Method for treatment of osseous disorders

FIELD: medicine.

SUBSTANCE: invention relates to a method for increasing osseous mass in osteoporosis disease. Method involves using sets containing standard doses of bisphosphonates in the amount sufficient for using in "impact" period from 7 to 180 days, and standard doses of bisphosphonate for the following using in supporting period. Bisphosphonate is chosen from group consisting of risedronate, alendronic acid, pamidronate, tiludronate, clodronate, cimadronate, ibandronate, zoledronate and their salts and esters. Standard doses of bisphosphonate in "impact" period are by 3-6 times higher as compared with standard doses of bisphosphonate in supporting period. Using sets of bisphosphonates in the given ratio of doses in "impact" and supporting periods provides increasing the osseous mass in osteoporosis of different genesis.

EFFECT: improved treatment method.

6 cl, 4 ex

 

The technical field

The present invention relates to a method of increasing bone mass and reducing the frequency of fractures in the treatment of osteoporosis and other bone metabolic disorders. In particular, the present invention relates to such methods of treatment, which include the introduction of a loading dose active against the bones of the phosphonate with subsequent therapy dose.

Prerequisites to the creation of inventions

Basic metabolic bone infringement is osteoporosis. In General, osteoporosis can be defined as a reduction in the quantity of bone or atrophy of skeletal tissue due to imbalance in the normal cycle of resorption/formation of bone in the bone remodeling unit. Generally there are two types of osteoporosis: primary and secondary. Secondary osteoporosis is a result of identifiable pathological process or agent. For example, it is known that glucocorticoid steroids induce osteoporosis. See, for example, the materials of the American College special rheumatology Committee on osteoporosis induced by glucocorticoids, "Recommendations for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis", Arthritis & Rheumatism,Vol. 44, No. 7, Juli 2001, p. 1496-1503 © 2001; B.P. Lukert, M.D., F.A.C.P. "Glucocorticoid-Induced Osteoporosis", Primer in the Metabolic Bone Diseases and Disorders of Mineral Metabolism, Fourth Edition, Chapter 55, p. 292-296, pub is icatio American society for the study of bone and mineral, Murray J. Favus, M.D. Editor, Dept of Medicine, The University of Chicago Medical Center, Chicago, Illinois. Approximately 85% of all osteoporosis are primary osteoporosis. See, for example, Marjorie M. Luckey, M.D., "Evaluation of Postmenopausal Osteoporosis", Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism,4thEdition, p. 273-277, Murray J. Favus M.D. Editor, Dept of Medicine, The University of Chicago Medical Center, Chicago, Illinois; and "Osteoporosis Prevention, Diagnosis and Therapy", JAMA,February 14, 2001 - Vol. 285, No. 6; p. 785-795. Such primary osteoporosis includes postmenopausal osteoporosis, osteoporosis associated with age (affecting most individuals over the age of 70-80 years), and idiopathic osteoporosis.

For some individuals suffering from osteoporosis, bone loss is quite large and can cause mechanical damage to the bone structure. Fractures often occur, for example, in the hip joint and spine of women suffering from postmenopausal osteoporosis. Also may develop kyphosis (abnormally increased curvature of the thoracic spine). Although its etiology is not fully installed, I believe that there are many risk factors associated with osteoporosis. These factors include insufficient body weight, low calcium absorption, physical inactivity and estrogen deficiency.

Described numerous compositions of the ways for treatment of osteoporosis. Many of them include the use of bisphosphonates or other phosphonates, active against bone. See, for example, J.Y. Reginster, et al., "Randomized Trial of the Effects of Risedronate on Vertebral Fractures in Women with Established Postmenopausal Osteoporosis", Osteoporosis International,(2000) 11: p. 83-91; Steven T. Harris, M.D., et al., "Effects of Risedronate Treatment of Vertebral and Nonvertebral Fractures in Women With Postmenopausal Osteoporosis, A Randomized controlled Trial" Journal of the American Medical Association,October 13, 1999, Vol. 282, No. 14, p. 1344-1352.

