Method of treating multiple sclerosis
SUBSTANCE: invention refers to medicine, namely to neurology, and can be used in treating the patients with multiple sclerosis. That is ensured by infusion of rituximab in a dose 1 g followed by introduction of mitoxantrone in a dose 20 mg and another infusion of rituximab in a dose 1 g 13-15 days later. A common preanaesthetic medication precedes infusion of rituximab.
EFFECT: method ensures fast therapeutic effect and prolonged remission in all forms of multiple sclerosis without a concomitant therapy, including chemotherapy.
1 ex, 11 dwg
The invention relates to medicine, namely, neurology, and can be used in the treatment of patients with multiple sclerosis, as well as in the treatment of other neurological diseases, the pathogenesis of which the leading place of autoimmune and inflammatory response.
Multiple sclerosis (PC) is a chronic inflammatory demyelinizing disease of the Central nervous system, which in view of its prevalence (50 cases / 100 thousand population) and a primary lesion of persons of working age has important medical and social importance. Today, the PC seems to be multifactorial disease, the leading pathogenetic mechanism which underlying inflammation, is an autoimmune process. Numerous evidence of autoimmune nature of PC obtained in a series of experimental and clinical works.
For a long time the main role in the pathogenesis of PC was attached to CD4 T-lymphocytes and cells of the monocyte-macrophage origin, but over time has accumulated a lot of facts pointing to an important role In cellular immunity in the initiation and maintenance of inflammatory process in the PC.
In animal models it was shown by a group of American researchers who have demonstrated that allergic encephalomyelitis cannot play back the of if after a preliminary Deplete b-cells [Myers, K.J., Sprent J., Dougherty, J.P., and Ron Y. Synergy between encephalitogenic T cells and myelin basic protein-specific antibodies in the induction of experimental autoimmune encephalomyelitis. J. Neuroimmunol., 1992. 41(1): p.1-8].
In humans, the role of humoral immunity in the pathogenesis of PC convincingly proved by the detection of oligoclonal bands of immunoglobulins (oligoclonal bands) and increased intrathecal synthesis of major classes of immunoglobulins: IgG, IgA, IgM and IgD [E.J. Thompson, P. Kaufmann, Shortman R.C., Rudge P. and McDonald W.I. Oligoclonal immunoglobulins and plasma cells in spinal fluid of patients with multiple sclerosis. Br Med J 1979. 1(6155): p.16-7]. Presents data on the existence of positive correlative relationship between the number of oligoclonal bands in the cerebrospinal fluid and the rate of progression of PC [Avasarala J.R., Cross, A.H., and Trotter J.L. Oligoclonal band number as a marker for prognosis in multiple sclerosis. Arch. Neurol. 2001. 58(12): p.2044-5].
The role of b cells in PC can be seen in the following:
1. Presentation of antigens.
2. Involved in the activation of T cells.
3. The production of proinflammatory cytokines.
4. The production of autoantibodies.
Thus, at the present time when PC there are substantial grounds for believing In cells one of the key participants in the process of inflammation and therefore a potential target for therapeutic intervention.
There is a method of treatment of PC, which consists in the appointment of mitoxantrone in a single dose of 12 mg/m2(included in the standard therapy PC), the maximum recommended cumulative dosese 24 months of therapy 140 mg [O. Neuhaus, Wiendl H., Kieseier BC, Archelos J.J., Hemmer Century, Stuve O. and Hartung, H.P., Multiple sclerosis: Mitoxantrone promotes differential effects on immunocompetent cells in vitro. J. Neuroimmunol., 2005. 168(1-2): p.128-37].
The disadvantages of this method are:
1. The duration of therapy is limited by the limit on the cumulative dose of 140 mg (24 months).
2. The risk of cytotoxic complications: infection, carcinogenesis!
3. Cardiotoxic effect, determined by cumulative dose of the drug.
4. Naturally there are relapses or disease progression after completion of the course of this therapy
There is a method of treatment of PC, which is to assign rituximab in the standard dose of 375 mg/m2four times with an interval of a week [Cross A.H., J.L. Stark, J. Lauber, Ramsbottom M.J. and J.A. Lyons Rituximab reduces In cells and T cells in cerebrospinal fluid of multiple sclerosis patients. J. Neuroimmunol., 2006. 180(1-2): p.63-70].
When assessing the dynamics of the content In the cells of the liquor through 24 weeks after therapy the majority of patients it was about a considerable reduction in the number of b cells, however, the full depletion was not reached.
