Classifications

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  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/45—Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
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• • A—HUMAN NECESSITIES
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  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
  • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
  • C07D211/86—Oxygen atoms
  • C07D211/88—Oxygen atoms attached in positions 2 and 6, e.g. glutarimide

Definitions

• the invention relates to the use of biologically active compounds of glutarimide derivatives or their pharmaceutically acceptable salts as agents for the treatment of eosinophilic diseases.
• Eosinophils are cells of innate immunity. They are produced in the bone marrow and primarily circulate in the blood. The main effector function of eosinophils is the immediate release of cytoplasmic granules in response to activation by various stimuli. Cytoplasmic granules contain pro-inflammatory mediators: cytokines, chemokines, lipid and neurotransmitters, growth factors and cationic proteins. Eosinophil cationic proteins include 4 classes: large basic protein (MBP), eosinophilic peroxidase (EPO), eosinophilic cationic protein (ECP), and eosinophil-dependent neurotoxin (EDN).
• MBP large basic protein
• EPO eosinophilic peroxidase
• ECP eosinophilic cationic protein
• EDN eosinophil-dependent neurotoxin
• the number of eosinophils in the blood is 0.02-0.3 ⁇ 10 9 / l, or 0.5-5% of all leukocytes.
• An increase in the number of eosinophils in the blood compared to normal is eosinophilia.
• Hyperereosinophilia, or large eosinophilia is a condition in which the content of eosinophils in the blood is 15% or more, usually with an increase in the total number of leukocytes [Hoffman R, Benz Jr. EJ, Shattil SJ, et al., Eds. Hematology: Basic Principles and Practice. 4th ed. Philadelphia, Pa: Churchill Livingston; 2005: 768].
• bronchial asthma a chronic inflammatory disease of the respiratory tract, characterized by episodic airflow obstruction, airway inflammation and increased bronchial reactivity to non-specific allergens.
• eosinophils are a key component of an allergic response in asthma. Secreted by mast cells, IL-3, IL-5 promote the accumulation of eosinophils in the lungs, subsequent activation of these cells with the release of LTC4, eosinophilic cationic protein, the main main protein, neurotoxin, eosinophilic peroxidase (EPO), transforming growth factor, free radicals [Blanchard C, Rothenberg ME. Biology of the eosinophil // Adv Immunol. 2009; 101: 81-121].
• Receptors for IL-2, IL-3, IL-5, GM-CSF, PAF, prostaglandins were also detected on the surface of eosinophils. Through these receptors, these cytokines and lipid mediators are able to induce the activation of eosinophils and their release of mediators (LTC4, PAF) and cytokines (IL-3, IL-4, IL-5, IL-8, GM-CSF, TGFp). The destruction of the epithelium of the respiratory tract arising under the influence of eosinophilic proteins contributes to the development of bronchial hyperreactivity, lowering the barrier functions of the mucous membrane of the respiratory tract.
• Eosinophils are the source of several fibrogenic and growth factors, including transforming factor- ⁇ (TGF- ⁇ ), fibroblast growth factor (FGF) -2, endothelial vascular growth factor (VEGF), matrix metalloproteinases (MMP) -9, IL- ⁇ , IL-13 and IL-17.
• TGF- ⁇ transforming factor- ⁇
• FGF fibroblast growth factor
• VEGF endothelial vascular growth factor
• MMP matrix metalloproteinases
• corticosteroids drugsesonide, beclomethasone dipropionate, fluticasone propionate, mometasone furoate
• corticosteroids function by inducing a general immunosuppressive effect, and there are adverse side effects associated with their prolonged use, including high blood pressure, osteoporosis, and the development of cataracts [Barnes PJ. New drugs for asthma // Semin Respir Crit Care Med. 2012; 33 (6): 685-94].
• Corticosteroids must be taken every day and therefore patient compliance with this requirement is another problem for the successful use of these drugs.
• SB240563 (mepolizumab, Glaxo Smith Kline) can be called the most effective.
• mepolizumab therapy of prednisolone-dependent asthmatics reduced eosinophilia in the blood and sputum, and, most importantly, improved the condition of patients by reducing the number of exacerbation episodes and the dose of prednisolone.