Have also been proposed permanent and cyclical introduction of bisphosphonates alone or with other drugs, such as parathyroid hormone, calcium and vitamin D in the treatment of osteoporosis. See, for example, the materials of the American College special rheumatology Committee on osteoporosis induced by glucocorticoids, "Recommendations for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis", Arthritis & Rheumatism,Vol. 44, No. 7, Juli 2001, p. 1496-1503 © 2001; J.Y. Reginster, et al., "Randomized Trial of the Effects of Risedronate on Vertebral Fractures in Women with Established Postmenopausal Osteoporosis", Osteoporosis International, (2000) 11: p. 83-91; Steven T. Harris, M.D., et al., "Effects of Risedronate Treatment of Vertebral and Nonvertebral Fractures in Women With Postmenopausal Osteoporosis, A Randomized controlled Trial" Journal of the American Medical Association,October 13, 1999, Vol. 282, No. 14, p. 1344-1352.

The authors found that the introduction of high-dose active against the bones of the phosphonate followed by the introduction of a lower maintenance dose reduces bone resorption and increases bone mA is su at higher speeds excretion and a more marked reduction in the incidence of fractures. This can be especially effective in patients with high bone resorption, such as cancer patients or patients with transplant.

Summary of invention

The present invention relates to a method of increasing bone mass and/or reducing the frequency of fractures in individuals affected by osteoporosis. The method includes the stages of: (a) loading dose of bisphosphonates during the period of time from about 7 to 180 days, more preferably from about 14 to 60 days, followed by (b) the introduction of the constant maintenance doses of bisphosphonates. Loading dose embodies the level of bisphosphonates approximately 2 to 20 times, preferably about 3 to 10 times, more preferably about 3-6 times higher than the corresponding supporting dose. A loading dose is administered over a period of approximately from 7 to 180 days. When oral administration of a loading dose is administered every day or two, while the maintenance dose can be administered every day, twice a week, weekly, biweekly, or monthly.

Description of the invention

The methods of the invention include the introduction of a loading dose active against the bones of the phosphonate and maintenance doses active against the bones of the phosphonate. Accordingly, the special joint and composition, which should be used in these methods are pharmaceutically acceptable.

Definitions:

Used in the description of the term "introduction" means any method by which in the current medical practice to deliver the active compounds used in this invention, the patient, therefore, to provide an effective effect on the bone structure. The active compounds can be entered by any of a number of known routes of administration, for example oral, dermatomyositis (e.g., dermal, sublingual, intranasal, and rectal), parenteral (e.g. subcutaneous injection, intramuscular injection, intra-articular injection, intravenous injection), topically (dermal) and through inhalation. Thus, it is not limited to, special methods of administration include oral, percutaneous, cressilia, sublingual, intramuscular, intravenous, intraperitoneal, subcutaneous administration and other local application.

Used in the description of the term "shock dose" means the dose, initially introduced to the patient. This dose is an effective amount to achieve the desired results.

The term "shock period" means the period of time during which the patient is administered an initial dose.

The term "maintenance dose" means the dose, modimoopelu after the "shock" period. This dose is an effective amount to achieve the desired results.

Used in the description of the term "maintenance period" means the period of time after the "shock" period, during which the patient is continuously injected dose bisphosphonates at lower doses than the dose.

Used in the description of the phrase "safe and effective amount" means an amount large enough to significantly induce a positive change in symptoms and/or condition of the patient, but small enough to avoid serious harmful side effects, commensurate with an acceptable ratio of benefit/risk. Safe and effective amount will vary depending on such factors as features treatable condition, age and physical condition of the patient, duration of treatment, the nature of concurrent therapy, used special dosage form and applied regimen of the drug.

Method:

The method according to the invention includes a stage

(a) loading dose of bisphosphonates during the period approximately from 7 to 180 days;

(b) introduction after stage (a) permanent maintenance doses of bisphosphonates,

and named the dose of from about two to twenty times higher than the product name is Naya maintenance dose.

Thus, the period of the loading dose comprises a separate scheme is the introduction of bisphosphonates. During a loading dose of a bisphosphonate should be administered with sufficient frequency to achieve a physiological effect in a patient. For example, in "shock" period, the oral dosage form of bisphosphonates is preferably introduced every day. It may be desirable to introduce one type of bisphosphonates within a few days of treatment and another type in the other days of treatment.

In addition, a bisphosphonate, you must assign at least once every three months after the "shock" period. However, bisphosphonate can be assigned every day, every other day, twice weekly, weekly, twice a week, once a month or in a month. It may be desirable to introduce one type of bisphosphonates in some days of treatment and another type in the other days of treatment.

A certain period of time and frequency assignment of certain doses of medicines which are sufficient to achieve the increase of the total skeletal mass of the patient may depend on a number of factors. Such factors include, for example, used certain active compounds, the amount of the active compounds, the route of administration (i.e. oral or parenteral), age and sex of the patient, especially the curable breach is, used concomitant therapy, General physical condition of the patient, the degree of osteoporosis in the individual and dietary habits of the individual.

