disease is remarkable young age of the patients affected by the disease, totipotent capacity for differentiation of tumor cells and its slickest; more than 90 percent of all newly diagnosed patients will be cured, and after the arrival of chemotherapy based on cisplatin cured approximately 70 to 80 percent of patients with metastatic disease.
Commonly used types of treatment are surgery, radiation therapy and chemotherapy, depending on the stage of the cancer and its spread. Chemotherapy is most often used for not semyonych those who ticularly cancers, however, it is also used for common seminoma. Testicular cancer can be treated with various combinations of drugs, most often in combinations using VER, Bleomycin, Etoposide and Cisplatin.
3.5. Prostate cancer
Prostate cancer is the most common malignant disease in men in the United States and is the third most common cause of death from cancer in men over the age of 55 (after lung carcinoma and colon). The most common prostate cancer treatment at the initial stage is surgery followed by radiotherapy. There are also different types of hormonal therapy. Prostate cancer cells do not have the tendency to grow rapidly as some other types of cancer. For this reason, it is not proved that traditional chemotherapy drugs are quite useful as well, as they are in other major cancers. However, as has been shown, some conventional chemotherapeutic drugs are appropriate, especially at a late stage prostate cancer. Although there are three chemotherapeutic drug, approved by the Administration for control of food and medicines of the USA for use in prostate cancer, Taxotere® (docetaxel), Novantrone® mitoxantrone hydrochloride) and Emcyt® (estramustine sodium phosphate) - apply a number of the most common chemotherapy drugs approved for other cancers, "unchecked (unapproved)" the basis for prostate cancer at a late stage. Chemotherapy is typically used in patients with advanced stage prostate cancer, which for a long time do not respond to hormonal therapy. None of these drugs is not consistently useful in disease. The most common places metastases in patients with prostate cancer are bone and lymph nodes. Bone metastases are particularly troublesome, as they can cause severe pain to the patient.
3.6. Secondary bone cancer
Secondary bone cancer starts in the bone, and is the result of the spread of cancer cells into the bone of the primary tumor. Sometimes only one part of the bone is affected, but other people develop a certain amount of bone derivatives, often in different bones in the body. Although any type of cancer can spread into the bone, the most common types of cancers are breast, prostate, lung and thyroid. Treatment for secondary bone cancer depends on the type of primary cancer. For example, cancer cells of the prostate gland can be separated from the prostate to move from the blood into the bone and begin to grow and velichevaetsa at this place. Such cancer cells in the bone will react to the same type of treatment as the cancer cells in the prostate gland. Although secondary bone cancer can occur in any bone in the body, in most cases, the affected bones are the bones of the spine, ribs, pelvic bones, cranial bones and the upper bones of the arms and legs.
3.7. Arsenic and its medical application
Arsenic was used as pharmaceutical agents for more than 2400 years to treat a number of diseases, including cancer, but it is also a poison and carcinogen. With the rapid development of medicine in the 20th century, the use of medicinal arsenic was quickly reduced. Interest in ARSENICAL compounds was revived when it was shown that daily intravenous administration of one of arsenic trioxide caused complete answers in the large majority of patients with newly diagnosed and relapsed acute promyelocytic leukemia. Additional trials are underway in patients with malignant hematological diseases and solid tumors, such as prostate cancer and pancreatic cancer. The disadvantage of arsenic trioxide is that its injected daily infusion within 1-4 hours for up to 6 weeks. Pilot (preliminary) examination with the use of oral fo the parallel language of arsenic trioxide in patients with acute promyelocytic leukemia is currently. Preliminary results show that the effectiveness and side effects comparable to intravenous arsenic trioxide. The same was observed in a pilot study of oral tetrasulfide of tetranychidae given to patients with acute promyelocytic leukemia. Thus, the oral preparation of arsenic with similar or better efficacy in leukemia and solid tumors and fewer side effects, especially in patients who require long-term treatment, will have cost advantages and quality of life. Arsenic exists in trivalent and pentavalent oxidized States as chemically unstable sulfide or oxide, or as a salt of sodium, potassium or calcium. Trivalent derivatives of arsenic containing sodium arsenite and arsenic trioxide inhibit many enzymes reacting with biological ligands, which are available sulfur group. Pentavalent arsenic is an agent, uncoupling of mitochondrial oxidative phosphorylation. Thus, it is not surprising that the trioxide of arsenic exerts antitumor effects through activation of apoptosis, induction of reactive oxygen species, inhibition of angiogenesis, and cell acute promyelocytic leukemia degradation of chimeric protein PML-RARα. Response dependence is on the cell type and species of arsenic.
In 1991 the national cancer Institute reported that arsenic trioxide inhibits growth and promotes apoptosis in various cancer cell lines, and began a research program to assess its clinical activity in hematological malignant diseases, such as acute promyelocytic leukemia, acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, non-Hodgkin's lymphoma, Hodgkin's disease, chronic lymphocytic leukemia, myelodysplastic syndrome and multiple myeloma. It also supports research on solid tumors, such as running hormone-resistant prostate cancer and renal cell cancer, and cervical cancer and refractory transitional cell carcinoma of the bladder.
Other clinical studies are in the process of implementation, including Phase II Studies in solid tumors. Based on promising preclinical data in full swing, or are in the final stages of planning clinical trials supported by NCI to study the potential of arsenic trioxide for the treatment of solid tumors.
4. Disclosure of inventions
The present invention relates to pharmaceutical compositions intended for the treatment of urogenital diseases and bone IU is astazou, and to method for the treatment of such diseases.
Accordingly, the present invention provides a pharmaceutical composition intended for the treatment of urogenital diseases and bone metastases in humans, where this pharmaceutical composition contains an effective amount of salt arsenic acid and alkali or alkaline earth metal and/or pharmaceutically acceptable adjuvant (excipient).
According to the present invention mentioned salt of an alkali metal with arsenious acid is a meta-sodium arsenite (AsO2Na) or meta-potassium arsenite (AsO2K).
An effective amount of salt arsenic acid and alkali or alkaline earth metal is 0,0001-1500 mg/kg, preferably 1-1000 mg/kg, more preferably 1-150 mg/kg and most preferably 50-100 mg/kg body weight/day.
Specified pharmaceutical composition preferably occurs in the form for oral administration, where the specified form for oral administration is a tablet, capsule, powder and/or a solution with a pharmaceutically acceptable carrier, solvent or excipient.
Specified urogenital disease includes mainly cancer of the prostate, bladder, kidney and testis.
According to the invention chemotherapeutic product contains sodium with the ü arsenic acid, having the formula (I):
In addition, the invention includes pharmaceutical compositions containing such products, together with a pharmaceutically acceptable carrier or solvent. Suitable carriers and solvents are well known, as are the basic technology of preparation of compositions in the form of a unit dosage for oral administration.
In an additional aspect, the invention includes a method for treating cancer in an animal or human body, the method containing simultaneous, separate or sequential introduction to the specified body sodium salt of arsenic acid.
The inventor investigated the effectiveness of three arsenic compounds of different valency and methylation on the set of cell lines of human tumors in vitro, sodium salt arsenic acid (As3+), dimethylsilicone acid (As5+) and arsenic acid (As5+). Suddenly sodium salt of arsenic acid was the most effective and showed antitumor activity in models of human tumor in vivo, which is the basis for the development of the sodium salt of arsenic acid hereinafter referred to as the new arsenic compounds. Sodium salt of arsenic acid was suddenly more effective in vitro and showed differential activity is ü on leukemia, melanoma and on the lines of breast cancer, and not AS2O3. Sodium salt of arsenic acid is unexpectedly allow the shortening of the telomeres of human cancer cells, causing cellular senescence and chromosomal abnormalities, but not directly inhibits telomerase activity. The results show that the sodium salt of arsenic acid is an inhibitor of the telomeres. Sodium salt of arsenic acid is rapidly absorbed after/and after oral administration and remained in plasma for extended periods. Unexpectedly, the bioavailability of oral sodium salt arsenic acid was approximately 100%. The toxicity study on animals has shown that the main target organs were the bone marrow and lymphoid organs. Thus, the sodium salt of arsenic acid can be administered orally. It can be used in long-term treatment of cancer patients with solid tumors or leukemia at doses below the maximum tolerated dose (MTD), alone or in combination with other therapeutic methods, maintaining a good quality of life.
This compound (NaAsO2) of the present invention is developed as a new anticancer agent. The compound has good cytotoxic activity on a set of 43 cell lines of human tumors in vitro with a value of IC5 0.6 microns. Pronounced selectivity was observed in tumor cell lines derived from leukemia, breast cancer and melanoma. In a direct comparison of the sodium salt of arsenic acid was suddenly at least 15 times more effective than the clinically used substance arsenic trioxide, and also had the best differential activity. Sodium salt of arsenic acid, combined with 5-fluorouracil (5-FU) or vinblastine may result in additive effects. Potassium arsenite reduces cytotoxic activity.
In vivo sodium salt arsenic acid (orally and administered intraperitoneally) was unexpectedly edge (extremely) active on 2/7 subcutaneously transplanted heterotransplantation human tumor (renal cell carcinoma RXF 944LX and breast cancer MAXF 401). Overall, the high efficiency sodium salt arsenic acid was obtained with doses of 1/3-2/3 of the maximum tolerated dose (MTD). The efficiency was better when using injections daily for 5 or more days compared with intermittent modes (every 4 days ×3, weekly ×3).
Surprisingly, the sodium salt of arsenic acid orally showed a high therapeutic efficacy in cancer patients suffering from urogenital cancer, the benefits of the natural enemy prostate cancer and bone metastases, after treatment with 2.5; 10; 12,5; 15; 17.5 and 20 mg of sodium salt of arsenic acid in the form of capsules for 14 consecutive days.
Suddenly all patients extremely well tolerated sodium salt of arsenic acid without adverse events (AE's) or significant adverse events (SAE's). Developed treatment did not cause any disturbances in the sense of health (well-being) in any of the patients. Was not observed changes during the course of the study in any activity ECG patients, loss or neurological examinations.
Suddenly sodium salt arsenic acid, the compound of the invention has great therapeutic benefits and safety benefits compared with arsenic trioxide. Of arsenic trioxide As2O3been shown to prolong QT and QT interval, adjusted for rate (QTc), which may predispose the patient to a potentially fatal atypical ventricular tachycardia and cause complete AV block.
