Method for treating the cases of brain, spinal cord and nerve injuries

FIELD: medicine.

SUBSTANCE: method involves applying composition based on receptor antagonist P substance and magnesium salt.

EFFECT: reduced hematoencephalic barrier permeability; reduced risk of vasogenic brain edema; prevented water accumulation in brain; smoothing consequences caused by reduced cognitive abilities.

23 cl, 2 dwg, 3 tbl

 

The technical field of the invention

The present invention relates to a method for the treatment of brain injuries, spinal cord and nerves. It refers also to the composition, particularly preferred embodiment of the method.

Brain damage lead to the development of motor deficits and deficits in cognitive ability that causes a serious disease survivors of brain injury. In addition, they are most often found in younger members of society. Consequently, damage to the brain leads to the most significant reduction in quality of life compared to any other painful process. Despite this, at present there is no effective treatment that provides relief for the effects of brain damage. In the present invention is proposed to use a method for the treatment of brain damage, which is a way of effective pharmacological intervention. Using experimental brain damage from medium to severe degree of severity is established that the application of this treatment significantly improves consequences associated with violations of both motor and cognitive processes, but also has a positive effect in the treatment of spinal cord mo the ha and nerves.

Background of invention

It is well known that brain damage leads to the development of neurological deficits by two mechanisms. The first one is related to the primary processes. They are specific to the moment of defeat and include mechanical processes, such as wound, tearing, stretching and compression of the nerve fibers. There is little that can be done with this type of damage after it has occurred. The second mechanism is a secondary injury, and it includes biochemical and physiological processes that are initiated by a primary lesion, but occur over time after injury. It was found that a large part of the disease after brain damage associated with the development of this secondary injury. Because secondary damage develops over a period of time from several minutes to several days after the initial injury, there is a period of time that is favorable to prevent this type of corruption and facilitation of its effects by pharmacological means. However, you must first determine the factors that contribute to secondary injury, and then to develop "antifaktorov", inhibiting the process of damage.

A study in the creation of the crust is asego of the invention, the identification of secondary factors damage after brain injury and the development of therapeutic intervention. One of the previously identified factors [1-4], which is crucial for overcoming the consequences of brain damage, is the concentration of magnesium ions in the brain. This ion is a regulatory factor in a number of biochemical and physiological processes, which are activated after brain damage. So, it was found that the decrease in the concentration of magnesium ions leads to an aggravation of the injury process, while increasing the concentration of magnesium ions weakens the process of damage and leads to the alleviation of the consequences [5]. It is established that the treatment of brain damage using magnesium is effective [1, 6-10] even with the introduction of up to 24 h after the time of injury and is a successful method of treatment that has been proven through studies on experimental animals and allowed to begin clinical trials in humans with brain damage.

Despite the relief of symptoms of deficits after brain damage by introducing magnesium clear that there are motor deficits and deficits in cognitive abilities, remaining after such treatment. In the claimed invention, first of all, the plot is was were the fact, that in younger animals, the water accumulation in the brain (i.e. cerebral edema or brain swelling) is retained after such treatment, and this may be an important risk factor. So, according to modern clinical research [11] slow brain swelling is the cause of death of 50% of young people from the total number of deaths due to brain damage.

Summary of the invention

Thus, the object of the invention is a method of treatment of a condition associated with brain damage, and the composition is intended for use according to the specified method.

The song, which is one of the objects of the invention contains a receptor antagonist of substance P and magisteriate connection, and the combined use of magnesium-containing compound and the receptor antagonist of the substance P leads to greater protection from damage than applying individually or magnesium-containing compounds, or antagonist of the receptor for substance P.

The method according to the invention provides for the stage of introduction of the composition to a patient suffering from brain damage. In an alternative embodiment, each of the components of the composition administered individually or through such a period of time after the damage, which as stated above,does not affect the effectiveness of the treatment, for example through 1-30 min and up to 24 hours

Substance P is a neurotransmitter excitation and plays a role in the transmission of pain, it is a peptide having the structure RPKPEEFFGLM-NH2. It is produced by the hypothalamus, Central nervous system and the intestines and increases the contraction of the smooth muscles of the gastrointestinal tract.

It is known that substance P binds to various receptors, including the receptor NK1 (i.e. receptor neirokinina 1), the receptor NK2 and NK3 receptor. These receptors are probably involved in the movement of blood in the brain.