Used in the methods according to the invention the treatment is preferably carried out at least for a period of approximately twenty-four months. Of course, the regimen can be continued indefinitely in accordance with current medical practice.

The preferred method of treatment of bone disorders includes initial diagnostic stage to establish the existence of a breach. Thus, a preferred method according to the invention includes the stage of the diagnostic examination of the patient to determine high bone resorption. High bone resorption can be installed, if the total bone resorption and increased bone resorption is higher than bone formation. Then after receiving a positive result when called diagnosis carry out the introduction of the active compounds in accordance with the methods according to the invention. It is possible to carry out measurement of biochemical markers to determine the rate of bone resorption. Reconstruction of the bone can be confirmed by methods of histomorphology.

Appropriate diagnostic studies to determine the set of osteoporosis is also well known in this field. Such methods include measurement of roentgenographically on radiographs of the skeleton, quantitative computed tomography, monoenergetic photon absorptiometry and dual energy photon absorptiometry. Diagnostic methods used in the invention, among others described W.A. Peck et al. Physician''s Resource Manual on osteoporosis (1987), published by the National osteoporosis Foundation (included in description of the citation).

Used in the description, the expression "active against bone phosphonate (bisphosphonate, diphosphonate) means acid, salts and derivatives thereof. Without limitation, examples of bisphosphonates used in the invention include 1-hydroxy-2-(3-pyridinyl)ethylidene-1,1-bisphosphonic acid (risedronate), which is described Benedict et al., in U.S. patent No. 5583122 of 10 December 1996, which is incorporated into this description by reference. 4-Amino-1-hydroxybutylidene-1,1-bisphosphonic acid (alendronat acid) described in U.S. patent No. 4621077 Rosini et al., on November 4, 1986; U.S. patent No. 4922007 Kieczykowski et al., from 1 may 1990 and in U.S. patent No. 5019651 Kieczykowski et al., on may 28, 1991, which are all included in the present description by reference. 3-Amino-1-hydroxypropylamino-1,1-bisphosphonic acid (pamidronate), (4-chlorophenyl)Tibetan-1,1-diphosphonic acid (tiludronate) described in U.S. patent No. 4876248 Breliere et al., on October 24, 1989, which included the n in the present description by reference. 1,1-Dihlormetilen-1,1-diphosphonic acid (clodronic) described in Belgium patent 672205 (1966), which is incorporated into this description by reference. Cycloheptylmethyl-1,1-bisphosphonic acid (comadronas) described in U.S. patent No. 4970335 Isomura et al., on November 13, 1990, which is incorporated into this description by reference. 1-Hydroxy-3-(N-methyl-N-pentylamine)propylidene-1,1-bisphosphonic acid (ibandronic acid) is described in U.S. patent No. 4927814 of 22 may 1990, which is incorporated into this description by reference. 1-Hydroxy-2-(1H-imidazol-1-yl)ethylidene-1,1-bisphosphonic acid (alendronate).

Preferred bisphosphonates are selected from the group consisting of risedronate, ibandronate, pamidronate, alendronate, timetonote, tiludronate, zoledronate, clodronate, peregrinate, their pharmaceutically acceptable salts and mixtures thereof.

The number of input bisphosphonates depends on its effectiveness. The effectiveness of a particular bisphosphonates can be expressed in units of its "LED" or "lowest effective dose", which is the minimum dose bisphophonates presented in mg P/kg (milligrams of phosphorus in the compound per kilogram of body weight of the patient), which in itself is effective to cause significant inhibition of bone resorption. Specific LED bisphosphonates vary depending on the chemical composition of bisphospho is the ATA and route of administration (i.e. oral or parenteral). The lower LED, the more potent is a bisphosphonate, and usually preferably, the introduction of highly effective bisphosphonates in lower doses and for fewer days. Similarly, the higher the light, the less effective is a bisphosphonate, and usually it is desirable introduction of inefficient bisphosphonates in higher doses and for more days. LED for oral administration of a medicinal product will be higher depending on the total suction of the phosphonate. Usually the absorption by oral administration is from about 1% to 10%. Thus, oral LED is usually about ten to hundred times higher than the LED parenteral.

There are a number of models that can be used to determine the LED phosphonates, active against bone. In addition, the model described in U.S. patent No. 4761406 Flora et al., on August 2, 1988, which is incorporated into this description by reference.

