RU2429017C1 - Antiaggregant activation in experiment in vitro - Google Patents
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- 239000003146 anticoagulant agent Substances 0.000 title claims abstract description 10
- 230000004913 activation Effects 0.000 title claims abstract description 4
- 238000000338 in vitro Methods 0.000 title claims abstract 3
- 230000002744 anti-aggregatory effect Effects 0.000 title abstract description 4
- 238000002474 experimental method Methods 0.000 title description 2
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 8
- 239000001116 FEMA 4028 Substances 0.000 claims abstract description 8
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims abstract description 8
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims abstract description 8
- 229960004853 betadex Drugs 0.000 claims abstract description 8
- 238000000034 method Methods 0.000 claims abstract description 4
- 230000000702 anti-platelet effect Effects 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 5
- 229940127218 antiplatelet drug Drugs 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 5
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 abstract 1
- 239000000126 substance Substances 0.000 abstract 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 210000004623 platelet-rich plasma Anatomy 0.000 description 6
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 5
- 229960001138 acetylsalicylic acid Drugs 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 3
- 210000002381 plasma Anatomy 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 2
- 238000012404 In vitro experiment Methods 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 229960001680 ibuprofen Drugs 0.000 description 2
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- NZRDKNBIPVLNHA-UHFFFAOYSA-N 5-Acetylsalicylic acid Chemical compound CC(=O)C1=CC=C(O)C(C(O)=O)=C1 NZRDKNBIPVLNHA-UHFFFAOYSA-N 0.000 description 1
- ADHFMENDOUEJRK-UHFFFAOYSA-N 9-[(4-fluorophenyl)methyl]-n-hydroxypyrido[3,4-b]indole-3-carboxamide Chemical compound C1=NC(C(=O)NO)=CC(C2=CC=CC=C22)=C1N2CC1=CC=C(F)C=C1 ADHFMENDOUEJRK-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241001482237 Pica Species 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- ANJXCDGVELYPJR-UHFFFAOYSA-N acetic acid;ethyl acetate;hydrate Chemical compound O.CC(O)=O.CCOC(C)=O ANJXCDGVELYPJR-UHFFFAOYSA-N 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Изобретение относится к биологии и медицине, а именно к экспериментальной фармакологии.The invention relates to biology and medicine, namely to experimental pharmacology.
На сегодняшний день известен способ антиагрегантной активации с помощью препарата ибупрофена, обладающего антиагрегантными и противовоспалительными свойствами [1], но на сегодняшний день этот препарат является устаревшим и обладает рядом побочных эффектов.To date, a known method of antiplatelet activation using the drug ibuprofen, which has antiplatelet and anti-inflammatory properties [1], but today this drug is obsolete and has a number of side effects.
Цель изобретения - расширение арсенала средств для увеличения антиагрегантной активности.The purpose of the invention is the expansion of the arsenal of funds to increase antiplatelet activity.
Поставленная цель достигается применением нового синтезированного химического соединения, являющегося конъюгатом бета-циклодекстрина с 1-(4-изобутилфенил)-пропионовой кислотой (ибупрофеном).This goal is achieved by the use of a new synthesized chemical compound, which is a conjugate of beta-cyclodextrin with 1- (4-isobutylphenyl) -propionic acid (ibuprofen).
Синтез применяемого соединенияSynthesis of the compound used
Конъюгат бета-циклодекстрина с 1-(4-изобутилфенил)-пропионовой кислотой синтезирован в научной лаборатории кафедры органической химии Московского государственного педагогического университета.A beta-cyclodextrin conjugate with 1- (4-isobutylphenyl) -propionic acid was synthesized in a scientific laboratory of the Department of Organic Chemistry of Moscow State Pedagogical University.
К раствору 0.50 г (0.441 ммоль) β-циклодекстрина в 8 мл пиридина при перемешивании прикапывали 0.69 г (3.09 ммоль) хлорангидрида 1-(4-изобутилфенил)-пропионовой кислоты в 2 мл бензола, выдерживали при 20°С 24 ч. Выпавший гидрохлорид пиридина отфильтровывали, фильтрат упаривали, остаток затирали в эфире (5 мл), образовавшийся осадок отфильтровывали, промывали водой (2×5 мл), остатки воды удаляли азеотропной отгонкой с бензолом и сушили в вакууме (1 мм рт.ст.) 3 ч при 60°C.To a solution of 0.50 g (0.441 mmol) of β-cyclodextrin in 8 ml of pyridine, 0.69 g (3.09 mmol) of 1- (4-isobutylphenyl) propionic acid chloride in 2 ml of benzene was added dropwise with stirring at 20 ° C for 24 hours. The precipitated hydrochloride pyridine was filtered off, the filtrate was evaporated, the residue was triturated with ether (5 ml), the precipitate formed was filtered off, washed with water (2 × 5 ml), the remaining water was removed by azeotropic distillation with benzene and dried in vacuum (1 mm Hg) for 3 h at 60 ° C.