Thus, the antagonist of the substance P is a substance that inhibits the binding of substance P with any of the above receptors. A list of acceptable antagonists of substance P are shown below in tables 1, 2 and 3.

As examples of antagonists of NK1 receptor can lead antagonists described in patent US 5990125, which is included in the present description by reference as specified therein antagonists of substance P can be used in compositions intended for use according to the method according to the invention. As specific examples may be mentioned compounds having a structure represented by formula Ia, Ib, Ic, Id, Ie, X, XVI, XVII, XVIII, XIX, XX and XXI, as well as other antagonists, which are derivatives of hinoklidina, piperidinylidene, pyrrolidin is and zaborney and related compounds, possessing activity of antagonists of substance P, which is described in column 33 of the patent US 5990125.

Such receptor antagonists can be used in the dosages indicated in column 34 of the patent US 5990125, and various forms of introduction, that individually or in combination with various pharmaceutically acceptable carriers or diluents by oral administration or parenteral administration, as indicated in column 34 of the patent US 5990125.

The activity of different substances as antagonists of the receptor for substance P, intended for use according to the invention, can also be identified using the assays described in columns 35-36 patent US 5990125.

As examples we can mention also the receptor antagonists of substance P, which is described in patent US 5977104, including various dosage forms and doses listed in this patent, which is also fully incorporated in the present description by reference.

You can mention the patent US 4481139, which describes various peptide antagonists, which is also fully incorporated in the present description by reference.

It should be understood also that the notion of "substance P" in the context of the present description also includes various shortened forms or analogs, as described in patent US 4481139, which is fully incorporated into the present description by reference.

In ka is este antagonists of the receptor for substance P, which can be used according to the present invention, mention should be made of different piperidine and morpholine derivatives described in patent US 4985896, or pieperazinove derivatives described in patent US 5981520. Both these publications are fully incorporated into the present description by reference.

As antagonists of receptors NK1 and NK2, which can be used according to the invention, it should be noted antagonists described in patent US 5998444, which cavity is incorporated into this description by reference.

Also worth mentioning is that the antagonists tachykinin described in patent US 4981744, can also be used as antagonists of the receptor for substance P, and this patent also a cavity included in the present description by reference.

Mention should also EP-A-1035115, fully incorporated into the present description by reference, which describes N-benzyl-4-carnicetine and related compounds as antagonists of the NK1 receptor, which can be used according to the present invention.

It should also mention the international patent application WO 00/50398, fully incorporated into the present description by reference, which describes various phenyl and pyridinoline derivatives as antagonists of the NK1 receptor, which can be used according to the present invention.

It should also mention the international patent applications WO 00/50401, WO 00/53572, WO 00/73278 and WO 00/73279, fully incorporated into the present description by reference, which describes 3-phenylpyridine, biphenylene derivatives, 5-phenylpyrimidine derivatives and 4-phenylpyrimidine derivatives, respectively. These descriptions apply to the NK1 receptor antagonists that can be used according to the present invention.

Mention should also be the directory company Sigma 1998, and more specifically pages 1194-1997, where the described embodiment, the substance P or fragments of substance P, which can be used as antagonists of substance P in accordance with the present invention. This publication is also fully incorporated in the present description by reference.

As for the magnesium-containing compounds, it may be any source of ions of magnesium, such as magnesium chloride, magnesium sulfate, magnesium oxalate, magnesium gluconate, or other non-toxic salt of magnesium.

Pharmaceutically composition according to the invention can also contain preservatives, soljubilizatory, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, corrigentov, salts for modifying the osmotic pressure, buffers, masking agents or antioxidants. They may also contain other therapeutically acceptable substance. That is, the term "comprising" should be interpreted in the context of the present description. The dose can vary within wide limits and, of course, can be fitted to the individual requirements in each particular case. In General, dosage is from 1 to 20000 mg per patient, preferably from 10 to 5000 mg, and most preferably it should contain from 50 to 2000 mg of the antagonist of the receptor for substance P.