In addition, adverse events occurring in 10% or more of patients treated with arsenic trioxide, include fatigue, fever, swelling, chest pain, chills, reactions at the injection site (i.e. pain, erythema, swelling), fatigue, weight gain, nausea, loss of appetite, a decrease is significant appetite, diarrhea or frequent loose stools, vomiting, abdominal pain, dyspepsia, sore throat, constipation, hypokalemia, hypomagnesemia, increased serum AST (SGOT) and/or ALT (SGPT), hyperkalemia, hypocalcaemia, headache, insomnia, paresthesia, dizziness, tremor, cough, shortness of breath, nasal bleeding, hypoxia, pleural effusion nasal drip (nasal discharge, wheezing, decreased breathing noises, traiterous wheezing, moist rales, dermatitis, itching, bruising, dry skin, erythema, sweating, tachycardia, ECG abnormalities, sinusitis, herpes simplex, upper respiratory tract infection, arthralgia, myalgia, bone pain, back pain, neck pain, pain in extremities, leukocytosis, anemia, thrombocytopenia, neutropenia (can be hectic), hypotension, hypertension, lacrimation, pallor, anxiety, depression, eye irritation, blurred vision and vaginal bleeding.
Suddenly it was not observed any of these adverse events with oral sodium salt arsenic acid, which is a compound of the present invention.
5. Detailed description of the invention
Here we describe methods and compositions for the treatment of primary and metastatic urological neoplasms and/or bone metastasis.
The invention is based in part on the regimen clearling the introduction of the composition, containing the sodium salt of arsenic acid. It is also partly based on therapeutic efficacy of sodium salt of arsenic acid of the invention against certain cancers.
The invention includes a method of treatment of primary solid tumors in a mammal, which relates to the introduction of non-lethal and a therapeutically effective amount of sodium salt arsenic acid by itself or in combination with one or more therapies to a mammal in need of such therapy.
The invention also includes a method of treating blood disorders in mammals, which concerns the introduction of the sodium salt of arsenic acid by itself or in combination with one or more therapeutic drugs affected the mammal.
Connection arsenic invention, sodium salt arsenic acid, can be used in a number of known forms, for example, as salt as organic/inorganic complex as an organic chelate, or in the form of an encapsulated system targeting drugs.
It should be recognized that the invention includes prodrugs of the sodium salt of arsenic acid or compounds which are converted in vivo to the biologically active form of sodium salt of arsenic acid. Such proletar the VA can be applied to to reduce the toxicity or to avoid the toxicity of the usual pharmaceutical substances or to optimize treatment efficiency. Sodium salt of arsenic acid can be synthesized or purchased in large quantities.
In this embodiment, the sodium salt of arsenic acid prepared in capsules. Generally, a qualified technician will recognize that the form of the sodium salt arsenic acid, which should be applied, should be therapeutically effective without excessive toxicity.
Any suitable route of administration of sodium salt of arsenic acid can be used in accordance with the present invention, including, but without limitation, oral introduction, parenteral administration such as intravenous, subcutaneous, intramuscular and intrathecal, intranasal, rectal or vaginal administration. The introduction can also be made directly into the tumor or via transdermal patch or implanted device (especially for slow release). You can also use the local introduction.
Pharmaceutical compositions for application can be in the form of a sterile physiologically acceptable (aqueous or organic) solutions, colloidal suspensions, creams, ointments, pastes, capsules, tablets in capsules, tablets and reg is current. Moreover, it should be borne in mind that also included forms with the delayed slow introduction or long-releasing form.
The arsenic compounds of the present invention can also be applied against a variety of primary and metastatic neoplastic diseases, including, but without limitation, primary and metastatic tumors of the Central nervous system, breast, colon, ovary, kidney, lung, liver, bladder, prostate and head and neck.
5.1. Pharmaceutical formulations
Therefore, the present invention relates to anticancer pharmaceutical compositions containing a therapeutically effective amount of sodium salt arsenic acid, represented by the following formula (I)
and its pharmaceutically acceptable salts, used for the manufacture of substances for the treatment of cellular proliferative disorders, and one or more pharmaceutically acceptable adjuvant, excipient, carrier, buffer, solvent and/or the usual pharmaceutical adjuvant. In a preferred embodiment of the invention, the compound of the invention can be introduced in a pharmaceutically acceptable formulation. The present invention refers to any pharmaceutically acceptable formulations, so the m as synthetic or natural polymers in the form of macromolecular complexes, nanocapsules, microspheres or beads, formulations based on lipids, including emulsion oil in water, micelles, mixed micelles, synthetic membrane vesicles and separate the red blood cells. In addition to the compound and pharmaceutically acceptable polymer pharmaceutically acceptable formulation used in the method of the invention may contain additional farmaceuticas acceptable carriers and/or excipients. When used in this description, the pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and substances that delay absorption, and the like, which is physiologically compatible. For example, the carrier can be suitable for intravenous injection. Excipients include pharmaceutically acceptable stabilizers and dezintegriruetsja substances. In another embodiment, pharmaceutically acceptable formulations include formulations based on lipids. Any of the known delivery systems matter on the basis of the lipids can be used in carrying out the invention. For example, multivesicular liposomes (MVL), multilamellar liposomes (also known as multilamellar vesicles, or MLV), adnyamathanha liposomes, including small od is lamellare liposomes (also known as adnyamathanha vesicles, or SUV) and large adnyamathanha liposomes (also known as large adnyamathanha vesicles, or LUV), all can be used, because it can be made continuous progress in the release of encapsulated compounds. In one embodiment, the formulation based on the lipid can be multivesicular liposomal system. The composition of the synthetic membrane vesicles is usually a combination of phospholipids, usually in combination with steroids, especially cholcompoundol. You can also use other phospholipids or other lipids. Examples of lipids useful in the preparation of (getting) a synthetic membrane vesicles include phosphatidylglycerol, phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, sphingolipids, cerebrosides, and gangliosides. Preferably use phospholipids, including egg phosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, dioleoylphosphatidylcholine, dipalmitoylphosphatidylcholine and dioleoylphosphatidylserine. In another embodiment, a composition comprising a connection can be made or filled in a bioabsorbable matrix. In addition, the matrix may consist of specified biopolymer. Suitable biopolymer to the present invention may also include one or more macrame cul, selected from the group consisting of collagen, elastin, fibronectin, vitronectin, laminin, polyglycolic acid, hyaluronic acid, chondroitin sulphate, dermatosurgery, heparansulfate, heparin, fibrin, cellulose, gelatin, polylysine, echinometra, antichina, thrombospondin, wooroolin, biglycan, decorin and dextran. The wording of these macromolecules in the biopolymer is well known in the art.
In a preferred embodiment, therapeutic composition is not immunogenic when administered to a patient-to man for therapeutic purposes.
A therapeutic composition of the present invention can include pharmaceutically acceptable salts of the components. Pharmaceutically acceptable salts include the acid adducts of salts which are formed with inorganic acids such as, for example, hydrochloric and phosphoric acids, or such organic acids as acetic, tartaric, almond, and the like. Physiologically satisfactory carriers well known in the art. Examples of liquid carriers are sterile aqueous solutions that do not contain substances in addition to the active ingredients and water, or contain a buffer such as sodium phosphate at physiological pH value, physiological age is the PR or both, such as a phosphate buffer solution. In addition, aqueous carriers can contain more than one buffer salt, as well as salts such as the chlorides of sodium and potassium, dextrose, propylene glycol, polyethylene glycol and other dissolved substances. Liquid compositions may also contain a liquid phase in addition to the water and save water. Examples of such incremental liquid phases are glycerin, vegetable oils, such as cottonseed oil, organic compounds such as etiloleat, and emulsions of water and oil. therapeutic composition comprises a polypeptide of the present invention, generally in amounts of at least 0.1 to weight percent of the polypeptide on the total weight of therapeutic composition. The weight percent is a ratio of weight of the polypeptide to the whole composition. Thus, for example, of 0.1 weight percent represents 0.1 gram of polypeptide per 100 grams of the composition.
The term "pharmaceutically acceptable salt" refers to those salts of the compounds which retain the biological effectiveness and properties of the free bases and which are obtained by reaction with inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonate, econsultation, toluensulfonate, salicylic acid and t the th similar. The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, pills, pellets, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more substances selected from the group consisting of sweetening agents, substances imparting taste, dyes and preservatives in order to provide pharmaceutically excellent and pleasant drugs. Tablets contain the active ingredient in a mixture with non-toxic pharmaceutically acceptable excipients, which is suitable for manufacture of tablets. These excipients may be, for example, inert solvents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and dezinfeciruyuhimi substances, such as corn starch or alginic acid; binding agents, for example starch, gelatin or gum Arabic, and lubricating agents such as magnesium stearate, stearic acid or talc. Tablet and may not be covered, or they can be coated by known techniques to delay the destruction and absorption in the gastrointestinal tract and thereby provide a prolonged action over a longer period. For example, you can use a substance for the time delay, such as glycerylmonostearate or glycerylmonostearate. Tablets also can be coated using the methods described in U.S. Patent No. 4,256,108; 4,166,452 and 4,265,874, to create an osmotic therapeutic tablets for controlled release. The pharmaceutical composition may also, or alternatively, can contain one or more substances, which may be associated with modulating substance or can be free inside the composition. Virtually any substance can be introduced in combination with a modulating substance, as described here, for a variety of purposes, as described below. Examples of the types of substances that can be entered with a modulating substance include analgesics, anesthetics, anti-media, antibiotics, anticancer drugs (e.g., Taxol or mitomycin C), anti-inflammatories (such as ibuprofen and indomethacin), antihelminthic, antidepressants, antidotes, antiemetics, antihistamines, antihypertensive drugs, antimalarials, antimicrotubule drugs is s (for example, colchicine or Vinca alkaloids), drugs for migraine headaches, antibacterial, antipsychotics, antipyretics (antipyretics), antiseptics, agents-anticipatory (for example, inhibitors of protein kinase C or inhibitors of intracellular mobilization of calcium), antiaritmicheskie, antithrombine tools, anti-tuberculosis drugs, antitussives, antivirals, drugs to suppress appetite, cardiotonic agents, drugs, chemical dependency, laxatives, chemotherapeutic agents, coronary, brain, or peripheral vasodilator, contraception, depressants, diuretics, expectorants, growth factors, hormonal substances, sleep AIDS, IMMUNOSUPRESSIVE substances, narcotic antagonist analgesics, parasympathomimetics, sedatives, stimulants, sympathomimetics, toxins (e.g. cholera toxin), tranquilizers and renal antibacterial agent.