• mepolizumab significantly reduced the content of ECP and the soluble form of IL-5Ra in the blood, as well as the concentration of IL-5Ra, IL-6, and IL-lb in the nose, which correlated with the relief of the disease according to the general polyp scale (total polip score) [Gevaert P, Van Bruaene N, Cattaert T, et al. Mepolizumab, a humanized anti-IL-5 mAb, as a treatment option for severe nasal polyposis. J Allergy Clin Immunol. 2011; 128 (5): 989-995].
• anti-IL-S antibodies are not limited to bronchial asthma and polypous rhinusinosopathy.
• This therapy is also effective for other eosinophil-mediated diseases.
• mepolizumab therapy reduced blood eosinophilia and reduced the dose of prednisone taken [Rothenberg ME, ⁇ AD, Roufosse FE, et al. Treatment of patients with the hypereosinophilic syndrome with mepolizumab. NEJM. 2008; 358 (12): 1215-28].
• mepolizumab has been successfully used as a therapy for eosinophilic vasculitis [Kahn JE, Grandpeix-Guyodo C, Marroun I, et al. Sustained response to mepolizumab in refractory Churg-Strauss syndrome. J Allergy Clin Immunol. 2010; 125: 267-70].
• Monthly administration of mepolizumab to a 28-year-old woman reduced the blood eosinophils to normal levels, prevented the formation of corticosteroid asthma and, according to the radiograph, improved the condition of the pulmonary parenchyma [Kim S, Marigowda G, Oren E, Israel E, Wechsler M.
• Mepolizumab as a steroid-sparing treatment option in patients with Churg-Strauss syndrome. J Allergy Clin Immunol. 2010; 125: 1336 ⁇ 3].
• mepolizumab therapy has reduced the dose of corticosteroids. Eosinophilia was also reduced, but after termination of the study, the exacerbations recur [Oldhoff JM, Darsow U, Werfel T, et al. Anti-IL-5 recombinant humanized monoclonal antibody (mepolizumab) for the treatment of atopic dermatitis. Allergy. 2005; 60 (5): 693-6].
• mepolizumab is in the second stage of clinical trials for the treatment of asthma, eosinophilic esophagitis in adults, eosinophilic esophagitis in children, eosinophilic vasculitis and polypous rhinusinosopathies, and in the third stage of clinical trials as a treatment for hypereosinophilic syndrome, eosinophilic esophagitis in children, asthma-induced rhinovirus bronchitis and chronic.
• resisumab (Cephalon), which is also humanized monoclonal antibody SCH55700 to IL-5, undergoes the second stage of clinical trials as a therapy for hypereosinophilic syndrome and loiasis, and the third stage as a therapy for asthma and eosinophilic esophagitis in children.
• mAb therapy entails several disadvantages.
• Monoclonal antibodies are expensive therapeutic agents that must be taken within a month or two months.
• An important factor is the problem of non-compliance with prescriptions by patients, which arises from repeated visits to the doctor for the introduction of an injectable drug.
• deviations in allotypes between the patient and the therapeutic antibody may lead to the fact that monoclonal antibody therapy will ultimately become ineffective.
• a high dose of mAbs and the possibility of the formation of immune complexes can also reduce the effectiveness of passive immunization.
• WO 97/45448 proposes the use of “modified and variant forms of IL5 molecules capable of antagonizing IL5 activity” to improve, attenuate or reduce otherwise abnormal effects caused by native and mutant forms of IL5. It is reported that the antagonizing effect is the result of variant forms of IL5 binding to the low affinity IL5R chain, but not to high affinity receptors. Acting in this way, variants compete with IL5 for binding to its receptors without affecting the physiological effects of IL5.
• WO 03/040164 proposes a composition for vaccination aimed at the endogenous formation of antibodies to IL-5, IL-13 and eotaxin, i.e. to key factors in the maturation, activation, localization and viability of eosinophils.
• the composition comprises a virus-like particle and at least one protein or peptide of IL-5, IL-13 or human eotaxin associated with it.