When creating the present invention, it was found that one of the reasons for high level of water accumulation in the brain after damage is the formation of patogennogo edema. This is the result of increased permeability of the blood-brain barrier, which allows vascular proteins and water to penetrate into the extracellular space and cause swelling. Only few studies evaluated the relationship between increased permeability of the blood-brain barrier and the development of neurological deficits after damage, but no data on whether the inhibition of swelling in the brain to overcome the consequences of the damage. The study of migraine [12, 13] suggest that the vascular network of the Dura (the outer meningeal layer) becomes more permeable to vascular components in the result of the release of substance P. Here is the second of the present invention put forward a hypothesis about that substance P may have a similar effect on the cerebral vasculature, and this exposure may lead to increased permeability of the blood-brain barrier and wuthenau cerebral edema. Also it has been hypothesized that the introduction of the receptor antagonist of the substance P may prevent brain swelling and the development of delayed neurological deficits after damage. This hypothesis led to the above discovery of the fact that the water accumulated in the brain, is the result of education patogennogo edema.

Thus, another object of the invention is the use of an antagonist of the receptor for substance P for reducing the permeability of the blood-brain barrier and/or patogennogo cerebral edema.

Experimental part

A large number of synthesized with a commercial purpose antagonists of the receptor for substance P, are presented in tables 1, 2 and 3, currently available from known suppliers of research chemicals. For the application you have chosen this connection, as N-acetyl-L-tryptophan, on the basis of its low solubility in fats and ability in vivo to penetrate the blood-brain barrier, and in view of its relatively low cost. Introduction N-acetyl-L-tryptophan DNAs is rivanna in dosage of 246 mg/kg (media - saline) 30 min after brain damage has resulted in significant alleviation of the consequences associated with deficits in cognitive abilities in animals with brain damage in the evaluation with the aid of a ring Barnes maze. Similarly found significant relief of impacts associated with motor deficit, which was installed using the Rotarod test. These facilitation effects were detected 24 h after brain damage, and they remained within the 14 day period of observation. The control (treated with carrier) animals found significantly more serious neurological consequences compared to treated animals in all studied time points.

In animals treated with N-acetyl-L-tryptophan significantly decreased the accumulation of water in the brain (i.e. cerebral edema) within 24 h after injury compared with the processed media control animals. This is consistent with evidence that N-acetyl-L-tryptophan reduced penetration into the brain of the dye Evans blue after 5 h after injury, i.e. in the time period, which is characterized by the maximum permeability of the blood-brain barrier after brain damage. Thus, the introduction of N-acetyl-L-tryptophan che is ez 30 min after brain damage resulted in lowering the blood-brain barrier permeability and reduction in the formation of patogennogo edema. The fact that these phenomena were observed when the composition of the NK1 antagonist, do not possess the ability to penetrate, suggests that these phenomena are mainly mediated by vascular receptors and do not depend on Central receptors.

Introduction N-acetyl-L-tryptophan dose of 24.6 mg/kg also significantly improved the consequence associated with impaired cognitive abilities in animals with brain damage. However, the drug had a less pronounced positive effect on overcoming disturbances in motor function. In addition, as always in all treated animals remained residual motor deficit and the deficit of cognitive abilities, it was concluded that the positive effects of treatment with the NK1 antagonist was shown to a lesser degree if the damage is moderate than the more serious the damage. This is the main limiting factor, since the head injury of medium gravity are most often found in patients with brain damage.

The combination of magnesium and N-acetyl-L-tryptophan

The most common form of brain injury is a head injury of medium gravity. According to the guidelines which must be entered in the next (2000) world Federation is her neurosurgeons, recommended in all cases of minor head injury involving any complications, such as vomiting, nausea, loss of consciousness or amnesia, be sure to refer patients to the hospital. This requires the health system to develop an appropriate treatment of these patients, which would inhibit the further development of secondary damage. Currently, this therapy is not available.

The results obtained using N-acetyl-L-tryptophan suggest that this connection closes the blood-brain barrier after a head injury and reduces the swelling of the brain or cerebral edema. This is especially important for young victims who received head injuries, which are particularly vulnerable to the slowdown of the brain swelling. In addition, the results obtained by treatment using magnesium suggest that treatment with magnesium effective in reducing neurological deficits, not necessarily related to increased permeability of the blood-brain barrier. Thus, in the present invention proposed combination containing receptor antagonist of substance P and magisteriate compound or its salt, which can be effective for the treatment of brain damage, independently researched the mo its severity.