Formulations for oral use may also be presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active substance in a mixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspendresume substances, such as sodium carboxymethyl cellulose, methylcellulose, hypromellose, polyvinyl-pyrolidone of sodium alginate, tragacanth gum and Arabic gum; dispersing or wetting agents may be natural phosphated, for example lecithin, or condensation products of alkylene oxide with fatty acids, for example polyoxyethylene, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecafluorooctane, or condensation products of ethylene oxide with partial compounds derived from fatty acids and exit, such as polyoxyethylene bulk compounds derived from fatty acids, and exit anhydrides, such as polyoxyethylenesorbitan. Aqueous suspensions can contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more substances, which impart taste, and one or more sweetening agent such as sucrose or saccharin.
Oil suspensions can be prepared by suspendirovanie AK the active ingredient in a vegetable oil, for example, peanut oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. To make appatichnosti oral drug can be added sweeteners, such as the above, and substance, giving a taste. Song data can be saved by the addition of an antioxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in a mixture with dispersing or wetting agent, suspenders substance and one or more protecting means. Suitable dispersing or wetting agents and suspendresume substances are shown, for example, sweeteners, gives taste, and tinted materials can also be submitted.
The pharmaceutical compositions of the invention may also be in the form of emulsions of oil-in-water". The oil phase may be a vegetable oil, such as olive oil or peanut oil, or mineral oil, for example liquid paraffin or mixtures of this. Suitable emulsifying agents may be natural gums, such as Arabian gum or traakan the new gum, natural phosphatides, for example cultural soy, lecithin, and connections or incomplete compounds derived from fatty acids and exit anhydrides, such as orbitonasal and condensation products of these partial connections with ethylene oxide, such as polyoxyethylenesorbitan. The emulsions may also contain sweetening matter, gives taste.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations can also contain a demulcent, preservative and coloring substances. The pharmaceutical compositions can be in the form of a sterile injection water or oil suspensions. This suspension may be formulated according to the known art using those suitable dispersing agents or wetting agents and suspendida substances that were mentioned above. Sterile injected the drug can also be injected in a sterile solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, dehydrated in 1,3-butanediol. To an acceptable carriers or solvents that can be used include water, ringer's solution and isotonic sodium chloride solution. In addition, sterile, the IRNA oils are conventionally used as solvent or suspendida environment. For this purpose you can use any soft fatty oils, including synthetic mono - or diglycerides. In addition, in the preparation of injectable funds are used fatty acids such as oleic acid.
The dosage levels of about from about 0.05 mg to about 140 mg per kilogram of body weight per day is suitable in the treatment of the above conditions (from about 2.5 mg to about 7 g per patient per day). For example, inflammation can be treated effectively by the introduction of from about 0.01 to 50 mg of compound per kilogram of body weight per day (from about 0.5 mg to about 3.5 g per patient per day). The amount of active ingredient which can be combined with substances-carriers in order to ensure the form of a single dosage will vary depending on who is treated and the particular route of administration. For example, a formulation intended for oral administration to humans may vary from about 5 to about 95% of the total composition. Form of a single dosage will contain in most cases, from about 1 mg to about 500 mg of the active ingredient. It is clear, however, that a single dose level for any particular patient will depend upon a number of factors, including the specific activity of the applied compound, the age, body weight, General health, sex, time of administration, route of administration, rate of excretion, combine the Oia drugs and the severity of the particular diseases, undergoing treatment. Dosage effective amount of the compounds according to the invention will vary depending on factors including the specific compound, toxic, inhibitory activity, the condition treated, and apply whether or not the connection with one or other therapies. Usually, the dosage of the effective amount will range from about 0,0001 mg/kg to 1500 mg/kg, more preferably from 1 to 1000 mg/kg, more preferably from about 1 to 150 mg/kg body weight and most preferably from about 50 to 100 mg/kg body weight. The invention relates also to the procedure or the method of treating the above-mentioned pathological conditions. Compounds of the present invention can be introduced prophylactically or therapeutically, preferably in an amount that is effective against the mentioned violations, the warm-blooded animal, such as man, in need of such treatment, the compounds are preferably used in the form of pharmaceutical compositions.
The formulation of pharmaceutically acceptable excipients and solutions-vectors are well known to specialists in this area, as are the development of suitable dosing and treatment regimens for using particular compositions described herein in a number of therapeutic regimes, including, in the example, oral, parenteral, intravenous, intranasal, and intramuscular administration and formulation.
5.1.1. Oral delivery
In a specific application of the pharmaceutical compositions disclosed herein may be delivered via oral administration to an animal. Essentially, these compositions can be formulated with an inert diluent or with an assimilable edible carrier, or they may be enclosed in a gelatin capsule with a hard or soft shell, or they may be compressed into tablets, or they can be directly incorporated into food.
The active compounds can even connect with eccipienti and apply in the form of a swallow tablets, buccal tablets, pastilles, capsules, elixirs, suspensions, syrups, wafers and the like. Tablets, pellets, pills, capsules and the like may also contain the following: a binder, as tragacanth gum, gum Arabic, corn starch or gelatin; excipients such as calcium diphosphate; dezintegriruetsja substance, such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and can be added sweetener, such as sucrose, lactose or saccharin, or a substance which imparts flavor, such as peppermint oil, oil of gaultheria or cherry with the Rav. When the form of a unit dosage is a capsule, it may contain in addition to the substances of the above type, a liquid carrier. Various other materials may be present as coating substances or to otherwise modify the physical form of a unit dosage. For example, tablets, pills or capsules can be coated with shellac, sugar or both. A syrup of elixir may contain the active compound, sucrose as a sweetening substance, methyl and propylparaben as preservatives funds, the dye and the substance giving the flavor, such as cherry or orange flavor. Of course, any substance used in the preparation of any form of a single dosage should be pharmaceutically pure and substantially non-toxic in the applied amounts. In addition, the active compounds may be included in preparations and formulations with delayed release.
Typically, such formulations may contain at least about 0.1% of active compound or more, although the percentage of active ingredient(s) may, of course, be varied and can easily be between approximately 1 or 2% and about 60% or 70% or more of the weight or volume of the entire formulation. Naturally, the number of active compound(s) in each therapeutically useful compositions, to the which can be prepared, is such that a suitable dosage will be obtained in any given unit dose of the compound. Factors such as solubility, bioavailability, biological half-life, route of administration, the shelf life of the product, as well as other pharmacological considerations will be reviewed by a specialist in the field of preparing such pharmaceutical formulations and as such a variety of dosages and treatment regimes that may be desirable.
For oral administration the compositions of the present invention can be an alternative combined with one or more excipients in the form of a solution for rinsing the oral cavity, tooth paste, buccal tablets, oral spray or sublingual orally applied formulations. For example, the solution to rinse the oral cavity can be prepared by incorporation of the active ingredient in the required amount in an appropriate solvent, such as decahydrate of sodium tetraborate (Solution of Dobele). Alternatively, the active ingredient can be incorporated into oral solution, such as solution containing decahydrate of sodium tetraborate, glycerin and potassium bicarbonate, or scattered in a tooth-powder, or added in a therapeutically effective amount of the composition which may include water, binders, abrasives, substances imparting taste, foam is forming substances and hygroscopic substances. Alternative compositions may be given the shape of tablets or solution, which can be placed under the tongue or in other words, dissolved in the mouth.
5.1.2. Delivery by injection
In certain cases it will be desirable to deliver the pharmaceutical compositions disclosed here, parenterally, intravenously, intramuscularly, or even administered intraperitoneally. Solutions of the active compounds as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surface-active substance, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures of the oils. Under normal conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for use in injection include sterile aqueous solutions or dispersions and sterile powders for unplanned preparation of sterile solutions or dispersions for injection. In all cases the form must be sterile and must be fluid in the sense that it should be easily injected. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of micro is organizmov, such as bacteria and fungi. The carrier can be a solvent or dispersion medium, including, for example, water, ethanol, high molecular weight alcohol (e.g. glycerol, propylene glycol and liquid polyethylene glycol and the like), suitable mixtures of this and/or vegetable oils. The proper fluidity can be saved, for example, by use of a coating such as lecithin, by maintaining the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can contribute to various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases it is preferable to include isotonic agents, for example sugars or sodium chloride. Prolonged absorption of injectable compositions made using the compositions of substances which delay absorption such as aluminum monostearate and gelatin.
For parenteral administration in an aqueous solution, for example, the solution should be suitably prepared in the buffer, if necessary, and the liquid solvent are first cited in isotonic condition with the corresponding saline or glucose solution. These particular aqueous solutions are especially suitable for ADAP is revenage, intramuscular, subcutaneous and intraperitoneal introduction. In this connection, sterile aqueous medium, which can be used will be known to experts in the art in light of the present disclosure. For example, one dosage may be dissolved in 1 ml of isotonic NaCl solution and either added to 1000 ml of fluid for injection into the subcutaneous tissue or injected at the proposed site of infusion. Some variation in dosage will necessarily occur depending on the condition of the subject undergoing treatment. The man in charge of the introduction, will, in any case, to determine the appropriate dose for the individual subject. Moreover, for the introduction of human drugs must meet the standards of sterility, progenote and basic standards of safety and purity, as required by state or regional services biological norms.
Sterile injectable solutions are prepared by introduction of active compounds in the required amount in the appropriate solvent with several of the other ingredients listed above, on request, followed by sterilization by filtration. The dispersions are usually prepared by introducing various sterilized active ingredients into a sterile vehicle, which contains the basic dispersion media and the required other ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation methods are vacuum drying and freeze-drying, which give a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solutions.
The compositions disclosed herein, can be designed in a neutral form or as a salt. Pharmaceutically acceptable salts include the acid adducts salts (formed with free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, almond, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases, such as, for example, hydroxides of sodium, potassium, ammonium, calcium or iron, and such organic bases as Isopropylamine, trimethylamine, histidine, procaine and the like. After preparation, the solutions can be introduced in a way compatible with the dosage form, and in such a quantity that is therapeutically effective. The formulations are easily introduced in a number of Lakers the governmental forms, such as solutions for injection, releasing medication capsules and the like.
When used in this description of the "carrier" includes any and all solvents, dispersion media, media coverage, diluent, antibacterial and antifungal agents, isotonic and delaying the absorption of substances, buffers, solutions-vectors, suspensions, colloids, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except that any conventional medium or agent is incompatible with the active ingredient, its use in pharmaceutical compositions being considered. Also in the composition may be introduced incremental active ingredient.