Dosage form:

Phosphonate, active against bone, you can enter in any of a number of pharmaceutically acceptable compositions. Such compositions may contain the active compound and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers include solid and liquid fillers, diluents or kapsulirujushchej substances and their mixtures, which are suitable for centuries the Denia human or lower animal. Used in the description, the term "compatible" means that the components of the pharmaceutical composition is able to be mixed with the active compounds and with each other in such a way that there is no interaction which would substantially reduce the pharmaceutical efficacy of the pharmaceutical composition under normal conditions of use. Pharmaceutically acceptable carriers certainly must have a sufficiently high purity and sufficiently low toxicity to their administration to a patient.

Some examples of substances which can serve as pharmaceutical carriers are sugars such as lactose, glucose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethylcellulose, acetylcellulose; powder tragakant; malt; gelatin; talc; stearic acid; magnesium stearate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and cocoa butter; polyols such as propylene glycol, glycerin, sorbitol, mannitol and polyethylene glycol; agar; alginic acid; pyrogen-free water; isotonic saline; phosphate buffer solutions; moisturizing agents and lubricants such as sodium lauryl sulfate; coloring agents; seasonings and Kon is Hervanta. Other compatible additives and active compounds may be included in the pharmaceutically acceptable carrier for use in the compositions according to the invention.

The choice of pharmaceutically acceptable carrier, which is used together with the active compound is determined, among other things, an active compound that is needed. If the active connection must be introduced by injection, the preferred pharmaceutical carrier is sterile water, saline solution or their mixture. the pH of such parenteral compositions is preferably approximately 7,4. Suitable pharmaceutically acceptable carriers for topical application include carriers, known in the field for use in creams, gels, tapes, bandages and similar local means of delivery.

Pharmaceutically acceptable carrier used together with the active compounds are used in concentrations sufficient to provide convenient size ratio of doses. In General, pharmaceutically acceptable carriers can be approximately from 0.1% to 99.9% by weight of the pharmaceutical compositions according to the invention, preferably from about 5% to 80% and most preferably from 10% to 50%.

The preferred method of administration of bisphosphonates is an oral introduction to the standards the drug form (that is, the dosage form, contains the number of active connections, suitable for administration in one single dose in accordance with current medical practice). Preferred standard dosage forms of bisphosphonates include tablets, capsules, suspensions and solutions containing a safe and effective amount of active compound. Pharmaceutically acceptable carriers suitable for the preparation of standard dosage forms for oral administration are well known in this field. Their choice will depend on additional circumstances such as taste, cost, stability during storage, which are not significant for the purposes of the present invention, and can be carried out without difficulty by a person skilled in the art. Preferably, standard oral dosage forms of risedronate for loading dose contains from about 15 mg to 50 mg per day, more preferably from about 20 mg to 40 mg per day and most preferably from about 25 mg to 35 mg per day. Oral standard dosage forms phosphonate, active against bone, a maintenance dose preferably contain from about 2.5 to 15 mg per day, more preferably approximately from 5 to 10. For alendronate dose of approximately 15 mg to 70 mg a day more preferably from about 20 mg to 50 mg per day and most preferably from about 25 mg to 40 mg per day. The equivalent dose, you can assign every other day, twice weekly, weekly, biweekly and monthly.

Another preferred method of administration of bisphosphonates is a subcutaneous injection in a standard dosage form. Preferred standard dosage forms for input with injection bisphosphonates, active against bone, include sterile solutions of water, saline, or a mixture thereof. the pH of these solutions should be approximately 7,4. Preferably, a standard dosage forms of risedronate for loading dose contains from about 0.75 mg to 15.0 mg per month and more preferably from about 1.5 mg to 10 mg per month. Standard dosage forms phosphonate, active against bone, a maintenance dose preferably contains from about 0.75 mg to 6 mg per month and more preferably from about 1.5 mg to 3 mg per month. Equivalent amounts of drug can be assigned every two weeks, every month, a month and every three months.

Sets:

The present invention also relates to kits for convenient and effective implementation of the methods according to the invention. These kits contain the bottom or more standard doses of phosphonate, active against bone, to "shock" period, one or more standard doses of phosphonate active against bone, for supporting period, and means to support the adherence regimens medication in accordance with the methods according to the invention. These kits are a convenient and effective means to ensure that the patient will receive an active connection in the exact dosage and appropriate way. Ensure accurate execution regimens medication means of such sets include any funds that contribute to the introduction of the active compounds in accordance with the method according to the invention. These tools include tools, packaging and distributing means, and combinations thereof. Examples of packaging and distributing means well known in this field, including the means described in U.S. patent No. 4761406, Flora et al., issued August 2, 1988, and U.S. patent No. 4812311, Uchtman, issued March 14, 1989, all included in the present description by reference.