There is also known a method for the treatment of PC, consisting in the use of higher doses of rituximab (1 g intravenous (IV) with an interval of 14 days) in order to achieve higher concentrations of the drug for the blood-brain barrier. Currently, this approach was successfully used in the framework of clincheck the th research the second phase of the HERMES (Helping to Evaluate Rituxan in Relapsing-Remitting Multiple Sclerosis) and demonstrated good efficacy and tolerability. This method adopted by the authors for the prototype.
However, the disadvantages of the method are the following:
1. Despite the high single dose of rituximab, is not achieved In full-cell Deplete 24 weeks.
2. Described relapse after a course of this treatment.
3. Saving signs of disease activity according to some laboratory and immunological parameters.
4. According to preliminary data should be re-cycle anti-b cell therapy after 6 months.
The objective of the invention is to achieve rapid therapeutic effect and long-term remission (time without increasing disability on the EDSS scale and without exacerbations) due to complete In-cell Deplete continued for long periods of time, and changes in immunological parameters.
This technical result is achieved in that in the method for the treatment of PC, including the infusion of rituximab at a dose of 1 g with premedication, according to the invention after infusion of rituximab administered mitoxantrone at a dose of 20 mg; and after 13-15 days repeat the premedication and infusion of rituximab at a dose of 1 g
The use of a combination of rituximab and cytotoxic drug mitoxantrone in the treatment of PC from literary sources is not known.
Studies in 7 patients with PC, showed that the obtained effects from combination therapy does not t yaytsa the sum of the effects as:
1. Complete b-cell depletion, both in blood and in cerebrospinal fluid was not achieved and was not supported for so long (48 weeks) when using rituximab as monotherapy. And the use of even higher doses of mitoxantrone or more frequent courses was not called In-cell Deplete at all.
2. Received prolonged b-cell depletion, both in blood and in cerebrospinal fluid, lasted for more than 24 weeks in all 7 patients, which showed a high degree of confidence.
3. The resulting changes in immunological parameters that have not been previously received under any existing treatment method PC (both in monotherapy and in combination):
a clear decrease in the number of oligoclonal bands of IgG in the CSF;
- rapid therapeutic effect of treatment: the decrease in EDSS 2.5 points 10 days;
- maintaining EDSS level of 6.5 points without concomitant therapy for 48 weeks.
Re-introduction of rituximab after 13-15 days due to the restoration of cellular blood after agranulocytosis, was observed in all 7 patients treated, and maintaining the concentration of rituximab in blood and CSF.
The method is as follows.
Mix in a carefully calculated sequence of drugs that affect the immune system.
The regimen includes PR is medicatio before each introduction of rituximab:
1. Set of peripheral catheter in any cubital vein. Or it is possible to install a Central catheter.
2. Alternately introduces the following drugs in the following dosages.
- Paracetamol 1 g intravenously.
- Ranitidine 300 mg orally (in the mouth) for 35 minutes prior to the infusion of Rituximab.
- Diphenhydramine 20 mg intravenously for 33 minutes before the introduction of rituximab.
- Methylprednisolone 1000 mg in 250 ml of physiological solution (infusion within 30 minutes after an infusion pump).
3. Start infusion of rituximab at a dose of 1 gram through the infusion pump according to existing protocols. (Intravenously. The pre-concentrate is diluted in an infusion bottle (pack) sterile 0,9% aqueous solution of sodium chloride or 5% aqueous glucose solution to a concentration of 1-4 mg/ml; initial infusion rate during the first administration of a 50 mg/h with a gradual increase to 50 mg/h every 30 min (maximum speed of 400 mg/h); in the subsequent procedures, you can start with 100 mg/h and increase it to 100 mg/h every 30 min up to a maximum of 400 mg/h)).
4. Odansetron (Emeset) at a dose of 4 to 8 mg intravenously to relieve nausea or vomiting.
5. The introduction of mitoxantrone (and all of its existing analogues) in the dosage of 20 mg/drip. The solution of mitoxantrone 20 mg diluted in 200 ml of physical solution.
6. After 13-15 days (or pic the e edema agranulocytosis - the normalization of the clinical picture of blood) in turn introduces the following drugs in the following dosages.
- Paracetamol 1 g intravenously.
- Ranitidine 300 mg orally (in the mouth) (or Omeprazol 40 mg) in 35 minutes prior to the infusion of rituximab.
- Diphenhydramine 20 mg intravenously for 33 minutes before the introduction of rituximab.