The phrase "pharmaceutically acceptable" refers to molecular structures and compositions that do not cause allergic or similar adverse reaction when administered to man. The preparation of an aqueous composition that contains the protein as an active ingredient, it is well known in this field. Typically, such compositions are prepared as an injection or as liquid solutions or suspensions; also can be prepared solid forms suitable for dissolution in the liquid or the preparation of suspensions in liquid prior to injection. The product t is the train can be emulsified.
5.1.3. Nasal delivery
In some embodiments, the implementation of the pharmaceutical compositions can deliver intranasal sprays, inhalation, and/or other intermediaries aerosol delivery. Moreover, delivery of substances through the use of intranasal microparticle resins and lysophosphatidylserine compounds are also well known in the pharmaceutical business.
5.2. Cancers of the target
Subjects undergoing treatment, will usually include mammals and most preferably will be human subjects, such as human subjects with cancer. Compounds of the invention can be used alone or in combination. Furthermore, this connection can be used with other types of treatment. For example, the subject compounds can be used with other chemotherapy drugs, such as tamoxifen, Taxol, methotrexate, biologic drugs, such as antibodies, growth factors or lymphokines, irradiation, etc. Combined therapy may result in synergistic results. The preferred reading is the cancer, especially cancers, pre-installed.
The compositions and methods provided herein, are particularly suitable for the treatment of primary and metastatic neoplastic tumors, including solid op is Holi, such as tumors of the breast, Central nervous system, colon, ovary, kidney, lung, liver, bladder, prostate, head and neck, etc. In particular, tumors that can be treated by the compositions and methods of the invention include tumors of epithelial nature, such as, but without limitation:
Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated both, adenocarcinoma), alveolar (alveolar cell) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous the hamartoma, mesothelioma; gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, gastric carcinoma, colorectal carcinoma; Urinary tract: kidney (adenocarcinoma, Wilms tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma, sarcoma), testis (seminoma); Liver: hepatoma (hepatocellular carcinoma); Bone: osteogenic sarcoma (osteosarcoma); Nervous system: neuroblastoma, retinoblastoma, glioblastoma, oligodendroglioma; Gynecological cervical (cervical carcinoma, the precancerous cervical dysplasia); Hematologic: blood (myeloid the th leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's disease, nahodkinskuju lymphoma [malignant lymphoma]; Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, sarcoma Galoshes; Glands and ducts: adenocarcinoma, papillary carcinoma and papillary adenocarcinoma. Thus, the term "cancer cell", as given here, includes cage, hurt any one of videopreteen States.
The term "leukemia" broadly refers to a progressive, malignant disease of the blood forming organs and, as a rule, characterized by distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is usually clinically classified based on (1) the duration and nature of the disease is acute or chronic; (2) the type of affected cells; myeloid (myelogenous), lymphoid (lymphogenous), or macrophage, and (3) increase or lack of increase in the number of abnormal cells in the blood - leukemia or leukemia (subleukemic). The model of leukemia R widely accepted as being predictive antileykemichesky activity in vivo. I think that the connection that was positive test result on R, as a rule, will be demonstrating some level antileykemichesky activity in vivo illegal is isimo on the type of leukemia, which is treated. Accordingly, the present invention includes a method of treating leukemia and preferably a method of treating acute nelimfocitarnaya leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, T-cell leukemia adults, lakemicski leukemia, leucocythemia leukemia, basophilic leukemia, dedifferentiated leukemia, leukemia in cattle, chronic miliitary leukemia, leukemia skin, embryonal leukemia, eosinophilic leukemia, leukemia gross, leukemia hairy cell hemoblastosis leukemia, hemocytoblasts leukemia, histiocytomas leukemia, leukemia stem cells, acute monocytic leukemia, leykopenicheskih leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, malignant lymphoma, tuckaleechee leukemia, megakaryocyte leukemia, microbiologists leukemia, monocytic leukemia, myeloblastic leukemia, miliitary leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, leukemia Negele, ploskokletochnogo leukemia, plasmacytomas leukemia, promyelocytic leukemia, leukemia cells Reader, leukemia Shilling, dedifferentiated Le is the goat, subleikemical leukemia and leukemia undifferentiated cells.
The term "sarcoma" usually refers to a tumor that is composed of a substance similar to embryonic connective tissue, and usually consists of tightly Packed cells, inserted into fibrous or homogeneous substance. Sarcomas that can be treated by the compounds of the invention and optionally potentiating agent and/or chemotherapeutic drug, include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanoma, myxosarcoma, osteosarcoma, sarcoma of Abemethy, adipose sarcoma, liposarcoma, alveolar soft tissue sarcoma, ameloblastoma, botryoid sarcoma, garamasala, horiokartsinoma, embryonal sarcoma, Wilms tumor, endometrial sarcoma, stromal sarcoma, Ewing sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, sarcoma, Hodgkin's lymphoma, idiopathic multiple hemorrhagic sarcoma, immunoblastic sarcoma In cell lymphoma, immunoblastic sarcoma of T-cells the Jensen sarcoma, sarcoma Galoshes, sarcoma Kupperbusch cells, malignant hemangioma, leucosarcia, malignant mesenchymal, proschalnuyu sarcoma, reticulocyte sarcoma, sarcoma of Rosa, serotesting sarcoma (serocystic), synovial sarcoma and osteogenic with Ramu.
The term "melanoma" is used to denote a tumor growing out of melanocyte system of the skin and other organs. Melanoma, which can be cured with the specified connection and select potentiating agent and/or chemotherapeutic drug, include, for example, lentigines limbs (melanoma from lentiginosa limbs), amelanotic melanoma, benign juvenile melanoma, melanoma of Klotman, S91 melanoma, melanoma Harding-Passy, juvenile melanoma, malignant melanoma, lentigo malignant melanoma, nodular melanoma, subungual melanoma and superficial disseminated melanoma.
The term "carcinoma" refers to a malignant new growth originating from epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases. Examples of carcinomas that can be treated with the specified connection and select potentiating agent and/or chemotherapeutic drug, include, for example, acinar carcinoma, acidsnow carcinoma, adenomatosnuu carcinoma, adenoid cystic carcinoma, adenoma carcinoma, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, carcinoma, basal cell, basal cell carcinoma, basaloid carcinoma, basal-squamous cell carcinoma, bronchial weraroa carcinoma, alveolar cell carcinoma, bronchogenic carcinoma, medullary carcinoma, cholangiocarcinoma carcinoma, horiokartsinoma, colloid cancer, ugrevidnye cancer, carcinoma of the trunk, resectively carcinoma, skin carcinoma, tubular carcinoma, carcinoma of the cylindrical cell carcinoma duct, solid carcinoma, embryonal carcinoma, encephaloid carcinoma, epidermoid carcinoma, adenoid epithelial carcinoma, exophytic carcinoma, cancer of ulcers, fibrous carcinoma, carcinoma gelatiniforni, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare (giant cell cancer), glandular carcinoma, granulation carcinoma, carcinoma of the matrix of the hair, Hematology carcinoma, hepatocellular carcinoma, carcinoma of cells Hurtle, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in place, intraepidermal carcinoma, intraepithelial carcinoma, carcinoma Krompecher, cancer cells Kulchytsky, both carcinoma, lenticular carcinoma, lenticular carcinoma, lipomatous carcinoma, lymphoepithelial carcinoma, cancer mozgoviy (brain, carcinoma medullare), medullary carcinoma, melanocytes carcinoma, soft carcinoma, slizeobrazujushchej carcinoma, muzinovy carcinoma, carcinoma mucocellulare, ecoepidemiology carcinoma, carcinoma mucosum, mucous carcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma references for additional information (ossificans), osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, carcinoma thorny epidermocytes, maseribane carcinoma, renal cell carcinoma kidney, reserve cell dysplasia carcinoma, arcompany cancer, carcinoma of the mucosa of the nasal cavity, sirrodney carcinoma, carcinoma of the scrotum carcinoma signet ring cells, simple carcinoma, small cell carcinoma, solenoidal carcinoma, servicecatalog carcinoma, ureterolithotomy carcinoma, trabecular cancer, squamous carcinoma, squamous cell carcinoma, fibrous carcinoma, teleangiectasias carcinoma, carcinoma of smooth muscle fibers and vascular tissue, transitional cell carcinoma, tuberose carcinoma, knobby carcinoma, verrucose carcinoma and villous carcinoma.
Additional cancers which can be treated with a compound according to the invention, include, for example, Hodgkin's disease, nahodkinskuju lymphoma, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, small cell lung cancer, primary brain tumors, cancer of the same is of RCU, colon cancer, malignant insulinoma of the pancreas, malignant carcinoid, unary bladder cancer, pre-malignant skin damage, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, cancer of the urinary tract, malignant hypercalcemia, cervical cancer, endometrial cancer, cancer of the cortex of the adrenal gland and prostate cancer.
In a specific embodiment, the present invention provides compositions and methods for amplification of tumor-specific immunity in individuals suffering from colorectal cancer metastatic to the liver, in order to inhibit the development of neoplastic disease. Preferred methods of treatment of these neoplastic diseases include the introduction of the composition of arsenic, which causes an immune response against tumor cells.
In another specific embodiment, the present invention provides compositions and methods for amplification of specific immunity in individuals suffering from hepatocellular carcinoma, in order to inhibit the development of neoplastic disease and to completely destroy all precancerous and neoplastic cells.
Finally, the present invention provides hsp compositions and methods for amplification of specific immunity to the precancer is new and neoplastic cells of the breast in women. The present invention also provides compositions and methods for inhibiting the proliferation of cancer cells and metastasis. These compounds can be used alone or in combination with each other or with modifiers biologic response.
6. Information confirming the possibility of carrying out the invention
The following subsections describe the study of the pharmaceutical compositions containing the sodium salt of arsenic acid, in vivo using cancer patients. The results show that the sodium salt of arsenic acid, administered orally, is effective in the treatment of genitourinary cancer.
6.1. Methods and materials
Cancer patients suffering from prostate cancer and/or urogenital cancer, were treated in a clinical study of ICH-GCP sodium salt of arsenic acid orally. Patients suffering from urogenital cancer, mainly prostate cancer and bone metastases, were not subject to any of the accepted methods of treatment and were subjected to treatment of the sodium salt of arsenic acid in the range of 7 different levels of dosing. It is believed that the sodium salt of arsenic acid acts as telomeric poison, as it allows the shortening of the telomeres of human cancer cells, which leads to chromosomal abnormalities, but not Inga the range telomerase activity.