The following examples illustrate the composition, method and use according to the invention, without limiting it.

EXAMPLE 1

A patient weighing approximately 60 kg and which is established postmenopausal osteoporosis, treated by the method according to the invention. More precisely, during tridtsat the days the patient was administered at 30 mg per day risedronate oral. Immediately after the described period, the patient was administered risedronate 35 mg / week orally for two years. Two years later he made a biopsy of the iliac crest and revealed an increase in the average wall thickness of resurfacing units compared with its baseline biopsy.

EXAMPLE 2

Man, weighing approximately 70 kg and who has prostate cancer and high bone resorption, was treated by the method according to the invention. More precisely, every day for fourteen days the patient received 35 mg of alendronate a day. Then after a given period of time the patient entered the maintenance dose of 70 mg per week of oral alendronate in one year.

EXAMPLE 3

The woman, whose weight was approximately 58 kg, established glucocorticoid-induced osteoporosis. Then the patient was treated by the method according to the invention. More precisely, the patient was administered at 30 mg risedronate orally daily for a period of thirty days. Thereafter, the dose was changed to a maintenance dose of 35 mg orally in a week for three years.

EXAMPLE 4

The patient man, the weight of which amounted to approximately 67 kg, treated intravenously; only 9 mg of risedronate divided into the same two-week dose (4.5 mg in week 1 and day 8). Maintenance dose of 3 mg was administered on day 29 (after what erway loading dose) followed 3 mg after a month of 29 days.

As particular aspects of the present invention are described, for professionals in this field it is obvious that various changes and modifications of the present invention can be made without departure from the ideas and goals of the invention. Appended claims cover all such modifications that are included in the scope of the present invention.

1. Set for treatment to increase bone mass, containing a number of standard doses of bisphosphonates for use during the "shock" period, which is from 7 to 180 days, and standard doses of bisphosphonates for use during maintenance period that follows after a "shock" period, with standard doses of bisphosphonates "shock" period from 3 to 6 times higher than standard doses of bisphosphonates support period.

2. The kit according to claim 1, where the kit further comprises means to support the accurate execution of the regimen used.

3. The kit according to claim 1 or 2, in which the bisphosphonate is chosen from the group consisting of risedronate, alendronova acid, pamidronate, tiludronate, clodronate, timetonote, ibandronate, zoledronate and their salts and esters.

4. The kit according to claim 1, in which the bisphosphonate is risedronate or alendronate.

5. The use of bisphosphonates for the production of pharmaceutical kit, which is used for the forgiveness of treatment to increase bone mass, including the number of standard doses of bisphosphonates for use during the "shock" period, which is from 7 to 180 days, and standard doses of bisphosphonates for use during maintenance period that follows after a "shock" period, with standard doses of bisphosphonates "shock" period from 3 to 6 times higher than standard doses of bisphosphonates support period, and a bisphosphonate selected from the group consisting of risedronate, alendronate, pamidronate, tiludronate, clodronate, timetonote, ibandronate, zoledronate and their salts and esters.

6. The use of bisphosphonates for the manufacture of a medicinal product for treatment to increase bone mass, representing a set of standard doses of bisphosphonates for use during the "shock" period, which is from 7 to 180 days, and standard doses of bisphosphonates for use during maintenance period that follows after a "shock" period, with standard doses of bisphosphonates "shock" period from 3 to 6 times higher than standard doses of bisphosphonates support period.



 

Same patents:

FIELD: medicine.

SUBSTANCE: method involves receiving mononuclear cells from 6-8 ml of patient blood by adhesion in control and case tablet cells. 9 mcl of Miacalcic solution of 500 IU/l are added into case cell and the same volume of solvent is added to control cell. Culturing begins. NO3 level increasing in Miacalcic medium to 10%, Miacalcic dose of 50 IU/day is to be prescribed. The value being equal to 10-30%, 100 IU/day is to be prescribed. The value being greater than 30%, 200 IU/day is to be prescribed.

EFFECT: enabled differential approach to treating osteoporosis cases.