- Methylprednisolone 1000 mg in 250 ml of physiological solution (infusion within 30 minutes after an infusion pump).
7. Start infusion of rituximab at a dose of 1 g in an infusion pump according to existing protocols. (Intravenously. The pre-concentrate is diluted in an infusion bottle (pack) sterile 0,9% aqueous solution of sodium chloride or 5% aqueous glucose solution to a concentration of 1-4 mg/ml; initial infusion rate during the first administration of a 50 mg/h with a gradual increase to 50 mg/h every 30 min (maximum speed of 400 mg/h); in the subsequent procedures, you can start with 100 mg/h and increase it to 100 mg/h every 30 min up to a maximum of 400 mg/h)).
The essence of the method is illustrated in figure 1-11.
Figure 1 - brain MRI 2005 in T2 and identified actively accumulating contrast (Gadovist®) T1 lesions.
Figure 2 - dynamics of EDSS and ongoing therapy.
Figure 3 brain MRI 2005 and 2008, Pd+T2.
4 is a brain MRI 2008, with the absence of contrast agent accumulation (Gadovist®) after conducting the military therapy.
5 is a immunophenotyping of peripheral blood cells 15.11.2007,
6 is a immunophenotyping of peripheral blood cells 16.05.2008,
Fig.7 - immunophenotyping of cells of the liquor 16.05.2008,
Fig - immunophenotyping of cells of the liquor. 15.11.2007,
Fig.9 - the dynamics of immunological indices on the background of therapy.
Figure 10 - the dynamics of IgG, IgM, IgA in serum.
11 - determination of oligoclonal IgG synthesis.
The method is illustrated by the following clinical example.
Example. Patient G., born in 1956 Caucasian race, does not smoke. In 1994, (38 years) underwent a retro-bulbar neuritis of the right, when the survey was identified slowing down impulses in the right optic nerve on visually evoked potentials (SGP), synthesis of oligoclonal IgG in the CSF, its absence in serum. On brain MRI over nine hyperintense lesions in T2-and two active focus, accumulate contrast - typical of multiple sclerosis. In neurological status: no focal symptoms. Was diagnosed with clinically isolated syndrome. Held pulse therapy with methylprednisolone: 3 g on the course with positive dynamics. A second clinical attack after 8 months: hemihypesthesia right, mild ataxia in his hand. Further, the average recurrence rate was 1 episodes the year. Therapy of acute exacerbations of 3 g of intravenous methylprednisolone. Anti-relapse therapy patient did not receive. By January 2005, the EDSS was 4.0 points. In the study by MRI were detected actively accumulate contrast (Gadovist®) T1 lesions. MRI from 2005 is presented in figure 1. He was appointed anti-relapse therapy with glatiramer acetate (Copaxone®) in the standard scheme 20 mg subcutaneously every day. During therapy was observed stabilization of the patient's condition, namely, the termination of relapses, stabilization EDSS at the level of 4.0 points. The excellent tolerability. Since October 2006 (1 year 10 months on treatment with glatiramer acetate) was noted to increase to EDSS 6.0 (2 points) by December 2006 Held pulse therapy of methylprednisolone in the standard dose without visible effect. Diagnosed with secondary-progredient form PC (ITRS). In connection with the progression of the disease, secondary inefficiency of glatiramer acetate with 17.01.2007, had started therapy with mitoxantrone 12 mg/m2every 3 months in combination with methylprednisolone 1 g intravenously. Copaxone is cancelled. Marked stabilization of conditions in the form of EDSS 6.0, without relapses. The good tolerability, without adverse events.
10.10.2007, the patient delivered at the Leningrad Regional Center of multiple sclerosis with the Central tetraparesis (hands up 2 points is in feet 0-1 score the dysfunction of pelvic organs by type of delay, the internuclear opthalmoplegia and coarse nystagmus) EDSS - 9.0. Fixed a severe exacerbation. MRI brain and spinal cord: identified spinal T2 lesion at the level of C3-C5 with signs of edema on T1, actively accumulating contrast (Gadovist®), typical PC. Started therapy with methylprednisolone 1 g daily intravenous No. 5 - without a clear positive dynamics. The dynamics of the disease the patient is presented in figure 2.
Given the severity of the disease, its deep and debilitating nature, resistance to standard therapy (save severe exacerbations in the background of the total dose of mitoxantrone 60 mg) after a consultation it was decided to conduct a concomitant immunosuppressive therapy. The patient signed the informed consent.