Sodium salt of arsenic acid was given daily for 14 consecutive days according to the level of dose of the medical scheme, is presented below:
Treatment level 1: One capsule every 2.5 mg meta-arsenite of sodium daily (every 24 hours), before Breakfast
Treatment 2: Two capsules, each 2.5 mg of sodium salt of arsenic acid, daily, 1 before Breakfast, 1 before lunch
Treatment 3: Four capsules, each 2.5 mg of sodium salt of arsenic acid, daily, 1 before Breakfast, 2 before lunch, 1 before lunch
Treatment 4: Five capsules, each 2.5 mg of sodium salt of arsenic acid, daily, 2 before Breakfast, 2 before lunch, 1 before lunch
Treatment 5: Six capsules, each 2.5 mg of sodium salt of arsenic acid, daily, 2 before Breakfast, 2 before lunch and 2 before dinner
Visit patients were scheduled for monitoring compliance, toxicity and safety, and were conducted as follows:
Visit 1: conducted between day - 7 and day 0 (start of treatment)
Visit 2: on the first day of treatment meta-arsenite sodium
Visit 3: day 8 of treatment sodium salt of arsenic acid
Visit 4: 15 day (approximately 24 hours) after treatment for 14 consecutive days, a sodium salt of arsenic acid
Visit 5: 22 day (approximately days) after treatment for 14 consecutive days, a sodium salt of arsenic acid
Visit 6: 42 day (approximately 28 days) after treatment for 14 consecutive days, a sodium salt of arsenic acid
During this study were evaluated the following target parameters: the toxicity profile, efficiency, parameters of liver enzymes (GOT, GPT, a-GT, AR), kidney function, hematological function, determination of tumor markers (CEA and PSA) and pharmacokinetics of sodium salt of arsenic acid.
Following is a summary of the clinical outcome for each patient participating in this study. Communicated the received data includes the value of tumour markers CEA (carcinoembryonic antigen) and PSA (prostate specific antigen) and the results on efficacy, toxicity and safety.
Tables 1 and 2 present summary data on patient with bringing the values of PSA and CEA:
|Groups with doses of 1, 3 and 5 sodium salt of arsenic acid|
|Dose 1 (2.5 mg)||Dose 3 (10 mg)||Dose 5 (15 mg)|
|Patient||Age||Visit 1||Visit 6||Visit 1||Visit 6||Visit 1||Visit 6|
|CYP||75||PSA: 0,29||PSA: 0,16||PSA: 0,16||PSA: 0,18||PSA: 0,17||PSA: 0,18|
|CEA: 1,13||CEA: 1,06||CEA: 1,06||CEA: 0,99||CEA: 0,92||CEA: 1,08|
|BORN||73||PSA: 1,61||PSA: 0,37||PSA: 0,37||PSA: 0,12||PSA: 0,11||PSA: 0,07|
|CEA: 1,29||CEA: 1,56||CEA: 1,56||CEA: 1,02||CEA: 0,10||CEA: 1,22|
|Y.S.||73||PSA: 0,24||PSA: 0,11||PSA: 0,11||PSA: 0,08||PSA: 0,09||PSA: 0,09|
|CEA: 1,40||CEA: 1,28||CEA: 1,28||CEA: 1,17||CEA: 1,12||CEA: 1,13|
|GS||84||PSA: 0,19||PSA: 0,21||PSA: 0,21||PSA: 0,27||PSA: 0,28||PSA: 0,24|
|CEA: 2,59||CEA: 3,38||CEA: 3,38||CEA: 2,48||CEA: of 2.51||CEA: 2,65|
|GB||65||PSA: 0,45||PSA: <0,04||PSA: <0,04||PSA: <0,04||PSA: <0,04||PSA: <0,04|
|CEA: 3,45||CEA: 4,65||CEA: 4,65||CEA: 4,62||CEA: 4,68||CEA: 5,26|
|Groups with doses of 2 and 4 sodium salt of arsenic acid|
|Dose 2 (5 mg)||Dose 4 (12.5 mg)|
|Patient||Age||Visit 1||Visit 6||Visit 1||Visit 6|
|Mr. V.S.||59||PSA: 725||PSA: 6,15||PSA: 6,15||PSA: to 3.67|
|CEA: 1,79||CEA: 1,89||CEA: 1,89||CEA: 2,64|
Suddenly, all the patients are very well experienced sodium salt of arsenic acid. No observed adverse is abiti (AE's) or significant adverse events (SAE's). Study medication did not cause any disturbances in the health of any patient. During the course of the study none of the patients was not observed changes in the activity of ECG, audiometry or neurological indicators. None of the patients had not undergone radiation therapy to the treatment of the sodium salt of arsenic acid. Sodium salt of arsenic acid showed a high level of efficiency.
6.2.1. Example 1: Patient CYP
Histology: Untreated, unresectable, solid prostate cancer with infiltration into the rectal mucous wall, 11.02.2004
Stage: stage Dyuks, RT 4 figure Gleason 6
Because the patient suffers from coronary heart disease with myocardial infarction and endoprosthesis implantation of the coronary vessels, radical removal of the prostate with seminal vesicles (prostatovesiculectomy) could not be performed, and started removing the complete androgen antagonist of LHRH (one scheduled subcutaneous injection every 3 months) and antiandrogens orally (tablets androcur in doservice 1×1/day after lunch). Palliative transurethral resection of the prostate (TURP) to relieve urination was completed in may 2004.
The patient participated in the study dose levels 1, 3 and 5 sodium salt of arsenic acid. The results of the s in respect of this patient clinically significant change in PSA levels for all 3 dose levels of drugs. Level one dose (2.5 mg of sodium salt of arsenic acid) showed a significant reduction in PSA from 0.29 ng/ml to 0.16 ng/ml, This reduction corresponds to the reduction of tumor activity in 44,83%. Level three doses (10 mg of sodium salt of arsenic acid) showed an increase in PSA from 0.16 to 0.18 ng/ml Level five doses (12.5 mg of sodium salt of arsenic acid) shows again increased, this time from 0.17 to 0.18 ng/ml, None of the dose levels 3 or 5 did not show any significant changes in tumor activity.
Level one dose showed a decrease in tumor size from 20×35 mm to 20×34 mm Level three doses also showed a decrease from 20×35 20×34 mm, whereas the dose five showed no change in size from 20×34 mm
Secondary settings (security settings) showed no clinically important results at any dose level. Observed reversible increase in liver transaminases sGPT and sGOT during reception of sodium salt of arsenic acid in the dose group III and V (visits 3 and 4). By the time of the visit 5 transaminases returned to normal values. This increase is apparently due to the introduction of the analyte, sodium salt arsenic acid.
Evaluation/critique of clinical response/progression to level dose one was a partial answer. For both dose levels three and five - disease screening who and stability.
6.2.2. Example 2: the Patient is BORN
Histology: Untreated, unresectable, solid prostate cancer with extraglandular tumor growth
Stage: stage Dyuks, RT 4 figure Gleason 4
This patient suffered from carcinoma of the prostate, and renal cell carcinoma after radical nephrectomy) and superficial bladder cancer (without tumor recurrence). The patient was included in the study due to the continued rise in PSA levels after complete removal of androgen antagonist of LHRH (one scheduled subcutaneous injection every 3 months) and antiandrogens orally (tablets casodex in the dosage of 1×1/day after lunch).
The patient participated in the study dose levels 1, 3 and 5 sodium salt of arsenic acid. The results in this patient showed a clinically significant change in PSA levels for all 3 dose levels of sodium salt of arsenic acid. Level one dose showed a significant decrease in PSA from 1,61 ng/ml to 0.37 ng/ml, This reduction corresponds to the reduction of tumor activity to 77.1%. The dose levels three and five show a decrease in PSA from 0.37 to 0.12 ng/ml and from 0.11 to 0.07 ng/ml, respectively. Level three doses showed a reduction in tumor activity 67,56%, while the rate of five doses did not show considerable the th changes.
Level one dose showed a decrease in tumor size from 12.5×65 mm to 0.8×30 mm Level three doses also showed reduced tumor of the prostate from 60×25 50×25 mm, whereas the dose five showed no change in size.
Secondary settings (security settings) showed no clinically important results at any dose level. Identified elevated before the study triglycerides and cholesterol, which was not changed during the test. Glucose levels were always elevated, which can be explained by reasons associated with food because the blood samples were always taken in the morning after a hearty Breakfast.
Evaluation/critique of clinical response/progression for all three dose levels was partial response.
6.2.3. Example 3: Patient K.S.
Histology: Untreated, unresectable, solid, androgen-resistant prostate cancer with uncapsulated tumor growth.
Stage: Dukes C, RT 4 Gleason score 4
As well as cancer of the prostate, the patient also suffers from rectal cancer. This patient was included due to running and inoperable situation. Was completed with the destruction of androgen antagonist of LHRH (one scheduled subcutaneous injection every 3 months).
This patient participated in the study, dose levels of 1, 3 and 5 is freeway salt arsenic acid. The results for this patient show a clinically important change in PSA levels for all 3 levels of the medication. The dose levels one and three show a decrease in PSA from 0.24 to 0.11 ng/ml and 0.11 to 0.08 ng/ml, respectively. Level five doses showed no changes from 0.09 ng/ml Level one dose showed reduced tumor activity 54,12% and level three, moreover 67,56%. Level five doses showed no significant changes.
Level one dose showed a decrease in tumor size from 30×35 mm to 30×30 mm dose Levels three and five showed no change in size.
Secondary settings (security settings) showed no clinically important results at any level doses. It was found reversible, and a weak increase in sGPT.
Evaluation/critique of clinical response/progression for dose levels one and three had partial response. Level five doses showed resistance to the disease.
6.2.4. Example 4: a Patient JS
Histology: Untreated, unresectable, androgen-resistant solid prostate cancer with uncapsulated tumor growth.
Stage: stage Dyuks, RT 4 figure Gleason 8
The patient was included in the study due to the continued rise in PSA levels after subcapsular blindness removal of androgens.
The patient participated in the study, dose levels of 1, 3 and 5 sodium salt of arsenic acid. The results for this patient showed a clinically significant change in PSA levels for all 3 dose levels of the drug. Level one dose showed an increase in PSA from 0.19 ng/ml to 0.21 ng/ml, the dose Levels three and five show the increase in PSA from of 0.21 ng/ml to 0.27 ng/ml and PSA reduction from 0.27 to 0.24 ng/ml, respectively. Dose levels one and three showed an increase in tumour progression, while level five doses showed no significant changes.