The introduction of combination, containing 246 mg/kg N-acetyl-L-tryptophan plus 30 mg/kg magnesium sulphate (intravenous), led to a pronounced softening as motor deficits, and deficits in cognitive abilities, greatly exceeding any of these drugs individually (figure 1 and figure 2).

Each connection in the combined composition has several properties that make it especially valuable agent for use in brain damage.

Found that antagonists of substance P (SP) just improve mood, exerting an antagonistic effect on caused by substance P anxiety. As a result, they have efficacy for treatment of depression after the injury. From the foregoing it is clear that the SP antagonists reduce the permeability of the blood-brain barrier and inhibit the formation of patogennogo edema and swelling of the brain or cerebral edema after injury. Found that antagonists can inhibit pain. A large number of receptors substance P is present in the hippocampus and striatum, i.e. in those parts of the brain that are known to be associated with learning and memory. Thus, by inhibiting binding of SP antagonists can be prevented caused by substance P induction of Def is the CIT learning ability and memory. The data above suggest that this may occur in this case. This fact has never been installed. In fact, the literature on the role of substance P or any other neuropeptides in the brain damage is absent.

Magnesium has an effect on more than 300 cellular enzymes. So it is not surprising that magnesium has numerous targets, through which he can improve damage. They include, among others, the blockade induced by glutamate of excitotoxicity, improving the stability of the membranes and reduce the production of reactive species of oxygen, improving energy status, inhibition of calcium channels, reducing the release of neurotransmitters, inhibition of the mitochondrial transition open the pores and inhibition of apoptosis. In addition, magnesium also inhibits induced glutamate release substance P. using physiological experiments [14-17]that magnesium improves cerebral blood flow, reduces cerebral vasospasm and reduces the production of vessels ceramide and prostaglandin.

The combined use of magnesium and antagonist of the substance P leads to a more pronounced protect nerves from damage than using any drug on on is alone.

Previously, applicants have found that magnesium has a beneficial effect when the injury when administered intravenously in doses of from 16 to 60 mg/kg In the introduction using intramuscular injection of an effective dose of from 45 to 90 mg/kg Goal is to increase the concentration of free magnesium in the blood to about 1.0 mm, which is two times higher than the normal blood concentration of free magnesium. Positive results were obtained regardless of the applied magnesium salt.

Studies using antagonist of the substance P showed that the effective intravenous dose varies from 24,6 to 240,6 mg/kg or higher, while higher doses have a greater beneficial effect on the consequence associated with motor deficit. In addition, these doses are suitable for antagonists, which have low solubility in lipids and therefore limited penetration across the blood-brain barrier. The composition having high solubility in lipids, can have absolutely these favorable effects, but it may also mediate the side effects that may be undesirable.

When used in combination in the composition can range specified range of the individual components. In the claimed invention, the best the results were obtained using the maximum intravenous dose specified for the individual components.

It is expected that the combination of magnesium/SP antagonists can be used in the following conditions:

- as a preventive treatment in the form of "first aid" after traumatic brain damage,

- as a preventive treatment in the form of "first aid" after a weak head injuries, including concussion,

as treatment effects nontraumatic brain injuries, including stroke, hypoxia, and any form of brain damage, accompanied by edema,

as maintenance therapy after brain damage.

LINKS

1. Vink R., Mclntosh BECAUSE, Demediuk P., Weiner M.W., Faden, A.I.: Decline in intracellular free magnesium concentration is associated with irreversible tissue injury following brain trauma. J. Biol. Chem., 263: 757-761, 1988.

2. Vink R., Heath D.L., Mclntosh AS: Acute and prolonged alteration in brain free magnesium following fluid percussion induced brain trauma in rats. J. Nurochem. 66:2477-2483, 1996.

3. Heath L., Vink R.: Brain intracellular free magnesium concentration declines following impact-acceleration induced brain injury in rats. Neurosci. Res. Commun., 18: 163-168, 1996.

4. Heath L., Vink R: Traumatic brain axonal injury produces sustained decline in intracellular free magnesium concentration. Brain Research, 738: 150-153, 1996.

5. Mclntosh BECAUSE, Faden, A.I., Yamakami I, Vink R: Magnesium deficiency = MKD exacerbates and pretreatment improves outcome following traumatic brain injury in rats:31P magnetic resonance spectroscopy and behavioural studies. J. Neurotrauma 5:17-31, 1988.