• this composition is applicable for the production of vaccines used to treat allergic diseases with an eosinophilic component and as a pharmaceutical vaccine for the prevention or treatment of allergic diseases with an eosinophilic component.
• Application N ° 8501 176 proposes the use of antibodies that bind IL-5R. These antibodies include a site that specifically binds to the IL-5 receptor (IL-5R) and the Fc fragment.
• the invented method reduces the number of eosinophils in the blood, in the bone marrow, gastrointestinal tract (for example, the esophagus, stomach, small and large intestine) or in the lungs and thereby reduces the clinical manifestations of asthma and chronic obstructive pulmonary bronchitis in humans (http: / / w w. patentgenius .com / patent / 8501 176.html).
• the described methods for the synthesis of glutaric acid imides consist in heating a dicarboxylic acid or its derivative, such as anhydride, diester, etc. with a primary amine or its amide (thermal cyclization) [Weigand-Hilgetag. Experimental methods in organic chemistry. Ed. prof. N. N. Suvorova. M., Chemistry, 1968, p. 446], cyclization of the monoamides of the corresponding dicarboxylic acids using a dehydrating agent as a reagent that activates a carboxy group, such as acetic anhydride [Shimotori et al, Asymmetric synthesis of ⁇ -lactones with lipase catalyst. Flavor and Fragrance Journal, 2007, V.
• the aim of the present invention is the use of non-toxic derivatives of glutarimides, effective for the treatment of eosinophilic diseases, mainly allergic in nature, such as bronchial asthma, allergic rhinitis, polypous rhinusinosopathies, eosinophilic colitis, eosinophilic syndrome, allergic conjunctivitis, atopic dermatitis, Cherg's syndrome anaphylactic shock, Quincke's edema, eosinophilic vasculitis, eosinophilic esophagitis, eosinophilic gastroenteritis and fibrosis.
• eosinophilic diseases mainly allergic in nature, such as bronchial asthma, allergic rhinitis, polypous rhinusinosopathies, eosinophilic colitis, eosinophilic syndrome, allergic conjunctivitis, atopic dermatitis, Cherg's syndrome anaphylactic shock
• the present invention relates to the use of glutarimide derivatives of general formula (I):
• Ri and R ' i independently represent hydrogen or C [-C 6 alkyl, for example methyl;
• R 2 represents
• eosinophilic diseases of a predominantly allergic nature such as bronchial asthma, allergic rhinitis, polyposis rhinusinosopathies, eosinophilic colitis, eosinophilic syndrome, allergic conjunctivitis, atopic dermatitis, Chergue-Strosock syndrome, anaphylaxis, anaphylaxis Quincke, eosinophilic vasculitis, eosinophilic esophagitis. eosinophilic gastroenteritis and fibrosis, disclosed in the application RU 20131 16826 from 04/12/2013.
• glutarimide derivatives suppress eosinophilia on various models of inflammation in all evaluated biological media (blood, bronchoalveolar lavage (BAL)) and tissues.
• BAL bronchoalveolar lavage
• the present invention relates to a therapeutic method for the treatment of eosinophilic diseases, mainly allergic in nature, preferably bronchial asthma, allergic rhinitis, polyposis rhinusinosopathies, eosinophilic colitis, eosinophilic syndrome, allergic conjunctivitis, atopic dermatitis, syndrome Cherzh-Strauss, anaphylactic shock, Quincke's edema, eosinophilic vasculitis, eosinophilic esophagitis, eosinophilic gastroenteritis or fibrosis, comprising administering to the patient an effective amount of glutarimide derivatives of general formula (I) or a pharmaceutically acceptable salt thereof.
• the present invention also relates to a medicament for the treatment of eosinophilic diseases, mainly of an allergic nature, preferably bronchial asthma, allergic rhinitis, polypous rhinusinosopathies, eosinophilic colitis, eosinophilic syndrome, allergic conjunctivitis, atopic dermatitis, Cherzhavin Stros syndrome, anaphylactic erythematosus, anaphylactic erythematosus, anaphylaxis vasculitis, eosinophilic esophagitis, eosinophilic gastroenteritis or fibrosis, which is a derivative of glutarimi s of general formula (I) or a pharmaceutically acceptable salt thereof.