Level one dose showed an increase in tumor size of 30×30 mm to 35×35 mm dose Levels three and five showed no change from 30×35 mm
Secondary settings (security settings) showed no clinically important results at any level doses. Existing before the study increased sGGT and platelet counts remained unchanged during the test.
Evaluation/critique of clinical response/progression for dose levels one and three was the progression of the disease. Level five doses showed a partial response to sodium salt of arsenic acid.
6.2.5. Example 5: a Patient must be
Histology: Local recurrence solid prostate cancer after radical prostatectomy (stage RTS Gleason 6) with infiltration of the bladder neck, inoperable.
Stage: stage Dyuks, RT 4 figure Gleason 6
This patient was included in the study in the later continuing rise in PSA levels after radical prostatectomy and complete removal of androgen antagonist of LHRH (one scheduled subcutaneous injection every 3 months) and antiandrogens orally (tablets casodex in the dosage of 1×1/day after lunch).
This patient participated in the study dose levels 1, 3 and 5 sodium salt of arsenic acid. The results for this patient show a clinically important change in PSA levels with level one dose of medication. Level one dose showed a significant reduction in PSA from 0.45 ng/ml to 0.04 ng/ml This decrease corresponds to the decrease tumor activity 91,11%. Dose levels three and five showed no change from 0.04 ng/ml.
Measurement of tumor lesions using any of the standard methods of measurement was not available.
Secondary settings (security settings) showed no clinically important results at any level doses. Observed reversible increase in transaminases sGOT, sGPT and sGGT.
Evaluation/critique of clinical response/progression for dose levels three and five was a partial answer. For both dose levels three and five disease showed a complete response to sodium salt of arsenic acid.
6.2.6. Example 6: the Patient MR. V.S.
Histology: Untreated, unresectable, solid prostate cancer with uncapsulated tumor growth in the neck of the bladder and the pelvic wall and the distribution of bone metastases.
Stage: stage Dyuks, RT 4 figure Gleason 9 M2
This patient was included in the study due to running the status detected prostate cancer with multiple bone metastases, put in the whole skeleton. Performed a complete uninstall of the androgen antagonist of LHRH (one scheduled subcutaneous injection every 3 months) and antiandrogens orally (tablets casodex in the dosage of 1×1/day after lunch).
This patient participated in the study, dose levels of 2 and 4 sodium salt of arsenic acid. The results for this patient show a clinically important change in PSA levels for both dose levels. Level two doses showed a decrease in PSA from 725 ng/ml to 6.15 ng/ml with decreasing tumor activity 99,15%, while the rate of four doses showed a decrease in PSA from 6,15 ng/ml to 3.67 ng/ml with a further reduction of tumor activity to 40,32%.
Level two doses showed a decrease in tumor size from 65×40 mm to 15×30 mm, whereas the dose four showed no change in the size of 15×40 mm
Secondary settings (security settings) showed no clinically important results at any level doses. The patient's quality of life was greatly improved sodium salt of arsenic acid. Existing before the study the rise of sGGT due to the consumption of alcohol has deteriorated over the continuation of the study. The hemoglobin concentration increased from 10.0 to 11.1 g/l, whereas PSA decreased from 725 to 3.67 ng/ml.
Evaluation/critique of clinical response/progression for both dose levels was part of the economic response to sodium salt of arsenic acid.
In General, the patients in dose levels 1, 3 and 5 showed mainly a decrease in PSA levels and tumor size. The majority of patients showed at least a partial answer to the sodium salt arsenic acid, with one patient showed stable disease status. The patient at dose levels 2 and 4, G-VS, showed a very clear response to treatment sodium salt of arsenic acid with remarkably decreasing PSA levels (99,15% reduction in tumor activity), and also a significant decrease in tumor size. Security settings (laboratory) showed no clinically important results. Sodium salt of arsenic acid was unexpectedly very well transferred without appearing AS ' s or SAE'S. In General, oral sodium salt arsenic acid, even at low doses for relatively short periods of treatment, unexpectedly showed the most positive response in the treatment of prostate cancer and/or urogenital cancer and bone metastasis.
1. A method for the treatment of metastatic neoplastic disease in a patient, comprising the administration to a patient a therapeutically effective amount of metaarsenite sodium.
2. The method according to claim 1, further comprising introducing a therapeutically effective amount of at least one homeotherapeutics the th substance.
3. The method according to claim 1, whereby metaarsenite sodium is administered orally.
4. The composition including metaarsenite sodium, for the treatment of metastatic neoplastic disease in a patient.
5. The composition according to claim 4, intended for oral administration.
6. The use of metaarsenite sodium for the preparation of pharmaceutical compositions for the treatment of metastatic neoplastic disease in a patient.
7. The use according to claim 6, wherein said metaarsenite sodium intended for oral administration.
8. Kit for inhibiting abnormal cell growth, comprising a therapeutically effective amount of a pharmaceutical composition containing metaarsenite sodium, and chemotherapeutic substance.
9. Kit for inhibiting abnormal cell growth, comprising a therapeutically effective amount of a pharmaceutical composition containing metaarsenite sodium.
SUBSTANCE: invention refers to medicine, namely to oncology, and can be used in metastasis prevention in puncture and surgical management of skin melanoma. The method involves superfacial and subfacial introduction of Klein's solution 20 ml around the tumour.
EFFECT: use of the invention reduces risk of the ingress of tumour cells in greater lymphatic vessels and venules in tumour puncture and surgical management due to spasm of lymphatic blood vessels ensured by Klein's solution.
SUBSTANCE: claimed invention related to novel substituted propanamide derivatives of general formula (I'), as well as their pharmaceutically acceptable salts and based on them pharmaceutical compositions, which possess suppressive activity against bone resorption and reduction of bone density, reducing concentration of calcium in blood. Claimed invention also relates to application of compounds of general formula (I') or their pharmaceutically acceptable salts and based on them pharmaceutical compositions for production of medications. Values m, n and R5-R9 substituents are given in invention formula.
EFFECT: invention results in methods of bone resorption suppression and reduction of bone mass, reduction of calcium concentration in blood, as well as to method of prevention and treatment of metabolic bone disease.
28 cl, 4 tbl, 102 ex
SUBSTANCE: invention refers to medicine and pharmaceutics and concerns the method for modulation of cell adhesion in a cancer patient by introducing to the patient the compound of formula (II) and measuring count of at least one inducible molecules of cell adhesion, molecule of vascular cell adhesion or a molecule of endothelial leukocyte adhesion.
EFFECT: method can ensure prevention of metastatic and other diseases mediated by molecules of cell adhesion.
30 cl, 1 tbl, 1 ex
SUBSTANCE: invention refers to medicine, namely to oncology and can be used for therapy of patients suffering from hepatic metastases of gastric carcinoma. The mode is implemented as follows. Celiac trunk is catheterised through femoral artery by Seldinger approach. That is followed with selective catheterisation of common hepatic artery wherein Cisplatin is injected within 24 hours, and Fluorouracil - within the next 72 hours. Therapeutic course includes 4-6 procedures every 4 weeks.
EFFECT: invention use allows downsizing the metastatic foci, extending life span and improving life quality of said patients.
SUBSTANCE: invention relates to novel compounds of general formula (I) , where R1 represents 3-10-member non-aromatic heterocyclic group, where group is limited by group containing nitrogen as ring-constituting atom, and nitrogen, having additional bond, or group represented by formula -NR11aR11b, where R11a and R11b can be similar or differ from each other, and each represents hydrogen, C1-6 alkyl, C3-10 cycloalkyl, C6-10 aryl, 5-10-member heteroaryl or 4-10-member non-aromatic heterocyclic group, and R11a and R11b can be substituted with substituent selected from group of substituents A or group of substituents B, and R1 can be substituted with substituent selected from group of substituents A or group of substituents B; R2 and R3 represent hydrogen; R4, R5, R6 and R7 can be similar or differ from each other, and each represents hydrogen, halogen, C1-6 alkyl; R8 represents hydrogen or C1-6 alkyl; R9 represents 3-10-member non-aromatic heterocyclic group, where group is limited by group containing nitrogen as ring-constituting atom, and nitrogen, having additional bond, or group represented by formula -NR11aR11b, where R11a and R11b have the same values as described above; n represents integer 1 or 2; and X represents group, represented by formula -C(R10)=, or nitrogen, where R10 represents hydrogen; where group of substituents A consists of halogen, hydroxyl and oxogroup; where group of constituents B consists of C1-6 alkyl, C3-10 cycloalkyl, C6-10 aryl, 5-10-member heteroaryl, 3-10-member non-aromatic heterocyclic group, C1-6 alkoxy, 5-10-member heteroaryloxy, 4-10-member non-aromatic heterocyclic oxygroup and group represented by formula -T1-T2-T3, and each group in group of substitutes B can be substituted with substituent selected from group of substituents C, where T1 represents direct bond or C1-6 alkylene, T2 represents group represented by formula -NRT1-, T3 represents hydrogen or C1-6 alkyl, and RT1 represents hydrogen or C1-6 alkyl; and where group of substutuents C consists of hydroxyl, C1-6 alkyl, 3-10-member non-aromatic heterocyclic group and di-C1-6 alkylaminogroup, to pharmaceutical composition possessing anti-tumor activity, to inhibitors of: hepatocyte growth factor receptor, angiogenesis and cancer dissemination, as well as to anti-tumor medication.
EFFECT: obtaining novel compounds which demonstrate anti-tumor activity.
31 cl, 111 ex, 18 tbl
SUBSTANCE: there is disclosed pharmaceutical product as prepared solution. The pharmaceutical product comprises a reservoir filled with dissolved zoledronic acid or its pharmaceutically acceptable salt. At least the internal surface of said reservoir contains plastic material that is polyolefin. The product is exposed to thermal sterilisation, preferentially to moist thermal sterilisation. Besides the product can contain a buffer component, preferentially the buffer organic base. Additionally, the product can contain an isotonic component, preferentially mannitol. The invention provides product sterilisation at high temperature 121°C during 150 minutes without visible deformations and damages of sealed integral reservoir, as well as decomposition of pharmaceutical substance.
EFFECT: thermal stability allows for multiple sterilisation cycle that leads to sterility assurance level at least 10-12.