6. Vink R., Mclntosh AS: Pharmacological and physiological effects of magnesium on experimental traumatic brain injury. Magnesium Res. 3: 163-169,1990.

7. Heath L., Vink R.: Magnesium sulphate improves neurologic outcome following severe closed head injury in rats. Neuroscience Letters 228: 175-178, 1997.

8. Heath L., Vink R.: Neuroprotective effects of MgSO4and MgCl2in closed head injury: a comparative phosphorus NMR study. J. Neurotrauma 15: 183-189, 1998.

9. Heath L., Vink R.: Delayed therapy with magnesium up to 24 hours following traumatic brain injury improves motor outcome. J. Neurosurg. 90: 504-509, 1999.

10. Heath L., Vink R.: Optimisation of magnesium therapy following sever diffuse axonal brain injury in rats. J. Pharmacol. Exp. Ther. 288: 1311-1316, 1999.

11. Feickert H.G., Drommer, S., Heyer, R.: Severe head injury in children: impact of risk factors. J Trauma 47: 33-38, 1999.

12. Moskowitz M.A.: The neurobiology of vascular head pain. Ann. Neurol. 16: 157-168, 1984.

13. Ferrari M.D.: Migraine. Lancet 351: 1043-1052, 1998.

14. B.T. Altura, Altura B.M.: The role of magnesium in the etiology of strokes and cerebrovasoxpasm. Magnesium 1: 277-291, 1982.

15. Farado M., Szabo, S., Dora E., Horvath I., Kovach A.G.B.: Contractile and endothelium-dependent dilatory responses of cerebral arteries at various increasing interest among magnesium concentration. J. Cereb. Blood Flow Metab. 11: 161-164, 1991.

16. Kemp P.A., S.M. Gardiner, March J.E., Rubin P.C., Bennett T.: Assessment of the effects of endothelin-1 and magnesium sulphate on regional blood flows in conscious rats. Br. J. Parmacol. 126: 621-626, 1999.

17. Morril M.A., Gupta R.K., Kostellow A.B., M. Gy, Zhang, A., B.T. Altura, Altura B.M.: Mg2+ modulates membrane sphingolipid and lipid second messenger levels in vascular smooth muscle cells. FEBS Lett., 167-171, 1998.

Table 2
Antagonists of NK2 receptor
Chemical codeChemical name
SR-48,968(S)-N-methyl-N-[4-(4-acetylamino-4-(phenylpiperidine)-2-(3,4-dichlorophenyl)butyl]benzamide
L-659877Cyclo[Gln, Trp, Phe, Gly, Leu, Met]
MEN 10627Cyclo(Met-Asp-Trp-Phe-Dap-Leu)cyclo(beta-beta)
SR-144190(R)-3-(1-[2-(4-benzoyl-2-(3,4-differenl)morpholine-2-yl)ethyl]-4-phenylpiperidine-4-yl)-1-dimethyloxetane
GR 94800PhCO-Ala-Ala-D-Trp-Phe-D-Pro-Pro-Nle-NH2

Table 3
The NK3 receptor antagonists
Chemical codeChemical name
SR-142,801(S)-N-(1-(3-(1-benzoyl-3-(3,4-dichlorophenyl)piperidine-3-yl)propyl)-4-phenylpiperidine-4-yl)-N-methylacetamide
R 8203-indolocarbazole-Hup-Phg-N(Me)-Bzl
R 486H-Asp-Ser-Phe-Trp-β-Ala-Leu-Met-NH2
SB 222200(S)-(-)-N(a-ethylbenzyl)-3-methyl-2-phenylindolin-4-carboxamid
L 758, 298phosphonic acid, [3-[[2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-forfinal)-4-morpholinyl]methyl]-2,5-dihydro-5-oxo-1H-1,2,4-triazole-1-yl]-, [2R-[2α(R*), 3α]]-
NK-608(2R,4S)-N-[1-{3,5-bis(trifluoromethyl)benzoyl}-2-(4-Chlorobenzyl)-4-piperidinyl]quinoline-4-carboxamide

1. nacirema composition for the treatment of brain damage, the spinal cord and nerves, containing a therapeutically effective amount of a receptor antagonist of substance P and salt of magnesium in amount sufficient to increase the concentration of free magnesium in the blood up to about 1.0 mm.