• eosinophilic diseases mainly of an allergic nature, preferably bronchial asthma, allergic rhinitis, polypous rhinusinosopathies, eosinophilic colitis, eosinophilic syndrome
• Another object of the present invention is a pharmaceutical composition for the treatment of eosinophilic diseases, mainly of an allergic nature, preferably bronchial asthma, allergic rhinitis, polypous rhinusinosopathies, eosinophilic colitis, eosinophilic syndrome, allergic conjunctivitis, atopic dermatitis, Cherg-Stros syndrome, anaphylaxis, anaphylaxis, anaphylactic eosinophilic vasculitis, eosinophilic esophagitis, eosinophilic gastroenteritis or fibrosis, including an effective amount of a glutarimide derivative of general formula (I) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
• a glutarimide derivative of general formula (I) or a pharmaceutically acceptable salt thereof including an effective amount of a glutarimide derivative of general formula (I) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier
• the compounds used in the present invention can be prepared by a process comprising heating the starting dicarboxylic acid monoamides with a water-removing agent in an organic solvent medium or in the medium of the water-removing agent itself, optionally with the addition of sodium acetate.
• Preferred compounds used in the present invention are compounds of general formula (I),
• the most preferred compounds of the present invention are the compounds shown in table 1.
• organic acid addition salts e.g., formate, acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.
• inorganic acid addition salts e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.
• salts with amino acids for example, aspartic acid salt, glutamic acid salt, etc.
• Derivatives of glucarimides of general formula (I) have a therapeutic effect against eosinophilic diseases.
• the compounds of the present invention can be used to treat bronchial asthma, allergic rhinitis, polypoid rhinusinosopathies, eosinophilic colitis, eosinophilic syndrome, allergic conjunctivitis, atopic dermatitis, Cherzh-Stros syndrome, anaphylactic shock, Quincke eosophilus, eosinophilus eosinophilus, eosinophilus eosinophilus gastroenteritis and fibrosis.
• the compounds of the present invention are administered in an effective amount that provides the desired therapeutic result.
• the compounds of general formula (I) can be administered orally, topically, parenterally, intranasally, inhalation and rectally in unit dosage forms containing non-toxic pharmaceutically acceptable carriers.
• parenteral administration means subcutaneous, intravenous, intramuscular injection or infusion.
• the compounds of the present invention can be administered to a patient in doses of 0.1 to 30 mg / kg body weight per day, preferably in doses of 0.25 to 10 mg / kg one or more times per day.
• the specific dose for each particular patient will depend on many factors, including the activity of the compound used, age, body weight, gender, general health status and diet of the patient, time and method of administering the drug, speed of its removal from an organism, the combination of drugs used specifically, and the severity of the disease in the individual being treated.
• compositions of the present invention contain a compound of general formula (I) in an amount effective to achieve the desired result, and can be administered in unit dosage forms (e.g., in solid, semi-solid or liquid forms) containing the compounds of the present invention as an active ingredient mixed with a carrier or excipient suitable for intramuscular, intravenous, oral, sublingual, inhalation, intranasal and intrarectal administration.
• a carrier or excipient suitable for intramuscular, intravenous, oral, sublingual, inhalation, intranasal and intrarectal administration.
• the active ingredient may be included in the composition along with commonly used non-toxic pharmaceutically acceptable carriers suitable for the manufacture of solutions, tablets, pills, capsules, dragees, suppositories, emulsions, suspensions, ointments, gels and any other dosage forms.
• Various substances can be used as fillers, such as saccharides, for example glucose, lactose or sucrose, mannitol or sorbitol, cellulose derivatives and / or calcium phosphates, for example tricalcium phosphate or calcium acid phosphate.
• a binder component substances such as starch paste, for example, corn, wheat, rice, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose and / or polyvinylpyrrolidone can be used.
• disintegrating agents such as the aforementioned starches and carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate, can be used.