38 cl, 19 ex
SUBSTANCE: invention refers to medical products and concerns pharmaceutical composition for treatment of the diseases associated with urokinase activator of plasminogen (u-PA) and/or with receptor of activator of urokinase plasminogen (u-PAR), containing: (i) amidino-, hydroxyamidino-, guanydino- and/or hydroxyguanydinophenylalanine derivative as an active material, (ii) mixed alcohol and polyol, and (iii) aqueous phase containing buffer solution. There is also disclosed stabilisation method of pharmaceutical composition.
EFFECT: physical and chemical stability.
25 cl, 6 dwg, 1 tbl, 9 ex
SUBSTANCE: invention refers to medicine, particularly to oncology, and concerns development of a medicinal agent for angiogenesis control. It is ensured by application of sphingosine-1-phosphate receptor agonist representing 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3 diol, or its hydrochloride, or phosphate. The present invention also can include these substances combined with chemotherapeutic agents.
EFFECT: invention provides angiogenesis regulation including inhibition of uncontrolled neoangiogenesis, particularly in solid tumour therapy.
9 cl, 7 dwg
SUBSTANCE: experimental thermochemotherapy treatment of tumours is ensured with introduction of magnetic antineoplastic preparation solution containing cytostatic agents. Then preparation is concentrated in tumour by exposure of inhomogeneous constant magnetic field followed by induction heating of tumour in variable magnetic field. After that tumour temperature is kept at +47 - +70°C. Then sphacelous tissues are removed using antiseptic solution. Cytostatic agents are introduced into metastasises.
EFFECT: higher life span in mammals, tumour debulking ensured with tumour tissue heating to such temperature at which cytostatic agents contained in magnetic preparation are activated thus invoking destruction of malignant membranes regardless of cell cycle phase.
4 tbl, 4 ex
FIELD: medicine; pharmacology.
SUBSTANCE: antitumoral composition contains taurolipidine, taurultam or their admixture in concentration approximately 0.1-160 mg/ml in combination with biodecomposable adhesive, including the fibrinous hermetic possessing ability to stick to a tissue of a live organism. Invention also concerns a way of processing for the prevention or the inhibition of growth of cancer cells consisting in drawing of an antitumoral composition on certain area of a tissue of a live organism after excising of a tumour. The composition is put on a tissue of an organism by a layer in the thickness from 0.1 to 10 mm.
EFFECT: invention allows preventing with high degree of efficiency repeated development of a tumour after its excising from organism tissues.
18 cl, 1 ex
SUBSTANCE: group of inventions relates to medicine, namely to oncology, and can be used for preparation of medication for treatment of cancer with expression of TLR3 in patient. For this purpose used is TLR3 agonist in combination with type I interferon in low dose. Impact efficiency is conditioned by synergic effect between TLR3 agonist and interferon.
EFFECT: invention allows to affect tumour due to induction of apoptosis in cancer cell TLR3 expressing.
18 cl, 14 ex, 1 dwg
SUBSTANCE: invention relates to anti-M-CSF-specific antibodies based on RX1 or originating from RX1, and which more than 785% compete with monoclonal antibodies RX1, MC1 and/or MC3 for bonding with M-CSF (macrophagal colony-stimulating factor). The non-mouse antibody is two-stranded, contains a certain amino acid sequence (given in the formula of invention and list of sequences) and retains high affinity towards M-CSF. The invention discloses an isolated nucleic acid which codes the said antibody, an expression vector, a host cell and a method of producing the anti-M-CSF-antibody using a host cell or hybridome, particularly ATCC PTA-6263 or ATCC PTA-6264 hybridome. The invention describes a pharmaceutical composition containing said antibodies, sets containing pharmaceutical compositions and methods of preventing and treating osteoporosis in a person suffering from an osteolytic disease.
EFFECT: disclosed antibodies can inhibit osteoclast differentiation, which facilitates their use as highly effective preparations for treating osteolysis, cancer with metastases and osteoporosis associated with cancer metastases.
131 cl, 44 dwg, 12 tbl, 16 ex
SUBSTANCE: invention relates to methyl ether of 2-cyano-3,12-dioxo-1(2), 11(9)-diene-11-desoxoglycyrrhetic acid of formula (1).
EFFECT: possibility of use in medicine as a medicinal agent having anti-tumour activity.
1 cl, 13 ex, 1 tbl, 3 dwg
SUBSTANCE: invention relates to pyrrolotriazines of formula (I) , where R1 is selected from a group which includes phenyl, naphthyl, benzyl and heteroaryl, which denotes a mono- or bicyclic radical containing 5-10 ring atoms and up to 2 heteroatoms selected from a group consisting of nitrogen, oxygen and sulphur, at least one ring of which is aromatic, where, if necessary, phenyl and heteroaryl may be substituted with 0, 1 or 2 substitutes independently selected from a group consisting of -(C1-C4)alkyl, where -(C1-C4)alkyl can be substituted with 0, 1, 2 or 3 halogens, 0 or 1 pyrrolidine, -(C1-C3)alkoxy group, where, if necessary, the (C1-C3)alkoxy group may be substituted with a (C1-C3)alkylamino group, halogen, trifluoromethyl, trifluoromethoxy group, phenyl, if necessary substituted with 1 or 2 halogens, - , where X denotes O, nitro group, - (C1-C3)alkylthio group, trifluoromethylthio group, - (C1-C3)alkylcarbonyl, - (C1-C6)alkoxycarbonyl, and a phenoxy group, and where the benzyl can be substituted with 0, 1, 2 or 3 groups selected from a group which includes halogen; R2 is selected from a group consisting of hydrogen, halogen; R3 is selected from a group consisting of carboxyl, - (C1-C6)alkylcarbonyl, - (C3-C6)cycloalkylcarbonyl, - (C1-C6)alkoxycarbonyl, if necessary substituted with 0, 1, 2 or 3 groups selected from a group which includes amino group and (C1-C6)alkoxycarbonyl; aminocarbonyl, -(C1-C6)alkylaminocarbonyl, where (C1-C6)alkylaminocarbonyl which, if necessary, can be substituted with 0, 1, 2 or 3 substitutes independently selected from a group consisting of (C3-C6)cycloalkyl, halogen, amino group, (C1-C6)alkylamino group, hydroxy group, (C1-C6)alkoxy group, (C1-C6))alkoxycarbonyl, (C1-C6)alkylthio group, (C1-C6)alkoxycarbonylamino group,and where, if necessary, (C1-C6)alkylaminocarbonyl may be substituted with 0 or 1 heterocyclyl, which denotes a monocyclic, non-aromatic radical containing 5-8 ring atoms and up to 2 heteroatoms selected from nitrogen and oxygen, where, if necessary, the hetecyclyl may be substituted with 0 or 1 (C1-C6)alkyl, heterocyclylcarbonyl, if necessary substituted with 0 or 1 (C1-C6)alkylamino group, cycloalkyl or (C1-C6)alkyl,where, if necessary, (C1-C6)alkyl may be substituted with 0 or 1 (C1-C6)alkylamino group, and where heterocyclyl denotes a monocyclic, non-aromatic radical containing 5-8 ring atoms and up to 2 heteroatoms selected from nitrogen and oxygen, -(C1-C6)alkyl if necessary substituted with 0, 1 or 2 substitutes independently selected from a group consisting of a) hydroxyl, b) (C1-C6)alkylamino group, where (C1-C6)alkylamino group may be substituted with 0, 1 or 3 substitutes independently selected from a group consisting of halogen, alkylamino group, methoxy group, methylthio group and methylsulphonyl, c) phenylamino group, where the phenylamino group may be substituted with 0, 1 or 2 substitutes independently selected from a group consisting of (C1-C6)alkoxy group and trifluoromethyl, d) heterocyclyl, where heterocyclyl denotes a monocyclic, non-aromatic radical containing 5-8 ring atoms and up to 2 heteroatoms selected from nitrogen and oxygen, and where the heterocyclyl may be substituted with 0 or 1 (C1-C6)alkyl, where (C1-C6)alkyl may be substituted with 0 or 1 methoxy groups or pyridyls, e) imidazolyl, f) pyridylamino group, g) (C1-C3)alkoxy group, if necessary substituted with fluorine or piperidine,where, if necessary, the piperidine may be substituted with 0 or 1 (C1-C6)alkyl, h) (C1-C3)alkoxy(C2-C3)alkoxy group, and i) (C1-C6)alkoxycarbonyl, j) (C3-C6)cycloalkyl, k) cyano group, - (C3-C6)cycloalkylaminocarbonyl, cyano group, heteroaryl, where heteroaryl denotes a monocyclic radical containing 5-6 ring atoms and up to 3 heteroatoms selected from a group consisting of nitrogen and oxygen, the ring of which is aromatic, where the heteroaryl may be substituted with 0, 1 or 2 groups independently selected from a group consisting of q) (C1-C6)alkyl, where the (C1-C6)alkyl may be substituted with 0 or 1 morpholine or 0 or 1 hydroxy group, r) (C1-C6)alkoxycarbonyl, thiophene carbonyl, and R4 is selected from a group consisting of hydrogen; to a pharmaceutically acceptable salt thereof. The invention also pertains to methods of obtaining said compounds.
EFFECT: obtaining novel compounds which can be used in medicine for preventing or treating hyper-proliferative disorders and diseases associated with angiogenesis.