Выход соединения (II) 0.70 г (65%), т.пл. 157-160°C, Rf 0.59 (на алюминиевых пластинках с закрепленным слоем силикагеля, в системе этилацетат-уксусная кислота-вода 3:1:3). Спектр ЯМР 1Н (d6-ДМСО), δ, м. д.: 0.78-0.85 м [42H, (CH3)2], 1.24-1.30 м (21H, CH3), 1.72-1.81 м [7H, CH(CH3)2], 2.37 уш. с (14H, CH2), 3.13-3.77 м (42H; C1H-C5H, C6H2], 3.47-3.51 м (5H, CH), 4.82 д (7H, C1H), 5.66-5.82 м (14H; C2OH, C3OH), 6.96-7.22 м (28H, CHаром). ЯМР 13C (d6-ДМСО), δ, м. д.: 18.2 (CH3), 22.2 [(CH3)2], 29.7 [CH(CH3)2], 40.3 (CHCH3), 44.3 (CH2), 63.2 [C 6OC(O)], 69.3 [C 5C6OC(O)], 72.0-73.0 (C2, C3, C5), 81.8 (C4), 102.1 (C1), 127.1-139.6 (CHаром.), 174.2 [C(O)]. Найдено, %: C 64.64; H 7.55. C133H182O42. Вычислено, %: C 65.13; H 7.48.The yield of compound (II) 0.70 g (65%), so pl. 157-160 ° C, R f 0.59 (on aluminum plates with a fixed layer of silica gel, in the system ethyl acetate-acetic acid-water 3: 1: 3). 1 H NMR spectrum (d 6 -DMSO), δ, ppm: 0.78-0.85 m [42H, (CH 3 ) 2 ], 1.24-1.30 m (21H, CH 3 ), 1.72-1.81 m [7H, C H (CH 3 ) 2 ], 2.37 br. s (14H, CH 2 ), 3.13-3.77 m (42H; C 1 HC 5 H, C 6 H 2 ], 3.47-3.51 m (5H, CH), 4.82 d (7H, C 1 H), 5.66-5.82 m (14H; C 2 OH, C 3 OH), 6.96-7.22 m (28H, CH arom ). 13 C NMR (d 6 -DMSO), δ, ppm: 18.2 (CH 3 ), 22.2 [( CH 3 ) 2 ], 29.7 [ C H (CH 3 ) 2 ], 40.3 ( C HCH 3 ), 44.3 (CH 2 ), 63.2 [ C 6 OC (O)], 69.3 [ C 5 C 6 OC (O) ], 72.0-73.0 (C 2 , C 3 , C 5 ), 81.8 (C 4 ), 102.1 (C 1 ), 127.1-139.6 (CH arom. ), 174.2 [C (O)]. Found,%: C 64.64; H 7.55. C 133 H 182 O 42. Calculated,%: C 65.13; H 7.48.
Формула полученного соединения:The formula of the obtained compound:
В эксперименте in vitro проводились испытания на антиагрегантную активность в отношении тромбоцитов плазмы крови богатой. Препаратом сравнения служила ацетилсалициловая кислота (аспирин).In an in vitro experiment, tests were carried out for antiplatelet activity against platelets rich in blood plasma. The reference drug was acetylsalicylic acid (aspirin).
Для исследования функционального состояния тромбоцитов фотометрическим методом использовали богатую тромбоцитами плазму (PRP) и суспензию отмытых тромбоцитов. Утром, до кормления лабораторных животных (белые беспородные крысы), брали кровь из яремной вены в пластиковые шприцы, содержащие антикоагулянт (3.8% (0.11 М) раствор цитрата натрия) в соотношении 9:1. Все манипуляции с кровью, плазмой, обогащенной тромбоцитами и суспензией отмытых тромбоцитов, проводились в полиэтиленовой посуде. Для получения богатой тромбоцитами плазмы кровь центрифугировали в пластиковых пробирках при комнатной температуре в течение 10 минут для осаждения эритроцитов и лейкоцитов. Количество тромбоцитов PRP подсчитывалось в камере Горяева на микроскопе МБИ-15 с фазово-контрастной приставкой и доводилось до 2×1011-2.5×1011 тромбоцитов/л при помощи плазмы, бедной тромбоцитами (РРР). PRP получали повторным центрифугированием крови в течение 10 минут. PRP хранилась при температуре 4°C.To study the functional state of platelets by the photometric method, platelet-rich plasma (PRP) and a suspension of washed platelets were used. In the morning, before feeding laboratory animals (white outbred rats), blood was taken from the jugular vein into plastic syringes containing an anticoagulant (3.8% (0.11 M) sodium citrate solution) in a 9: 1 ratio. All manipulations with blood, plasma, enriched in platelets and a suspension of washed platelets, were carried out in plastic dishes. To obtain platelet-rich plasma, blood was centrifuged in plastic tubes at room temperature for 10 minutes to precipitate red blood cells and white blood cells. The platelet count of PRP was counted in a Goryaev’s chamber with an MBI-15 microscope with a phase-contrast attachment and brought up to 2 × 10 11 -2.5 × 10 11 platelets / l using platelet-poor plasma (PPP). PRP was obtained by repeated centrifugation of blood for 10 minutes. PRP was stored at 4 ° C.