• Optional additives such as flow control and lubricating agents such as silica, talc, stearic acid and its salts such as magnesium stearate or calcium stearate and / or propylene glycol may be used.
• the core of the dragee is usually coated with a layer that is resistant to the action of gastric juice.
• concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, and suitable organic solvents or mixtures thereof.
• additives As additives, stabilizers, thickeners, colorants and perfumes can also be used.
• hydrocarbon ointment bases such as white and yellow petroleum jelly (Vaselinum album, Vaselinum flavum), liquid paraffin (Oleum Vaselini), white and liquid ointment (Unguentum album, Unguentum flavum), and as additives for giving more dense consistency, such as paraffin wax and wax; absorbent ointment bases, such as hydrophilic petrolatum (Vaselinum hydrophylicum), lanolin (Lanolinum), cold cream (Unguentum leniens); ointment bases washable with water, such as hydrophilic ointment (Unguentum hydrophylum); water-soluble ointment bases, such as polyethylene glycol ointment (Unguentum Glycolis Polyaethyleni), bentonite bases and others.
• absorbent ointment bases such as hydrophilic petrolatum (Vaselinum hydrophylicum), lanolin (Lanolinum), cold cream (
• methyl cellulose sodium salt of carboxymethyl cellulose, hydroxypropyl cellulose, polyethylene glycol, polyethylene oxide or carbopol can be used.
• water-insoluble bases such as cocoa butter can be used; bases soluble in water or miscible with water, such as gelatin-glycerol or polyethylene oxide; combined bases - soap-glycerin.
• the amount of active ingredient used in combination with a carrier may vary depending on the recipient being treated, on the particular route of administration of the drug.
• the content of the active agent in them is up to 5% by weight.
• diluents 0.9% sodium chloride solution, distilled water, novocaine solution for injection, Ringer's solution, glucose solution, specific additives for dissolution can be used.
• their amount is up to 200 mg per unit dosage form.
• Dosage forms of the present invention are obtained according to standard methods, such as, for example, mixing, granulating, dragee formation, dissolution and lyophilization.
• Chromatograms and electrophoregrams exhibit chlorotetramethylbenzidine reagent and Pauli reagent.
• HPLC SCLlOAvp PE SCIEX API 165 (150) mass spectrometer (Canada).
• Analytical reverse-phase HPLC was carried out on an instrument: Shimadzu HPLC chromatograph under conditions: Luna C18 (2) 100A column 250A 250x4.6 mm (ser. 599779-23), elution gradient in the system phosphate buffer solution pH 3.0: methanol (conditions A ); Merk.LiChroCART column 250x4 mm 5 ⁇ m. LiChrospher 100RP-8E 5 ⁇ m. C8. Serial number 1.50837.0001, gradient of elution in the system of acetate-ammonia buffer solution, pH 7.5.
• ⁇ -NMR spectra were recorded on a Bruker DPX-400 instrument (Germany). High-resolution mass spectra are obtained on a time-of-flight mass spectrometer by matrix laser desorption ionization using 2,5-dihydroxybenzoic acid as a matrix, Ultraflex device ('Bruke', Germany).
• the protection of the nitrogen atom in the heterocycles is used, for example, a carbamate-type protecting group, such as tert-butoxycarbonyl (Boe).
• a carbamate-type protecting group such as tert-butoxycarbonyl (Boe).
• composition per coated tablet Composition per coated tablet.
• Morphological examination of histological preparations was carried out using a Leica DM LS light-optical microscope (Leica Microsystemc, Germany). Micromorphic analysis was performed using a Leica DM LS microscope eyepiece micrometer. Microphotography was performed using a Leica DC320 digital camera (Leica Microsystemc, Germany).
• the studied compounds were administered to animals intragastrically daily once a day for 6 or 10 days, ending 2 days before the introduction of the resolving dose of antigen.
• BAL bronchoalveolar lavage
• the predominantly studied compounds reduced the number of eosinophils: in the control group, the number of eosinophils in the BAL was 7.05 x 10 9 cells / l, in the groups receiving treatment - 0.60 - 1.61 x 10 9 cells / l, i.e. 91-77% less.