Was appointed: infusion of rituximab at a dose of 1 g with standard premedication, sequential intravenous odansetron at a dose of 6 mg of mitoxantrone at a dose of 20 mg per 200 ml of physical solution and after 14 days of repeated sedation and infusion of rituximab at a dose of 1 g
Upon completion of the assigned treatment was evaluated in laboratory and clinical settings.
Neuroimaging was performed on the apparatus MRI 1.5 T (Magnetom Vision; Siemens AG, Germany ®). With Andrenyi Protocol scanning and contrast gadovist (Bayer Schering Pharma, Germany®)
Evaluation of laboratory parameters:
Peripheral blood (PC) and cerebrospinal fluid (CSF) was studied before, during and after therapy. PC got the standard method from a peripheral vein into a vacuum container. At the same time produced the fence CSF. Control points were 15.11.2007, (before therapy) and 16.05.2008, (24 weeks). Clinical analysis of blood in the interval between infusions of rituximab was carried out on a daily basis.
Typing of cell populations was performed by flow cytometry using 2 labels at baseline and after 6 months after therapy. Defined markers of T cells CD3+CD19-T-lymphocytes CD3+CD4+, cytotoxic T-lymphocytes CD3+CD8+the population of natural killer cells CD3-CD(16+56)+T-cells bearing activation markers CD3+HLA-DP+, T cells with immunoregulatory phenotype CD4+CD25+and b-lymphocytes - CD3-CD19+.
The study of humoral included: evaluation synthesis of oligoclonal IgG and light chains, according to standard methods (isoelectrofocusing proteins in CSF and serum by Western blot turns IgG), IgG, IgM, IgA in serum.
Also was estimated standard biochemical panel, urinalysis, ECG and ECHO-KG.
Clinical scales and neurophysiological method is:
EDSS, Multiple Sclerosis Functional Composite (MSFC) test was estimated by the standard method.
Visual evoked potentials (SGP) was performed according to standard methods: during stimulation reversing checkerboard pattern, the main potentials No. 75, R, No. 145.
Toxicity was assessed standard on a scale of toxicity CTC-NCIC criteria.
After the combination therapy received rapid therapeutic response. Was reduced EDSS from 9.0 to 6.5 points 10 days. During 48 weeks of stabilization continues EDSS at the level of 6.5 points, without further maintenance therapy (figure 2). Reduction of disease activity reflected on MRI in the form of a reduction of some lesions on T2 and the absence of active lesions. The data presented in figure 3, 4
Here the most interesting aspects of the functional and neurophysiological tests: MSFC test: PASAT-3 27 correct answers on 19.11.07,; 36 correct answers on 15.05.08,
VIZ: R(100) left = 143 MS (19.11.07 g); P(100) left = 135 MS (15.05.08 g); P(100) right = 138 MS (19.11.07 g); P(100) right = 126 MS (15.05.08 year). Considering the obtained data, we can cautiously assume the development process of remyelination.
Received a complete b-cell depletion in peripheral blood and cerebrospinal fluid after combined modality therapy, continuing for 24 weeks.
Data immunophenotyping of peripheral cells is Ravi and liquor are presented on figure 5-8.
Dynamics of immunological indices on the background of the treatment presented in Fig.9. Source-defined reduction subpopulation of cytotoxic T-lymphocytes, b-lymphocytes and the number of cells bearing a late activation marker, most likely reflects the impact of ongoing immunosuppressive drugs - mitoxantrone and pulse therapy with methylprednisolone. The increase in the number of immunoregulatory CD4+CD25+on the background of the progressive course of the disease in the peripheral blood in the absence of detectable quantities of them in the liquor in our opinion may reflect the inefficiency of the homeostatic mechanisms aimed at suppressing an autoimmune response.
As a result of therapy were observed persistent significant dynamics from first indicators of humoral immunity: by 6 months of therapy was documented achievement of full Deplete b-lymphocytes in peripheral blood and cerebrospinal fluid of the patient, accompanied by a decrease in serum IgG. To date, no clear quantitative criteria in the evaluation of oligoclonal IgG synthesis, but we noted an apparent decline in the number of bands in the CSF, Figure 10, 11. It should be noted that the level of total protein in the cerebrospinal fluid was unchanged at two points of the fence.
