BR112015014161B1 - use of 3-carboxy-n-ethyl-n, n-dimethylpropan-1-amine or its pharmaceutically acceptable salt in the treatment of atherosclerosis - Google Patents
use of 3-carboxy-n-ethyl-n, n-dimethylpropan-1-amine or its pharmaceutically acceptable salt in the treatment of atherosclerosis Download PDFInfo
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- 230000002265 prevention Effects 0.000 claims abstract description 3
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- 239000003814 drug Substances 0.000 claims 1
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- PHIQHXFUZVPYII-LURJTMIESA-O (S)-carnitinium Chemical compound C[N+](C)(C)C[C@@H](O)CC(O)=O PHIQHXFUZVPYII-LURJTMIESA-O 0.000 description 1
- JMVZMDGLIJEIPK-WLHGVMLRSA-N (e)-but-2-enedioate;hydron;2-methylbutan-2-ylazanium Chemical compound [H+].CCC(C)(C)[NH3+].[O-]C(=O)\C=C\C([O-])=O JMVZMDGLIJEIPK-WLHGVMLRSA-N 0.000 description 1
- JFWLFLLRLZSBRA-UHFFFAOYSA-N 3-[(trimethylazaniumyl)amino]propanoate;dihydrate Chemical compound O.O.C[N+](C)(C)NCCC([O-])=O JFWLFLLRLZSBRA-UHFFFAOYSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- Urology & Nephrology (AREA)
- General Chemical & Material Sciences (AREA)
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Abstract
USO DE 3-CARBÓXI-N-ETIL-N,N-DIMETILPROPAN-1-AMÍNIO OU SEU SAL FARMACEUTICAM ENTE ACEITÁVEL NO TRATAMENTO DA ATEROSCLEROSE. O uso de 3-carbóxi-N-etil-N,N-dimetilpropan-1-amínio e seus sais farmaceuticamente aceitáveis: fumarato de hidrogênio de 3-carbóxi-N-etil-N,N-dimetilpropan-1-amínio e fosfato de dihidrogênio de 3-carbóxi-N-etil-N,N-dimetilpropan-1-amínio na prevenção e tratamento de aterosclerose.USE OF 3-CARBÓXI-N-ETIL-N, N-DIMETILPROPAN-1-AMÍNIO OR ITS PHARMACEUTICAL SALT THAT IS ACCEPTABLE IN THE TREATMENT OF AEROSCLEROSIS. The use of 3-carboxy-N-ethyl-N, N-dimethylpropan-1-amine and its pharmaceutically acceptable salts: 3-carboxy-N-ethyl-N, N-dimethylpropan-1-amine hydrogen fumarate and phosphate 3-carboxy-N-ethyl-N, N-dimethylpropan-1-amine dihydrogen in the prevention and treatment of atherosclerosis.
Description
[001] A presente invenção refere-se ao 3-carbóxi-N-etil-N,N- dimetilpropan-1-amínio ou seu sal farmaceuticamente aceitável para o uso na prevenção e tratamento da aterosclerose. Exemplos de sais farmaceuticamente aceitáveis de 3-carbóxi-N-etil-N,N-dimetilpropan-1-amínio são: fumarato de hidrogênio de 3-carbóxi-N-etil-N,N- dimetilpropan-1-amínio e fosfato de dihidrogênio de 3-carbóxi-N-etil-N,N-dimetilpropan-1-amínio.[001] The present invention relates to 3-carboxy-N-ethyl-N, N-dimethylpropan-1-amine or its pharmaceutically acceptable salt for use in the prevention and treatment of atherosclerosis. Examples of pharmaceutically acceptable salts of 3-carboxy-N-ethyl-N, N-dimethylpropan-1-amine are: 3-carboxy-N-ethyl-N, N-dimethylpropan-1-amine hydrogen fumarate and dihydrogen phosphate of 3-carboxy-N-ethyl-N, N-dimethylpropan-1-amine.