2. Injectable composition according to claim 1, where the combined use of an antagonist of the receptor for substance P and magnesium leads to greater protection from damage than the individual application of the receptor antagonist of the substance P and magnesium salt.

3. The composition according to claim 1 or 2, where the receptor antagonist of the substance P is an antagonist of the NK1 receptor.

4. The composition according to claim 3, where the NK1 receptor antagonist is chosen from the group comprising CGP49823, CP-96,345, SR,994, CP-122,721, FK88, GR203040, GR205171, GR82334, GR94800, HSP-117, L-703,606 oxalate, L-732,138, L-733060, L-742,694, L-745,030, L-668,169, LY-303241, LY-303870, LY306740, MEN-11149, MK-869, PD-154075, R-544, RP-67580, RPR100893, Candid, Spantide II, Spantide III, SR140333, WIN-41,7098, WIN 62,577.

5. Composition according to any one of claims 1 to 4, wherein the receptor antagonist of the substance P is a NK2 receptor antagonist.

6. The composition according to claim 5, where receptor antagonist R is chosen from the group comprising SR-48968, L-659877, GR103637, MGN-10627, SR144190 and GR94800.

7. The composition according to claim 1 or 2, where the receptor antagonist of the substance P is a NK3 receptor antagonist.

8. The composition according to claim 7, where receptor antagonist R is chosen from the group comprising SR-143,801, R820, R486, SB222200, L758,298 and NKP608.

9. the song according to any one of claims 1 to 8, where the magnesium salt selected from the group including magnesium chloride, magnesium sulfate, magnesium oxalate, magnesium gluconate, or other non-toxic salt of magnesium.

10. Composition according to any one of claims 1 to 9, where a therapeutically effective amount of an antagonist of the receptor for substance P is 1-20000 mg.

11. Composition according to any one of claims 1 to 9, where a therapeutically effective amount of an antagonist of the receptor for substance P is 10-5000 mg

12. Composition according to any one of claims 1 to 9, where a therapeutically effective amount of an antagonist of the receptor for substance P is 50-2000 mg

13. A method for the treatment of brain damage, spinal cord and nerves by injection to a patient suffering such damage, a therapeutically effective amount of an antagonist of the receptor for substance P and magnesium salts in a quantity sufficient to increase the concentration of free magnesium in the blood up to about 1.0 mm, separately or in the form of a composition according to claims 1-12.

14. The method according to item 13, where the damage caused by injury, rupture, elongation and compression of the nerve fibers.

15. The method of reducing the permeability of the blood-brain barrier by introducing a patient in need of such reduction, the composition of claims 1 to 12.

16. The way to reduce education patogennogo edema by introducing a patient suffering from such a swelling composition according to claims 1-12.

17. The method according to clause 16 where vasogenic edema is vasogenic cerebral edema.

18. The way to prevent a high level of water accumulation in the brain after damage by introducing a patient in need of such prevention, the composition according to claims 1-12.

19. Method of facilitating the consequences associated with impaired cognitive abilities after brain damage, by introducing a patient suffering from such a violation, the composition according to claims 1-12.

20. Notification method called substance P deficits in learning and memory after brain damage by introducing a patient in need of such prevention, the composition according to claims 1-12.

21. Method of facilitating the consequences associated with impaired motor and cognitive abilities after brain damage from medium to serious gravity by introducing a patient suffering from such a violation, the composition according to claims 1-12.

22. The method according to any of PP-21, where the receptor antagonist of the substance P has low solubility in lipids.

23. The method according to any of PP-21, where the receptor antagonist of the substance P is specified in p-8.



 

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SUBSTANCE: compositions against headache, migraine, sickness, and retch contain S-alkylisothiouronium. Disclosed are method for production of drug and treatment methods.

EFFECT: pharmaceutical composition of improved effectiveness.

48 cl, 3 tbl, 4 ex

FIELD: pharmacy.

SUBSTANCE: invention proposes pharmaceutical compositions consisting of multiple particles with sustained-release of serotonin reuptake selective inhibitor (SRSI) with membrane cover comprising ammonium-methacrylate copolymer, or compositions comprising SRSI particles mixture, or compositions comprising SRSI particles mixture in form of sustained-release of SRSI, Also, invention relates to method for treatment of depression involving administration of these compositions. In particular, SRSI represents fluoxetine, fluvoxamine, sertraline or their salt. Proposed compositions provide a less index of fluctuations that reflects lower values of maximal concentrations of substance in plasma blood after multiple administrations, safety and good tolerance also.