1 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to triheterocyclic compound of the formula (I): wherein X represents carbon atom; Y represents carbon or nitrogen atom; W represents carbon or nitrogen atom; U represents -CR2, and Z represents -CR2 or nitrogen atom; ring A represents (C5-C6)-cycloalkyl ring or 5-membered heterocyclic ring comprising one nitrogen, oxygen or sulfur atom; R1 represents alkyl, alkenyl, alkynyl, -NR4R5, -OR6 and others; R3 represents phenyl ring substituted with 1-3 substitutes or pyridyl or 1,3-dioxoindanyl ring substituted with 1-2 substitutes, and its pharmaceutically acceptable salts and pharmaceutical composition containing thereof as an active component. Also, invention relates to derivatives of pyrazolopyrimidine and derivatives of pyrrolopyrimidine. Compounds of the formula (I) show antagonistic activity with respect to corticotropin-releasing factor receptors. The compound can be used in treatment and/or prophylaxis of depression, anxiety state, disorders in food intake, post-traumatic stress, ulcerous disease, irritable bowel syndrome, Alzheimer's disease, abuse in drugs using or alcoholic syndrome dependence.

EFFECT: valuable medicinal properties of compounds and pharmaceutical agent.

7 cl, 1 dwg, 24 ex

FIELD: medicine.

SUBSTANCE: method involves applying N-bisphosphonates like Zoledronic acid and its derivatives for prolonged inhibiting bone tissue resorption in states distinguished by increased bone tissue renewal like it occurs in osteoporosis cases by periodically administering the drug at a dose of 2 to 10 mg. Pauses between drug introductions have become longer when compared to periodicity considered to be required in earlier times, while being greater than 6 months.

EFFECT: enhanced effectiveness of treatment.

10 cl, 1 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrimidine of the general formula (I) that possess properties of antagonists to adenosine A2-receptors and can be effective in relieve, for example, of defecation. In compound of the general formula (I) each R1 and R2 represents hydrogen atom; R3 represents hydrogen atom, halogen atom, amino-group, cyano-group, alkyl group comprising 1-6 carbon atoms, alkoxy-group comprising 1-6 carbon atoms, alkenyloxy-group comprising 2-6 carbon atoms, phenyl group that can be substituted with halogen atom, pyridyl group, furyl group or thienyl group; R4 represents pyridyl that can be substituted with a substitute chosen from the group comprising: hydrogen atom, halogen atom, amino-group, mono- or dialkylamino-group, aminoalkylamino-group wherein each has in alkyl residue from 1 to 6 carbon atoms, alkyl group comprising from 1 to 6 carbon atoms that can be substituted with halogen atom, hydroxy-group, amino-group, mono- or dialkylamino-group, alkoxycarbonyl wherein each has in alkyl residue from 1 to 6 carbon atoms, alkoxy-group comprising in alkyl group from 1 to 6 carbon atoms substituted with phenyl or pyridyl, hydroxyalkoxy-group comprising in alkyl residue from 1 to 6 carbon atoms, hydroxycarbonyl, alkoxycarbonyl comprising from 1 to 6 carbon atoms in alkyl residue, alkenyl group comprising from 2 to 6 carbon atoms, alkynyl group comprising from 2 to 6 carbon atoms, piperidinyl group that can be substituted with hydroxyl group, or represents group of the formula (IV): R5 represents phenyl that can be substituted with halogen atom, pyridyl group, thienyl or furyl group.

EFFECT: valuable biological properties of derivatives.

16 cl, 2 tbl, 185 ex

FIELD: pharmaceutics.

SUBSTANCE: a solid pharmaceutical composition contains therapeutically efficient quantity of peptide as a pharmacological active substance, crospovidone or povidone, and an agent that favors peptide's introduction. A peptide is being calcitonin, salmon's calcitonin preferably. The above-mentioned agent is being 5-CNAC (N-(5-chlorsalicyloyl)-8-aminocaprylic acid), preferably, disodium salt 5-CNAC. The composition suggested provides high biological availability of peptides, such, for example, as calcitonin.

EFFECT: higher efficiency of application.

9 cl, 5 ex, 4 tbl

FIELD: biotechnology.

SUBSTANCE: invention relates to inhibitor of matrix metalloproteinases representing extract from fungus Canoderma atrum obtained by using of water and/or lower alcohols as extractant. Also disclosed are pharmaceutical agent for inhibition of tumor metastasis containing of 0.03-10 wt.% of abovementioned extract and foodstuff containing claimed extract.

EFFECT: improved inhibitor of matrix proteinases.