The staging was carried out Western blot turns us combine the time in both samples of biological material (CSF at baseline and after 24 weeks after depletio) on the same gel, allowing more accurately assess the dynamics of the content of oligoclonal circuits. It should be noted that due to the fact that Mature plasma cells producing IgG - do not carry the CD20 antigen and therefore are not the target of action of rituximab, this effect (reduction of IgG) we presumably due to the elimination within a specified period of time short-lived population data cells.
Dynamics of cellular immunity differently and harder to interpret. The decrease in the content of populations of T cells (in our case to undetectable values in the CSF was previously described in patients with PC, the last effective therapy with rituximab, and certainly should be considered as a positive fact. We assume that it reflects the importance of T-cell interactions in the pathogenesis of PC, and, in particular, to attract populations of T cells in the CNS. The increase in the number of CD3+CD8+cytotoxic T-lymphocytes and normalization of the number of cells T-lymphocytes bearing the late activation marker in the peripheral blood, in our opinion reflects the lack of formation of secondary immunodeficiency, partly perhaps due to the cancellation of mitoxantrone and glucocorticoids. Clinically, the patient also was not observed signs of the formation of immunodeficiency States (there were single episode of ARI for 6 months).
Eulalie effects and safety of therapy.
Toxicity was assessed standard CTC-NCIC CRITERIA.
The observation period was divided into 3 stages: 1) during infusion and after 24 hours; 2) 1-4 week; 3) 4-24 weeks.
For the first stage of observation was not recorded any adverse events. At the second stage: the decrease of white blood cells (wbc-2,8*109) on day 13. Without changing other parameters of blood. The development of neutropenia grade 4 wbc - 1,7*109; neutrophils - 0,2*109on day 16 after the first year. Toxicity of 4 degrees. The duration of agranulocytosis was 7 days. The patient was in Oncohematology Department, have taken all the necessary precautions. During the time spent in agranulocytosis no signs of infection and/or rise in body temperature. On the 25th day after the first course of therapy the clinical picture of blood has fully recovered. Colony-stimulating factors were not applied. From other organs and systems did not reveal any pathological changes.
In the third period, 18 week - documented acute respiratory disease with symptoms of catarrhal rhinitis. Without specific therapy, duration of 3 days.
Conducted a combined therapy allowed to reach clinical stabilization of the patient, despite high levels of resistance to all standard therapies.
On the clinical data example confirms the achievement of the technical result of the invention and its inventive step.
The proposed method has the following advantages:
1. The relief of inflammation and changes in the immune system and, consequently, reducing the number of exacerbations and/or reducing the progression of PC on the EDSS scale.
2. The change of the current PC.
3. Achieving long-term remission (time without increasing disability on the EDSS scale and without exacerbations).
A method of treating multiple sclerosis comprising the infusion of rituximab at a dose of 1 g with premedication, characterized in that after infusion of rituximab administered mitoxantrone at a dose of 20 mg, and after 13-15 days repeat the premedication and infusion of rituximab at a dose of 1,
SUBSTANCE: present invention relates to new compounds of formulae and , in which radicals and symbols assume values defined in the formula of invention, e.g. to 1H-indazoles, 1,2-benzisoxazoles and 1,2-benzisothiazoles. Said compounds are receptor ligands of the α-7 nAChR subtype. The invention also relates to a pharmaceutical composition containing the said compounds.
EFFECT: possibility of using the said compounds to make medicinal agents for treating diseases associated with impaired functioning of nicotinic acetylcholine receptors and their abnormal functioning, primarily in brain cells.
46 cl, 85 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: according to the invention, a pharmaceutical composition contains aripiprazole metabolite combined with serotonin reuptake inhibitor. Aripiprazole metabolite is chosen from dehyoaripiprazole DM-1458, DM-1451, DM-1452, DM-1454 or DCPP. Aripiprazole metabolite is a stabiliser of dopamine-serotonin system. Serotonin reuptake inhibitor can be fluoxetine, duloxetine, venlafaxine, milnaciprane, citalopram, fluvoxamine, paroxetin, sertraline or escitalopram and their salts. The pharmaceutical composition contains one weight part of said aripiprazole metabolite and 0.01 to 50 weight parts of said serotonin reuptake inhibitor. The pharmaceutical composition under the invention can be used for treating the patients with phrenopathies, particularly with depression or major depressive disorder.
EFFECT: pharmaceutical composition is effective and does not cause by-effects.