[002] A aterosclerose é um complexo processo inflamatório crônico da parede vascular que progride ao longo de décadas. É caracterizada pelo acúmulo de lipoproteínas de baixa densidade (LDL) oxidadas, aumento da morte celular e degeneração hipertrófica da parede arterial, provocando um estreitamento do diâmetro interno do vaso e, assim, prejudicando o fluxo sanguíneo. Pode ocorrer em qualquer área do corpo, mas é mais importante quando se desenvolve nos vasos sanguíneos do coração ou cérebro. O estreitamento ocorre devido à formação de placas (placas elevadas) no revestimento interno das artérias. Estas placas são compostas por LDL oxidadas, células musculares enfraquecidas, tecido fibroso, aglomerados de plaquetas sanguíneas, colesterol, macrófagos, linfócitos T e, às vezes, cálcio. As lesões ateroscleróticas comumente se desenvolvem em regiões de fluxo sanguíneo turbulento e são encontradas mais frequentemente em pessoas com concentrações elevadas de colesterol. O número e a espessura das placas aumentam com a idade, causando a perda do revestimento liso dos vasos sanguíneos e estimulando a formação de trombos (coágulos sanguíneos). Às vezes, fragmentos dos trombos se rompem e formam êmbolos, que correm através da corrente sanguínea e bloqueiam os vasos menores, assim, causando dano isquêmico dos tecidos.[002] Atherosclerosis is a complex chronic inflammatory process of the vascular wall that progresses over decades. It is characterized by the accumulation of oxidized low-density lipoproteins (LDL), increased cell death and hypertrophic degeneration of the arterial wall, causing a narrowing of the inner diameter of the vessel and thus impairing blood flow. It can occur in any area of the body, but it is more important when it develops in the blood vessels of the heart or brain. The narrowing occurs due to the formation of plaques (elevated plaques) in the inner lining of the arteries. These plaques are composed of oxidized LDL, weakened muscle cells, fibrous tissue, clusters of blood platelets, cholesterol, macrophages, T lymphocytes and, sometimes, calcium. Atherosclerotic lesions commonly develop in regions of turbulent blood flow and are found more often in people with high cholesterol concentrations. The number and thickness of plaques increases with age, causing the loss of the smooth lining of blood vessels and stimulating the formation of thrombi (blood clots). Sometimes fragments of the thrombi break and form emboli, which flow through the bloodstream and block smaller vessels, thereby causing ischemic tissue damage.
[003] A aterosclerose e as suas manifestações clínicas são uma das principais causas de morbidade e mortalidade na sociedade moderna. A doença cardíaca aterosclerótica, envolvendo as artérias coronárias (doença coronariana), é a causa mais comum de morte, sendo responsável por um terço de todas as mortes. A interferência aterosclerótica ao fornecimento sanguíneo ao cérebro (acidente vascular cerebral) é a terceira causa mais comum de morte depois do câncer. A insuficiência vascular é outra manifestação clínica da aterosclerose que causa uma grande quantidade de doenças graves por meio da redução do fluxo sanguíneo em outras artérias principais, tais como, aos rins, pernas e intestinos.[003] Atherosclerosis and its clinical manifestations are one of the main causes of morbidity and mortality in modern society. Atherosclerotic heart disease, involving the coronary arteries (coronary artery disease), is the most common cause of death, accounting for one third of all deaths. Atherosclerotic interference with the blood supply to the brain (stroke) is the third most common cause of death after cancer. Vascular insufficiency is another clinical manifestation of atherosclerosis that causes a large number of serious illnesses by reducing blood flow in other major arteries, such as the kidneys, legs and intestines.
[004] Infelizmente, a aterosclerose não causa sintomas até que o dano às artérias seja grave o suficiente para restringir o fluxo sanguíneo. A restrição do fluxo sanguíneo para o músculo cardíaco devido à aterosclerose pode causar angina de peito ou infarto do miocárdio (ataque cardíaco). A restrição do fluxo sanguíneo para os músculos das pernas induz a claudicação intermitente (dores nas pernas, que ocorrem durante o exercício e são aliviadas pelo repouso). O estreitamento das artérias que fornecem sangue ao cérebro pode causar ataques isquêmicos transitórios (sintomas e sinais de um acidente vascular cerebral que duram menos de 24 horas) e episódios de tontura, ou em último caso, um acidente vascular cerebral, em si.[004] Unfortunately, atherosclerosis does not cause symptoms until the damage to the arteries is severe enough to restrict blood flow. The restriction of blood flow to the heart muscle due to atherosclerosis can cause angina pectoris or myocardial infarction (heart attack). The restriction of blood flow to the leg muscles induces intermittent claudication (pain in the legs, which occurs during exercise and is relieved by rest). The narrowing of the arteries that supply blood to the brain can cause transient ischemic attacks (symptoms and signs of a stroke that last less than 24 hours) and episodes of dizziness, or ultimately, a stroke itself.