3 cl, 18 ex, 4 tbl

FIELD: medicine, medicinal biochemistry, pharmaceutical technology.

SUBSTANCE: invention proposes the composite that comprises complex of vitamins D3, B6, C, K and calcium salts, citric acid, lactose and sorbitol as the special supplement, and lubricating agent and correcting agent for taste and/or odor. The method for preparing the composite involves mixing the above said components and if necessary the following tableting process of the prepared mixture. The new composite shows stability of quality indices in the store process being among them index "the content of vitamin D3" that provides the fitness time above 2 years and absence of by-side adverse toxic effect that is typical for destruction products of active components.

EFFECT: improved preparing method, improved and valuable properties of composite.

7 cl, 1 tbl, 4 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes phenylpyridazine compounds represented by the following formula (I): wherein R1 represents unsubstituted or substituted phenyl wherein substitutes are taken among the group comprising halogen atom, lower alkyl, lower alkoxy-group and phenylthio-group, or pyridyl; R2 represents lower alkoxy-group, lower alkylthio-group, lower alkylsulfinyl or lower alkylsolfonyl; R3 represents hydrogen atom or lower alkoxy-group; or R2 and R3 can be condensed in common forming lower alkylenedioxy-group; R4 represents cyano-group, carboxyl, unsubstituted or substituted lower alkyl wherein substitutes are taken among the group comprising hydroxyl, carboxyl and N-hydroxy-N-lower alkylaminocarbonyl; lower alkenyl; lower alkylthio-group; lower alkylsulfinyl; lower alkylsulfonyl; lower alkylsulfonyloxy; unsubstituted or substituted phenoxy-group wherein substitutes are taken among the group comprising halogen atom, lower alkoxy-, nitro-, cyano-group; unsubstituted phenylthio-group or phenylthio-group substituted with halogen atom; pyridyloxy-; morpholino-group; morpholinylcarbonyl; 1-piperazinylcarbonyl substituted with lower alkyl; unsubstituted or substituted amino-group wherein substitutes are taken among the group comprising lower alkyl, benzyl, phenyl that can be substituted with halogen atoms or lower alkoxy-groups, and n = 0, or their salts. Proposed compounds possess the excellent inhibitory activity against biosynthesis of interleukin-1β and can be used in preparing a medicinal agent inhibiting biosynthesis of interleukin-1β, in particular, in treatment and prophylaxis of such diseases as diseases of immune system, inflammatory diseases and ischemic diseases. Also, invention proposes intermediate compounds for preparing compounds of the formula (I). Except for, invention proposes a medicinal agent and pharmaceutical composition that inhibit biosynthesis of interleukin-1β and inhibitor of biosynthesis of interleukin-1β.

EFFECT: valuable medicinal properties of compounds and composition.

7 cl, 1 tbl, 66 ex

FIELD: medicine, orthopedics.

SUBSTANCE: the present innovation deals with treating osseous diseases caused by calcium exchange disorders. For this purpose certain calcium preparations should be reduced up to amorphous state to be perorally applied per 0.5-1.0 g, 2-4 times daily, at courses of not less than 10 d. The innovation provides efficient treatment due to high biodigestibility of amorphous calcium and its active accumulation in bony tissue.

EFFECT: higher efficiency of therapy.

1 cl, 2 ex

FIELD: medicine; medical engineering.

SUBSTANCE: biotransplant has genetically unmodified mesenchyma stem cell culture as active component obtained from fetal donor autologous material. The tissue is subjected to disaggregation and the produced cell suspension is resuspended and cultivated on growth medium containing transferrin, insulin, fibroblast growth factor and heparin to accumulate mature stroma in cell culture. Method involves intravenously dropping mesenchyma stem cell culture in the amount of 50 to 500 mln in 50-100 ml of physiologic saline.

EFFECT: accelerated recovery of bone tissue; positive biochemical factors dynamics; improved patient locomotor activity.

6 cl

FIELD: medicine.

SUBSTANCE: method involves applying N-bisphosphonates like Zoledronic acid and its derivatives for prolonged inhibiting bone tissue resorption in states distinguished by increased bone tissue renewal like it occurs in osteoporosis cases by periodically administering the drug at a dose of 2 to 10 mg. Pauses between drug introductions have become longer when compared to periodicity considered to be required in earlier times, while being greater than 6 months.

EFFECT: enhanced effectiveness of treatment.