22 cl, 8 dwg, 3 tbl, 9 ex
SUBSTANCE: invention relates to medical agents and concerns a remedy in the form of an injection precursor product for obtaining liquid injectable composition, containing as agent for prevention and/or treatment of neurodegenerative diseases, nervous disorders or diseases requiring nerves regeneration the effective quantity of (2R)-2-propyloctane acid or salt thereof, and 1-5 equivalents of the basic ion of metal as per 1 equivalent of (2R)-2-propyloctane acid or salt thereof, metal salt selected from phosphoric acid metal salt, carbonic acid metal salt, and sulfurous acid metal salt and may optionally contain metal hydroxide as the source(s) of the basic metal ion.
EFFECT: development of the remedy which is resistant to pH fluctuations and does not grow turbid at solution.
21 cl, 3 dwg, 21 tbl, 22 ex
SUBSTANCE: invention relates to novel naphthalene derivatives of general formula I , as well as to their pharmaceutically acceptable salts, which can be used for treating and/or preventing diseases associated with H-3 receptor modulation. In formula I, R1 is selected from hydrogen, lower alkyl, phenyl, phenyl-lower alkyl and lower alkoxyalkyl; R2 is selected from hydrogen, lower alkyl, C3-C7-cycloalkyl, lower alkoxyalkyl or lower alkylsuphanylalkyl (all values of R1 and R2 are given in the formula of inventions); or R1 and R2 together with the nitrogen atom to which they are bonded form a 4-7-member saturated or partially unsaturated heterocyclic ring which can contain one more heteroatom selected from nitrogen, oxygen and sulphur atoms, where the said heterocyclic ring can be unsubstituted or substituted with 1-2 groups, or can be condensed with an unsubstituted phenyl ring; A is selected from (values of R3-R7, R9, R10, X, m, n, t, p, q and s are given in the formula of invention). Invention also pertains to a pharmaceutical composition containing formula I compounds.
EFFECT: increased effectiveness of application.
30 cl, 2 tbl, 188 ex
SUBSTANCE: therapeutically effective amount of a proteosome composition containing a preparation of outer membrane protein of gram-negative bacteria.
EFFECT: reduced amyloid deposit ensured by activated microglial phagocytosis without induction of neurotoxic effects.
17 cl, 9 dwg, 4 tbl, 1 ex
SUBSTANCE: invention relates to medicine, namely to neonatology, and can be used in treatment of newborns who are on ILV in critical state, conditioned by perinatal affection of central nervous system. For this purpose preliminarily rate of blood flow in vein of Galen is determined by dopplerography. If rate of blood flow decreases lower than 4 cm/s, inhalation with nitrogen oxide in concentration 15 ppm during 24 hours is carried out.
EFFECT: method allows to considerably reduce lethality of newborns in case of said pathology due to respiratory therapy with nitrogen oxide which is endothelial relaxing factor, and in case of introduction through inhalation - selective pulmonary vasodilatator.
SUBSTANCE: invention relates to compounds of formula (I) , where A, B represent C; D is selected from N; X is selected from -CRaRb-, -O-; Y is selected from O; Z1 and Z2 are independently selected from hydrogen, substituted or unsubstituted alkyl having 1-8 atoms, R1-R4 are independently selected from hydrogen or halogen; R5-R16 independently represent hydrogen; where Ra and Rb independently represent hydrogen; n equals 1-3; m equals 0 or 1, k equals 2; or to pharmaceutically acceptable salts or solvates of the said compounds. The invention also relates to a pharmaceutical composition based on the said compounds which inhibits butyrylcholin esterase (BuChE).
EFFECT: obtaining novel compounds and a pharmaceutical composition based on the said compounds, which can be used for treating or preventing cognitive disorders and/or neurodegenerative disorders.
10 cl, 1 tbl, 2 ex
SUBSTANCE: invention relates to novel pyrrolopyrimidine and pyrrolopyridine of general formula (I), substituted with a cyclic amino group (II), or their pharmaceutically acceptable salts having CRF antagonist properties. In general formula the cyclic amino group has formula , in which the cyclic amino group is a 6-member saturated cyclic amine, the said cyclic amine is substituted with a group of formula -(CH2)mX; in which X is -CO2H, -CONH2,-P(=O)(OH)2 or -S(=O)2OH; Y is N or CH; m is an integer selected from 1, 2 and 3; R4 is hydrogen; R5 is hydrogen; R6 is C1-5alkyl; R7 and R8 are identical or different and independently represent hydrogen, C1-5alkyl, Ar is phenyl which is unsubstituted or substituted with one or more substitutes which are identical or different and are selected from a group consisting of halogen, C1-5alkyl, C1-5alkoxy, C1-5alkylthio, trifluoromethyl and trifluoromethoxy.