EFFECT: improved medicinal and pharmaceutical properties of compositions.

11 cl, 5 dwg, 26 tbl, 6 ex

FIELD: pharmacy.

SUBSTANCE: invention proposes pharmaceutical compositions consisting of multiple particles with sustained-release of serotonin reuptake selective inhibitor (SRSI) with membrane cover comprising ammonium-methacrylate copolymer, or compositions comprising SRSI particles mixture, or compositions comprising SRSI particles mixture in form of sustained-release of SRSI, Also, invention relates to method for treatment of depression involving administration of these compositions. In particular, SRSI represents fluoxetine, fluvoxamine, sertraline or their salt. Proposed compositions provide a less index of fluctuations that reflects lower values of maximal concentrations of substance in plasma blood after multiple administrations, safety and good tolerance also.

EFFECT: improved medicinal and pharmaceutical properties of compositions.

11 cl, 5 dwg, 26 tbl, 6 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention proposes a pharmaceutical preparation based on angiotensin-converting enzyme inhibitor, its using in prophylaxis of insult, diabetes and/or congestive cardiac insufficiency and corresponding methods for its using in patient with maintenance heart function and subjected for risk of cardiovascular attack due to previous history of ischemic disease, insult or peripheral arterial disease. In particular, inhibitor of angiotensin-converting enzyme can be chosen from ramipril, ramiprilat, lisinopril, enalapril and enalaprilat. Invention promotes to reducing the total lethality of patients group in case of cardiovascular diseases, cardiac attacks and insults, the necessity for carrying out procedures for revascularization (such as surgery operation for coronary shunt, angioplasty with using balloon and so on) and diabetic complication are diminished.

EFFECT: improved and valuable medicinal properties of preparations.

19 cl, 1 ex

FIELD: medicine.

SUBSTANCE: method involves introducing solutions into articulation to inhibit cartilage destruction. The solutions contain: (a) therapeutically effective amount of anabolic chondroprotective agent selected from a group composed of interleukine antagonists stimulating anabolic processes in cartilage, members of superfamily transforming growth β-factor including TGF-β agonists and agonists of morphogenous bone proteins stimulating anabolic processes in cartilage, insulin-like fibroblast growth factors stimulating anabolic processes in cartilage; (b) therapeutically effective amount of a cartilage catabolism inhibitor selected from a group composed of antagonists of interleukine-1-receptors, antagonists of TGF-α-receptors, specific cyclo-oxygenase-2 inhibitors, nitrogen oxide synthase inhibitors, nuclear kB factor inhibitors, matrix metalloproteinase inhibitors, cell adhesion molecules including integrin agonists and integrin antagonists, anti-chemotaxis agents, intracellular signal transmission inhibitors including protein kinase C inhibitors and tyrosine protein kinase inhibitors, intracellular (protein-tyrosine)-phosphatases and SH2-domain inhibitors inhibiting cartilage catabolism. The solution is locally supplied.

EFFECT: stimulated integration and modulation of anti-inflammatory synoviocyte and chondrocyte responses.

54 cl, 9 dwg, 30 tbl

FIELD: medicine.

SUBSTANCE: invention proposes a method for inhibition of chorionic neovascularization. Method involves irradiation of undesirable novel vascular reticulum in combination with photosensitive agent (porphyrine) and an anti-angiogenic agent taken among antagonist of phospholipase A2, inhibitor of complex kappa B, inhibitor of the growth hormone, inhibitor of insulin-like growth factor-1, inhibitor of cyclooxygenase II, inhibitor of protein kinase C (stautosporin PKC 412) and inhibitor of angiotensin II. The claimed combined treatment provides potentiation of effect of adjunctive photodynamic therapy in combination with enhanced safety.

EFFECT: improved treatment method.

7 cl

Nutrient module // 2268069

FIELD: medicine.

SUBSTANCE: method involves adding to patient food one or several compositions via closed system in module form containing nutrient substances selected and adapted to given clinical state. The modules are most kept in dry form.