10 cl, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: the present innovation deals with rectal suppositories that contain biphosphonic acids and their pharmacologically acceptable salts applied for preventing and treating diseases caused by affected calcium and magnesium balance in the body. The suggested new suppositories contain 0.1-10 weight% xydiphone and 0.5-10 weight emulsifiers, the rest - the foundation for one suppository of 1.125-2.5 g weight. Rectal xydiphone-containing suppositories could additionally contain medicinal and/or biologically active supplements, for example 0.1-1.0 weight% trisodium salt of phosphonoformic acid as medicinal additive, and, also, biologically active additive chosen out of the group of vitamin B6, B12 or carbon dioxide solution of common camomile, olive oil. The innovation provides the chance to avoid some complications occurred at applying this preparation in known forms and, also, in some cases leads to its increased efficiency.

EFFECT: higher efficiency of application.

4 cl, 4 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: the present innovation deals with applying biphosphonate for treating osteonecrosis and/or osteonecrosis dissecans. This medicinal preparation could be additionally applied for preventing the development of osteonecrosis and/or osteonecrosis dissecans and any complications associated with both diseases. Biphosphonate acts for the decrease or prevention of severe degree of deformation and/or destruction of a bone or a cartilage and provides the chance to form new bony tissue in a patient.

EFFECT: higher efficiency of therapy.

38 cl, 7 dwg, 1 tbl

FIELD: medicine, pharmacy, pharmaceutical technology.

SUBSTANCE: invention relates to pharmaceutical compositions as tablets, namely, to a tablet preparing by direct pressing and comprising 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or its pharmaceutically acceptable salts as an active component taken in the amount from 5 to 140 mg as measured for a pure acid, an excipient, a dry binding agent, a disintegrating agent and a lubricating substance, and to a method for its preparing. As an excipient the claimed composition comprises the combination of at least two recipients but with exception of lactose, and it comprises 20-80 weight% of excipient chosen from group comprising microcrystalline or powder-like cellulose and calcium hydrophosphate, and 0.001-50 weight% of one or more recipients chosen from group comprising mannitol and phosphates or hydrophosphates of alkaline or alkaline-earth metals. As a disintegrating agent the composition comprises maize starch taken in the amount 7-15%. The content of lubricating agent is 1%.

EFFECT: improved preparing method of tablet.

3 cl, 19 tbl, 7 ex

FIELD: experimental medicine.

SUBSTANCE: on should introduce solution into fracture area at the following ratio of ingredients, g/l: 1-hydroxyethylidenediphosphonic acid 1.80 - 2.06, water-free calcium chloride 1.44 - 2.22, gadolinium (III) nitrate hexahydrate 0.30 - 0.40, dysprosium (III) chloride hexahydrate 0.038 - 0.076, moreover, solution's pH corresponds to 7.3 - 7.8. The present innovation enables to shorten the process of bony tissue regeneration in the site of its lesion or defect and, also, shorten the period for restoring normal physiological function of traumatized bone.

EFFECT: higher efficiency of regeneration.

22 ex, 1 tbl

The invention relates to new derivatives of anhydride methylenephosphonic acid of the formula I, where Y1, Y2, Y3and Y4group OR1, NR2R3, OCOR1, OCNR2R3, O(CO)OR1, O(SO2R1or OP(O)R2(OR3), where R1, R2and R3- H, C1-22alkyl, aryl, possibly substituted, or SiR3where R3- C1-C4alkyl, provided that at least one of the groups Y1, Y2, Y3and Y4other than the group OR1or NR2R3, Q1and Q2Is H, F, Cl, Br, I, methods of obtaining these new compounds as well as pharmaceutical preparations containing these new compounds

The invention relates to medicine, namely to pharmaceutical drugs ibandronate or its physiologically acceptable salts for oral administration, and is a drug for the treatment of hypercalcemia, osteoporosis, tumor osteolysis, Paget's disease
The invention relates to medicine

FIELD: experimental medicine.

SUBSTANCE: on should introduce solution into fracture area at the following ratio of ingredients, g/l: 1-hydroxyethylidenediphosphonic acid 1.80 - 2.06, water-free calcium chloride 1.44 - 2.22, gadolinium (III) nitrate hexahydrate 0.30 - 0.40, dysprosium (III) chloride hexahydrate 0.038 - 0.076, moreover, solution's pH corresponds to 7.3 - 7.8. The present innovation enables to shorten the process of bony tissue regeneration in the site of its lesion or defect and, also, shorten the period for restoring normal physiological function of traumatized bone.

EFFECT: higher efficiency of regeneration.

22 ex, 1 tbl

Up!