5 cl, 313 ex
SUBSTANCE: invention relates to novel compounds of formula (I), specifically compounds of formula (Ia) which have inhibiting activity during activity of kinase selected from Abl, BCR-AbI, PDGF-R, trkB, c-SRC, BMX, FGFR3, b-RAF, SGK, Tie2, Lck, JNK2a2, MKK4, c-RAF, MKK6, SAPK2a and SAPK2P and pharmaceutical compositions containing such compounds. In the compound of formula I, Ia, m and n are equal to 0; R1 denotes XNR5R6, where X denotes a bond; R5 is selected from hydrogen, C1-6alkyl, phenyl, C5-10heteroaryl-C0-4alkyl, C3-6cycloalkyl and C3-10heterocycloalkyl-C0-4alkyl, where the heteroaryl and heterocycloalkyl contain 1-2 heteroatoms selected from nitrogen and oxygen; and R6 is selected from hydrogen and C1-6alkyl; or R5 and R6 together with the nitrogen atom with which both are bonded form a heteroaryl or heterocycloalkyl; where any of phenyl, heteroaryl, cycloalkyl and heterocycloalkyl, R5 or a combination of R5 and R6 can be optionally substituted with 1-3 radicals independently selected from a halogen group, C1-6alkyl, C1-6alkoxy group, halogen-substituted alkyl, -XNR7R8, -XOR7, -XR8, -XC(O)NR7R8, -XC(O)NR7XNR7R8, -XNR7C(O)R8, -XR9; where X denotes a bond or C1-4alkylene; R7 and R8 are independently selected from a group consisting of hydrogen and C1-4alkyl;and R8 is selected form C5-6heterocycloalkyl and C5-6heteroaryl; where said heterocycloalkyl or heteroaryl contain 1-2 heteroatoms selected from nitrogen and oxygen, and said heterocycloalkyl or heteroaryl in R8 is optionally substituted with a radical selected from a group consisting of C1-4alkyl and XOR7; R3 denotes -NR10R11; where R10 denotes hydrogen; R11 denotes phenyl; where phenyl in R11 is optionally substituted with 1-3 radicals selected from a halogen group, C1-6alkyl, C1-6alkoxy group, halogen-substituted alkyl, halogen-substituted alkoxy group, -NR12C(O)R13, -NR12C(O)NR12R13 and -NR12S(O)0-2R13; where R12 denotes hydrogen; R13 is selected from phenyl, C5-6heteroaryl and C5-6heterocycloalkyl; where any of phenyl, heteroaryl, cycloalkyl or heterocycloalkyl contains 1-2 heteroatoms selected from nitrogen and oxygen, and said heterocycloalkyl or heteroaryl in R13 is substituted with 1-3 radicals independently selected from a halogen group, C1-6alkyl, halogen-substituted C1-6alkyl, C1-6alkoxy group, halogen-substituted C1-6alkoxy group, -XNR7R8, phenyl-C0-4alkyl, C5-6heteroaryl-C0-4alkyl, C5-6heterocycloalkyl-C0-4alkoxy group and C5-6heterocycloalkyl-C0-4alkyl; where X, R7 and R8 are described above, and where any of the phenyl, heteroaryl or heterocycloalkyl fragments contain 1-2 heteroatoms selected from nitrogen and oxygen, and said heterocycloalkyl or heteroaryl in R13 optionally further substituted with 1-3 radicals independently selected from a halogen group, C1-6alkyl, halogen-substituted C1-6alkyl, hydroxy-substituted C1-6alkyl, C1-6alkoxy group; R15 and R16 are selected from phenyl substitutes given in values of R11 and R12 for formula I compounds.
EFFECT: compounds can be used to treat or prevent such diseases as proliferative disorders, and diseases resulting from anomalous activation of the immune and nervous systems.
8 cl, 1 tbl, 1 dwg, 1 ex
SUBSTANCE: invention relates to novel pyrimidine derivatives having FAK inhibitory activity of formula (I), where R0 is hydrogen; R1 is a 5- or 6-member heterocycle containing 1 or 2 nitrogen atoms substituted with (C1-C7)alkyl, hydroxyl group, dialkylamino group or a 6-member heterocycle containing one nitrogen atom; R2 is hydrogen; R3 is carbamoyl substituted once or twice with (C1-C7)alkyl; a 5-member heterocycle containing 4 nitrogen atoms; SO2N(R12)R13, where R12 is hydrogen or (lower)alkyl, and R13 is hydrogen, (C1-C7)alkyl, (C1-C7)alkoxy(C1-C7)alkyl, di(C1-C7)alkylamino(C1-C7)alkyl, hydroxy(C1-C7)alkyl, or R12 and R13 together a nitrogen atom with which they are bonded form a 6-member heterocycle containing two nitrogen atoms, where the said heterocycle is not substituted or substituted with (C1-C7)alkyl; R4 is hydrogen; R5 is a halide; R6 is hydrogen; R7 is hydrogen; (C1-C7)alkoxy; carbamoyl which is not substituted or substituted with (lower)alkyl; a 5- or 6-member heterocycle containing 1 or 2 nitrogen or oxygen atoms, unsubstituted or substituted with di(C1-C7)alkylamino, (C1-C7)alkyl, hydroxy, 6-member heterocycle containing 1 or 2 nitrogen or oxygen ring atoms, unsubstituted or substituted with (C1-C7)alkyl; 6-member heterocycle-oxy containing 1 nitrogen ring atom, unsubstituted or substituted with (C1-C7)alkyl; heterocycle(C1-C7)alkyloxy, where heterocycle denotes a 5- or 6-member heterocycle containing 1 or 2 nitrogen or oxygen ring atoms which is not substituted or substituted with (C1-C7)alkyl; R8 is hydrogen; halide; (C1-C7)alkoxy, carbamoyl unsubstituted or substituted with (C1-C7)alkyl; heterocycle(C1-C7)alkyloxy, where heterocycle denotes a 5-member heterocycle containing 1 nitrogen ring atom, unsubstituted or substituted with (C1-C7)alkyl; 5- or 6-member heterocycle containing 1 or 2 nitrogen or oxygen atoms, unsubstituted or substituted with one or two substitutes independently selected from hydroxy, (C1-C7)alkyl, aminocarbonyl and (C1-C7)alkylamino; 6-member heterocycle-oxy, containing 1 nitrogen ring atom, unsubstituted or substituted 1-5 times with (C1-C7)alkyl or di(C1-C7)alkylamino; or R7 and R8 together with atoms with which they are bonded form a 6-member heterocycle containing two nitrogen or oxygen atoms, unsubstituted or substituted once or twice with (C1-C7)alkyl or oxo group; R9 is hydrogen; R10 is (C1-C7)alkoxy, as well as to their pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition and synthesis method.
EFFECT: novel compounds have useful biological activity.
4 cl, 167 ex
SUBSTANCE: method involves polychemotherapy followed by radiation therapy (RT) with underlying plant-based mouth rinsing and oral administration of Colegel with Derinat and Lidocaine 3 times a day and more often. The polychemotherapy is performed by no more than 2 courses with the radiation started not earlier than in 10-15 days after the polychemotherapy to total basic dose 66-70 Gy and with peripheral blood of an exposed patient analysed for lymphocyte count once in 10 days and more often. If lymphocyte count is 1.2×109/l or less, the following RT sessions are carried out with underlying additional intensive local and system therapy, or the therapy is interrupted for the hemostimulation therapy.
EFFECT: use of the invention allows preventing severity gain in a radiation involvement of oropharyngeal mucosa due to well-timed intensification of local and system therapy, performing a radical RT course and improving clinical effectiveness.
2 cl, 2 ex
SUBSTANCE: pharmaceutical composition for treating syphilis and viral diseases specified from influenza, human immunodeficiency virus, cytomegalovirus infections, viral hepatitis type A, D, C and herpes infections, containing an amount of polyphenol compounds of sea buckthorn leaves, including at least 60 % of halloellagotannines, flacoside, a pharmacologically acceptable carrier and a substance of licorice extract, or glycyrrhizic acid, or its pharmaceutically acceptable salt, acridonoacetic acid or its pharmaceutically acceptable salt, birch bark extract or betulin taken in therapeutically effective amounts. A method of treating syphilis and viral diseases, including the introduction of the declared pharmaceutical composition by 2-3 doses 3 times a day.
EFFECT: composition exhibits an evident antiviral action with respect to the infections stated above.
22 cl, 1 dwg, 12 tbl, 7 ex
SUBSTANCE: invention relates to novel crystalline modifications of [6-methoxy-5-(2-methoxyphenoxy)-2-pyridin-4-ylpyrimidin-4-yl]amide-5-methylpyridine-2-sulfonic acid, which produces an endothelial antagonistic effect and is suitable for treating diseases associated with abnormal vascular tone and endothelial dysfunction, such as heart failure, pulmonary hypertension etc. The crystalline modification which is denoted modification B is characterised by a powder X-ray diffractogram with characteristic peaks expressed through the d-parametre value (interplanar distance) (Å) obtained on a conventional X-ray powder diffractometre using Cuka radiation: 10.7 (m), 9.4 (m), 8.6 (vs), 8.3 (m), 7.6 (m), 6.7 (m), 6.4 (m), 6.0 (m), 5.69 (m), 5.30 (m), 5.17 (m), 4.95 (vs), 4.76 (m), 4.56 (m), 4.43 (s), 4.13 (vs), 3.80 (s), 3.45 (s), 3.41 (s), 3.37 (s) and 3.03 (m). The invention also relates to crystalline pseudopolymorphous modifications of [6-methoxy-5-(2-methoxyphenoxy)-2-pyridin-4-ylpyrimidin-4-yl]amide-5-methylpyridine-2-sulfonic acid selected from: a) pseudopolymorphous modification, solvate with ethanol, denoted modification D; b) pseudopolymorphous modification, polysolvate with acetone, denoted modification E; c) pseudopolymorphous modification, solvate with tetrahyrofuran, denoted modification F; d) pseudopolymorphous modification, solvate with methanol, denoted modification G; e) pseudopolymorphous modification, solvate with isopropanol, denoted modification H; f) pseudopolymorphous modification, solvate with dichloromethane, denoted modification I; and g) pseudopolymorphous modification, solvate with 2-butanol, denoted modification J. The invention also relates to a method of obtaining crystalline modification B, a pharmaceutical composition and use.
EFFECT: wider field of use of the compounds.
8 cl, 9 dwg, 9 tbl, 12 ex
SUBSTANCE: invention relates to medicine, oncology, and can be used for chemoradiation therapy of low-located tumours of rectum and anal canal. For this purpose standard teleirradiation is performed. Additionally performed is conformal intraluminal brachytherapy of high power dose 5-10 Curie 4-6 irradiation sessions with reference dose 3.5 Gy at depth of 10 mm from irradiation source. In addition, on daily basis derivative of capecitabine fluoropyrimidines in amount 600 mg/m2 is introduced per os.
EFFECT: method allows to increase treatment efficiency, increase local response of tumour and reduce risk of metastases development due to exposing tumour to higher tumoricidal doses of irradiation and adding brachytherapy, intake of capecitabine enhancing local regress and reducing risk of tumour metastasis.
FIELD: medicine, veterinary science.
SUBSTANCE: method involves application of EVL-Se COMPOSITION solution, which is introduced to animal inside orally by a group method with water (milk or imitation milk) once a day for 10 days in single dosage 1.0 ml per a head.
EFFECT: application of the method allows reducing disease incidence and recovery time, increasing average daily weight gains, ensures more rapid microflora formation and has no by-effects.
2 tbl, 3 ex