EFFECT: enhanced effectiveness in preparing patient food; avoided contamination with microorganisms; enhanced effectiveness in treating and feeding patients.

20 cl

FIELD: medicine.

SUBSTANCE: method involves administering a combination of an agent reducing cholesterol content in blood and reduced coenzyme Q10 of general formula .

EFFECT: enhanced effectiveness of treatment.

8 cl, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: the present innovation deals with pharmaceutical preparations for treating wounds and/or infections of human or animal internal organs being sensitive to injection of such agents. The preparation suggested is being a liposome including, at least, one antiphlogistic agent chosen out of antiseptics group that represent compounds producing oxygen or halogen, metal compounds, such as compounds of silver or mercury, organic disinfecting substances including compounds producing formaldehyde, alcohols, phenols, including alkyl- and arylphenols, and, also, halogenated phecols, quinolines and acridines, hexahydropyrimidine, quaternary ammonium compounds and iminic salts and guanidines, or its combination with, at least, one agent that stimulates wound healing chosen out of agents stimulating granulation and epithelization, such as dexpanthenol, allantoins, azulenes, tannins, compounds of vitamin B row or agents of similar action. The innovation enables to obtain highly tolerant, easily introduced preparation that provides prolonged removal and prolonged local effect of the action of active agent inside the body due to interaction with cell surface.

EFFECT: higher efficiency.

12 cl, 3 ex, 1 tbl

FIELD: medicine, pharmacy.

SUBSTANCE: invention proposes implant prepared by mixing a carrier material with components of the preparation antibiotic/antibiotics with delayed release of an active substance (aminoglycoside, lincosamide antibiotics, 4-quinolone antibiotics and tetracyclines), and a method for preparing the implant. Release of an active substance from implant during from some days to some weeks doesn't dependent from a carrier material and adsorption effects of a carrier-material surface.

EFFECT: improved and valuable properties of preparation.

13 cl, 1 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: the present innovation deals with composition for fertilization in vitro and the system for its delivering (device). The composition suggested contains steroid at the quantity of below 5% (weight/weight), that is: 4.4-dimethyl-5α-cholesta-8.14.24-trien-3β-ol, hemisuccinate of 4.4-dimethyl-5α-cholest-8.14.24-trien-3β-ol; 5α-cholest-8.14-dien-3β-ol; hemisuccinate of 5α-cholest-8.14-dien-3β-ol; (20S)-cholest-5-en-3, 20-diol; N-(methionine)amide of 3β-hydroxy-4.4-dimethyl-5α-chol-8.14-dien-24-oic acid or cholest-5-en-16β-ol, and, also, additive (water-soluble protein or phosphoglyceride). Delivering system has got either one foramen or one cavity that contains the composition mentioned as a solid product or solution. The composition of sterols contains no constituents negatively affecting oocytes and could be dissolved in aqueous medium without physical impact (that is, heating, mixing or ultrasound treatment).

EFFECT: higher efficiency of fertilization in vitro.

8 cl, 5 ex, 3 tbl

FIELD: medicine, narcology, pharmacy.

SUBSTANCE: invention proposes applying the following agonists of gamma-aminobutyric acid receptors of B-type: β-(4-chlorophenyl)-GABA (Baclofen), 3-aminopropyl(methyl)-phosphinic acid, 3-aminopropylphosphinic acid, Y-amino-β-4-(4-chlorophenyl)-nitropropane or their salts, esters, ethers, complexes and their corresponding isomers used in treatment of nicotine dependence. Invention provides the selective suppression of smoking addiction and effect on behavior indices causing the abuse relapse and with absence of symptoms typical in nicotine dependence.

EFFECT: valuable properties of compounds.

9 cl

FIELD: medicine, ophthalmology, pediatrics.

SUBSTANCE: method involves apparatus treatment for 10 days with preliminary intramuscular administration of neuropeptide cortexin in the dose 5-10 mg, 10 injections. During apparatus treatment nootropic agent semax is administrated by intranasal route as instillations in the dose 1-2 drops, 2-3 times per 24 h for 10 days. Method provides improving eye memory, increasing rate in delivery and processing the eye information and the prolonged memory concentration necessary for effective apparatus method of treatment. Invention can be used in treatment of amblyopia in children with delayed intellectual development.

EFFECT: improved treatment method.

1 tbl, 2 ex

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