• the studied compounds reduced the number of lymphocytes and, in some doses, the number of monocytes in BAL, which indicates the suppression of local inflammatory response in the lung.
• Test compounds reduced blood eosinophilia.
• the number of eosinophils in the blood was 6-8 times higher than this indicator of intact animals.
• the introduction of the studied compounds allowed to keep it at the level of intact animals (table 6).
• the comparison drug budesonide was administered according to the same scheme as an inhalation dose of 0.5 mg / kg. 48 hours after Sephadex inhalation, bronchoalveolar lavage was collected. In lavage, the total number of leukocytes was evaluated and the leukocyte formula was determined. The number of rats in the group is 7-10 pcs.
• G-200 rats cause a marked influx of white blood cells into the lung.
• the number of all cell types was increased in the control group compared to intact ones, however, the maximum increase was noted for eosinophils (tables 8-9).
• the model of leukotriene-induced eosinophilic pneumonia in guinea pigs was implemented according to the standard method [Underwood DC1, Osborn RR, Newsholme SJ, Torphy TJ, Hay DW. Persistent airway eosinophilia after leukotriene (LT) D4 administration in the guinea pig: modulation by the LTD4 receptor antagonist, pranlukast, or an interleukin-5 monoclonal antibody // Am J Respir Crit Care Med. 1996 Oct; 154 (4 Pt l): 850-7.].
• the intragastric administration of the test compound to guinea pigs decreased the eosinophil content in BAL by 2.1-3.4 times.
• the compound had an effect in a wide range of doses (0.14-14 mg / kg).
• a comparative analysis of the effectiveness of the test compound and montelukast showed that the effect of the test compound is not inferior to the antagonist of leukotriene receptors.
• the model of allergic rhinitis was implemented according to the standard method [Vishnu N. Thakare, M.M. Osama, Suresh R. Naik. Therapeutic potential of curcumin in experimentally induced allergic rhinitis in guinea pigs // Int Immunopharmacol. 2013 Sep; 17 (l): 18-25].
• Guinea pigs (250-300 g) were immunized with 4-fold (on 0, 7, 14 and 21 days) intraperitoneal administration of a mixture of ovalbumin (100 ⁇ g / mumps) and aluminum hydroxide (5 mg / mumps), diluted and suspended in physiological saline.
• an ovalbumin solution (60 mg / ml) was administered intranasally to the animals with 20 ⁇ l in each nostril.
• the animals were injected with an OVA solution (200 ⁇ g / ml, 25 ⁇ l) intradermally, after having previously shaved a skin area on the back. Sensitization was confirmed by the formation of edema and redness at the injection site.
• test compounds 14 mg / kg were administered intragastrically to animals 3x multiple times: 48, 24, and 1 hour before the last intranasal administration of OVA.
• the comparison drug dexamethasone was administered intragastrically once - 3 hours before the last intranasal administration of OVA.
• the clinical manifestations of rhinitis were assessed: the number of sneezes and scratches of the nose were counted. 24 hours after the last administration of ovalbumin, a nasal wash was taken. In a nasal wash, the total number of leukocytes was evaluated and the leukocyte formula was determined. The number of guinea pigs in the group - 8 pcs.
• the model of atopic dermatitis was implemented according to the standard method [Mechanism of dinitrochlorobenzene-induced dermatitis in mice: role of specific antibodies in pathogenesis // PLoS One. 2009; 4 (1 1).].
• mice On day 0 and 12, male Balb / c mice were sprayed with 100 ⁇ l of a 2% solution of 1-chloro-2,4-dinitrobenzene (DNCB, Sigma-Aldrich, USA) prepared on a 95% ethanol solution on shaved back areas. On the 17th day of the study, 20 ⁇ l of 2% was applied to the animals' right “experimental” ear an alcoholic solution of DNCB twice with an interval of 1 hour. The test compound and the dexamethasone reference drug were administered intragastrically to animals once a day on the 8-17th day of the study.
• DNCB 1-chloro-2,4-dinitrobenzene
• the reaction index (IR) was calculated, expressed as a percentage of the difference in the masses of the “experienced” and “control” ears.

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