EFFECT: compounds can be used for therapeutic or preventive treatment of diseases where CRF is considered to be involved, such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension etc.
12 cl, 6 dwg, 1 tbl, 10 ex
SUBSTANCE: invention relates to novel antagonists of serotonin 5-HT6 receptors - substituted 2-amino-3-sulfonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidines of general formula 1 and substituted 2-amino-3-sulfonyl-5,6,7,8-tetrahydro-pyrazolo[1,5-a]pyrido[4,3-d]pyrimidines of general formula 2 or their pharmaceutically acceptable salts and/or hydrates, method of producing said compounds and pharmaceutical compositions, medicinal agents and treatment method. In compounds of formula 1 and general formula 2 , Ar is phenyl which is possibly substituted with halogen atoms, or a 6-member nitrogen-containing heteroaryl; R1 is a hydrogen atom, C1-C3alkyl which is possibly substituted with phenyl, C1-C5alkoxycarbonyl; R2 is a hydrogen atom, halogen or C1-C3alkyl; R1 3 and R2 3 are optionally identical substitutes selected from a hydrogen atom, optionally substituted C1-C3alkyl or R1 3 and R2 3 together with the nitrogen atom with which they are bonded form a nitrogen-containing 6-member saturated heteroaryl optionally substituted with C1-C5alkoxycarbonyl, where the said heteroaryl has 1-2 heteroatoms selected from nitrogen.
EFFECT: compounds can be used to prevent and treat diseases of the central nervous system, pathogenesis of which is associated with 5-HT6 receptors for enhancing mental capacity.
14 cl, 3 tbl, 19 dwg, 16 ex
SUBSTANCE: invention relates to novel compounds of formula IA and their pharmaceutically acceptable salts. Claimed compounds have inhibitory effect on DAAO. In formula IA , A denotes hydrogen; Z denotes O; R1 is selected from a hydrogen atom, hydroxy or methoxy; R2 is selected from a hydrogen atom, F, Cl, hydroxy, methoxy and methyl; or R1 is selected from a hydrogen atom, F, hydroxy and methoxy; and R2 is selected from a hydrogen atom, Cl, hydroxy, methoxy and methyl; R3 is selected from C1-C6alkyl, hydroxy, methoxy, halogen, cyano, CH2-CH2-phenyl and OCH2-phenyl; R4a is selected from C1-C6alkyl, hydroxy, methoxy and halogen. The invention also relates to use of compounds in which R3a denotes hydrogen, C1-C6alkyl, hydroxy, methoxy, halogen, cyano, CH2-CH2-phenyl, O-CH2-phenyl, NH-CO-O-CH2-phenyl, R4a denotes H, C1-C6alkyl, hydroxy, methoxy, halogen, NH-CO-O-CH2-phenyl, for making a medicinal agent.
EFFECT: wider field of use of the compounds.
14 cl, 4 tbl, 8 ex
SUBSTANCE: group of the inventions refers to medicine, namely to oncology, and can be used in bone cancer related pain management. The method involves administration to the patient of effective amount of a nerve growth factor (NGF) antagonist representing a NGF antibody. A set includes the NGF antagonist in the form of the NGF antibody and application instructions.
EFFECT: inventions allow for effective pain management, both constant, and motion related, due to high affinity of the NGF antibody without affecting the initial thresholds of thermal and mechanical sensitivity.
20 cl, 4 tbl, 14 dwg, 4 ex
SUBSTANCE: invention refers to medicine, namely to oncology, and can be used in treating the patients with Non Hodgkin Lymphoma. That is ensured by administration of a combination containing an effective amount of CCI-779 and rituximab in the form of a dosage form with one or more neutral components added. The combination is introduced simultaneously, separately or consistently with the other agents.
EFFECT: method allows improving clinical effectiveness for the given pathology, including in the patients resistant to rituximab due to synergetic interactions of these preparations.
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to pharmaceutical industry, particularly to new drugs and preparations containing effective anticancer agent with anti-Hsp90 antibody.
EFFECT: invention improves clinical effectiveness in treating cancer and leukemia.
48 cl, 25 tbl
SUBSTANCE: there are offered versions of human IL-13 antibodies, including based on CDR antibody BAK278D6. There is described a based composition, and also isolated nucleic acid, a host cell for preparing antibodies and versions of the method for preparing antibodies. There is disclosed application of antibodies for preparing a drug and a composition for treating various diseases mediated by IL-13 activity. Application of the invention provides antibodies neutralising IL-13.