Оценку агрегации тромбоцитов производили на агрегометре PICA (модель 330, США), а также на двухканальном агрегометре LaborAPACT (США) с графической регистрацией и автоматической калькуляцией амплитуды и максимальной скорости агрегации. Агрегатограммы анализировали по амплитуде (максимальная величина падения оптической плотности, выраженная в %); максимальной скорости агрегации (выраженной в %/мин). Все эксперименты проводились в шести параллельных испытаниях, где опытная проба сравнивалась с контрольным образцом. В качестве индукторов агрегации тромбоцитов использовали тромбин в конечной концентрации 0.5 ед/мл. Кровь инкубировали 5 мин с образцами при 37°C.Platelet aggregation was evaluated on a PICA aggregometer (model 330, USA), as well as on a two-channel laborAPACT aggregometer (USA) with graphic recording and automatic calculation of the amplitude and maximum aggregation rate. Aggregates were analyzed by amplitude (maximum value of the optical density drop, expressed in%); maximum aggregation rate (expressed in% / min). All experiments were carried out in six parallel tests, where the experimental sample was compared with a control sample. Thrombin at a final concentration of 0.5 u / ml was used as inducers of platelet aggregation. Blood was incubated for 5 min with samples at 37 ° C.
В качестве примера в таблице №1 приведены данные антиагрегационной активности конъюгата бета-циклодекстрина с ацетилсалициловой кислотой, полученные в эксперименте in vitro.As an example, table No. 1 shows the anti-aggregation activity of the beta-cyclodextrin conjugate with acetylsalicylic acid obtained in an in vitro experiment.
Источники информацииInformation sources
Машковский М.Д. Лекарственные средства. Москва. Изд. «Новая волна» 2005 г. 1206 с.Mashkovsky M.D. Medicines Moscow. Ed. “New Wave” 2005, 1206 p.
1. Руководство по экспериментальному (доклиническому) изучению новых фармакологических средств. Под общей ред. Р.У.Хабриева. Москва. 2005.829 с.1. Guidance on the experimental (preclinical) study of new pharmacological agents. Under the general ed. R.U. Khabrieva. Moscow. 2005.829 p.
2. К.Uekama, F.Hirayama, Т.Irie, Chem. Rev, 98 (5), 2045-2076 (1998).2. K. Uekama, F. Hirayama, T. Irie, Chem. Rev. 98 (5), 2045-2076 (1998).
3. M.E.Davis, M.E.Brewster, Nature Rev. Drug Discovery, 3, 1023-1035 (2004).3. M.E. Davis, M.E. Brewster, Nature Rev. Drug Discovery, 3, 1023-1035 (2004).
4. Cyclodextrins and their complexes. Chemistry, analytical methods, applications // Ed. H.Dodziuk, Wiley-VCH, Weinheim. 2006. 489 p.4. Cyclodextrins and their complexes. Chemistry, analytical methods, applications // Ed. H. Dodziuk, Wiley-VCH, Weinheim. 2006.498 p.
5. K.Uekama, K.Minami, F.Hirayama, J. Med. Chem, 40 (17), 2755-2761 (1997).5. K. Uekama, K. Minami, F. Hirayama, J. Med. Chem. 40 (17), 2755-2761 (1997).
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2072361C1 (en) * | 1993-08-30 | 1997-01-27 | МГУ (химический факультет) | CONJUGATES OF α OR b-CYCLODEXTRINS WITH POLYETHYLENE OXIDE AS COMPLEXING AGENT AND EMULSIFIER AND METHOD FOR THEIR PRODUCTION |
| RU2094059C1 (en) * | 1993-08-30 | 1997-10-27 | Московский государственный университет, химический факультет | Method of transport of neurotropic preparation to brain |
| WO2006005794A1 (en) * | 2004-07-13 | 2006-01-19 | Schering Oy | A delivery system |
| RU2288921C2 (en) * | 2000-12-19 | 2006-12-10 | Калифорниа Инститьют оф Текнолоджи | Inclusion complexes-containing compositions |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2072361C1 (en) * | 1993-08-30 | 1997-01-27 | МГУ (химический факультет) | CONJUGATES OF α OR b-CYCLODEXTRINS WITH POLYETHYLENE OXIDE AS COMPLEXING AGENT AND EMULSIFIER AND METHOD FOR THEIR PRODUCTION |
| RU2094059C1 (en) * | 1993-08-30 | 1997-10-27 | Московский государственный университет, химический факультет | Method of transport of neurotropic preparation to brain |
| RU2288921C2 (en) * | 2000-12-19 | 2006-12-10 | Калифорниа Инститьют оф Текнолоджи | Inclusion complexes-containing compositions |
| WO2006005794A1 (en) * | 2004-07-13 | 2006-01-19 | Schering Oy | A delivery system |
Non-Patent Citations (1)
| Title |
|---|
| Машковский М.Д. Лекарственные средства. - М.: Новая волна, 2005, ч.1, с.205. * |
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