EFFECT: applicable in medicine for preparing a vaccine.
52 cl, 32 dwg, 7 tbl, 29 ex
SUBSTANCE: invention relates to immunology and biotechnology. Described are versions of the humanised antibody CD45RO/RB which carry a light and a heavy strand. Versions of the following are disclosed: isolated polynucleotide, coding antibody, expression vector containing a polynucleotide and host cells containing the expression vector. Described also is use of the antibody to treat and/or prevent various diseases, including as a component of a pharmaceutical composition.
EFFECT: invention provides antibodies identified as CD45RO and CD45RB, which can find use in medicine.
9 cl, 14 dwg, 2 tbl, 13 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to medical technologies, immunology, pharmacology and particularly to drugs for treating the patients with rheumatoid arthritis (RA) and to methods of treating thereof to be used in rheumatology. Substance of the invention includes application of Fc-fragments of immunoglobulin class G as an antigen for treating RA, a remedy for treating RA, produced by mixing the antigen and an adjuvant, and the related method of treating RA.
EFFECT: improved effect to suppress autoimmune response.
6 cl, 3 ex, 4 dwg
SUBSTANCE: invention is related medicine and concerns applications of antibodies specifically recognising any prevailing variants of beta-amyloid peptide, Aβ40 and Aβ42, in preparation of a drug applied for prevention and-or treatment of Alzheimer's disease.
EFFECT: invention provides prevention of progression or reduction of symptoms, and/or decrease in amyloid deposition in an individual when administering an immunostimulating dose of peptide or specific antibody.
7 cl, 3 ex, 2 dwg
SUBSTANCE: anti-Cd20 antibodies are administered in amount of 0.5-4.0 g. 16-60 weeks later administration is repeated. To 4 and more antibody effects are performed. Each effect comprises one or two dosages of antibody. Antibody can be introduced intravenously, subcutaneously or subtunically. The second medicine can be used therewith. A product containing the instructions and a container with 0.5-4.0 g of antibody. In addition, the product can contain the container with the second medicine and the application instructions.
EFFECT: invention allows for prolonged period before stated progression of disease, reduced recurrence rate.
38 cl, 6 dwg, 4 ex
SUBSTANCE: there is offered a monoclonal antibody specific to human interleukine-4 (hIL-4) containing two domains with the related CDR1-3 region. There are described versions thereof that contain specified CDR, polynucleotide coding said antibody. There are described an expression vector and a host-cell for preparing the antibody to human interleukine-4 (hIL-4). There are opened: application of the antibody for preparing a pharmaceutical agent for treating the diseases mediated by interleukine-4 and/or IgE. There is discovered the pharmaceutical composition for treating the diseases mediated by interleukine-4 and/or IgE is opened.
EFFECT: application of the invention ensured the high-affinity neutralised monoclonal antibodies to human interleukine-4.
14 cl, 1 tbl, 6 ex
SUBSTANCE: substance of the invention involves sterile liquid or dry specifically active F(ab')2-fragments of anti-anthrax antibodies containing (35±5) mg·cm3 of protein and at least 96% of F(ab')2-fragments of antibodies recovered from liquid equine anti-anthrax immunoglobulin prepared of blood serum of horses preliminary immunised with strains B anthracis "СТИ"-1 and Ichtiman, and also a anthrax toxin produced by the Kohn's spirit deposition method.
EFFECT: lower reactogenicity and improved immunogenicity.
SUBSTANCE: invention refers to medicine, specifically to otorhinolaryngology and toracal surgery, and can be used for prevention and treatment of chronic cicatrical stenosis of larynx and trachea. To that end, mixture of diprospan (0.5 - 1.0 ml), longidasa (1500-3000 UI), 2% lidocain (0.04 g) and ketorolac (0.03 g) diluted to 5 ml with 10% glucose solution is administered retrosternally, peritracheally. The mixture is administered once a week, a course including 1-3 injections. 3-5 inhalations are performed with compressor nebuliser of longidasa 1500 ME dissolved in 3 ml of broncholytic or mucolytic medicine once a week in intervals between administrations.
EFFECT: increased therapeutic efficiency in stenoses treatment and restenosis process prevention due to improved lymph flow, blood flow, microcirculation, tissues trophism, prolonged anaesthesia and lowering of endotoxemia level leading to quick inflammation relief and prevention of excessive development of cicatrical and granulation tissue in larynx and trachea.