[005] O 3-carbóxi-N,N,N-trimetilpropan-1-ammio (GBB) é conhecido principalmente como um bioprecursor de carnitina, uma molécula-chave na regulação do metabolismo energético do miocárdio, foi caracterizado primariamente como uma substância tóxica, que acelera respiração, provoca salivação e lacrimejamento, dilatação da pupila, vasoconstrição e parada cardíaca em diástole (LINNEWEH, W. Gamma-Butyrobetain, Crotonbetain und Carnitin im tierischen Stoffwechsel. Hoppe-Seylers Zeitschrift fur physiologische Chemie. 1929, vol.181, p.42-53). Ao mesmo tempo, em trabalhos posteriores, foi demonstrado que a administração de 3-carbóxi-N,N,N-trimetilpropan-1-ammio não induz quaisquer efeitos tóxicos, uma vez que ele é extremamente de baixa toxicidade (LD50 7000 mg/kg, s.c.) (ROTZSCH, W. Iber die Toxizitat des Carnitins und einiger verwandter Stoffe. Acta biol. med. germ. 1959, vol.3, p.28-36).[005] 3-carboxy-N, N, N-trimethylpropan-1-ammium (GBB) is known mainly as a carnitine bioprecursor, a key molecule in the regulation of myocardial energy metabolism, has been characterized primarily as a toxic substance , which accelerates breathing, causes salivation and tearing, pupil dilation, vasoconstriction and diastolic cardiac arrest (LINNEWEH, W. Gamma-Butyrobetain, Crotonbetain und Carnitin im tierischen Stoffwechsel. Hoppe-Seylers Zeitschrift fur physiologische Chem81. 1929, 29 p.42-53). At the same time, in later work, it was shown that the administration of 3-carboxy-N, N, N-trimethylpropan-1-ammium does not induce any toxic effects, since it is extremely low toxicity (LD50 7000 mg / kg , sc) (ROTZSCH, W. Iber die Toxizitat des Carnitins und einiger verwandter Stoffe. Acta biol. med. germ. 1959, vol.3, p.28-36).
[006] A combinação de 3-carbóxi-N,N,N,-trimetilpropan-1-ammio com diidrato de 3-(2,2,2-trimetil-hidrazínio)-propionato para o tratamento de aterosclerose na publicação internacional WO 2010/149654 A (GRINDEKS JSC) publicada em 29.12.2010. No entanto, o efeito de 3-carbóxi-N,N,N-trimetilpropan-1-ammio, onde ele é usado sozinho, para o tratamento da aterosclerose não é relatada.[006] The combination of 3-carboxy-N, N, N, -trimethylpropan-1-ammium with 3- (2,2,2-trimethylhydrazinium) -propionate dihydrate for the treatment of atherosclerosis in the international publication WO 2010 / 149654 A (GRINDEKS JSC) published on 12/29/2010. However, the effect of 3-carboxy-N, N, N-trimethylpropan-1-ammium, where it is used alone, for the treatment of atherosclerosis is not reported.
[007] Um novo derivado de 3-carbóxi-N,N,N-trimetilpropan-1-ammio, 3-carbóxi-N-etil-N,N,N-dimetilpropan-1-ammio, como um novo composto com atividade cardioprotetora foi divulgado na publicação internacional WO 2011/048201 A (GRINDEKS JSC) publicada em 28.04.2011.[007] A new derivative of 3-carboxy-N, N, N-trimethylpropan-1-ammonium, 3-carboxy-N-ethyl-N, N, N-dimethylpropan-1-ammonium, as a new compound with cardioprotective activity was published in the international publication WO 2011/048201 A (GRINDEKS JSC) published on 28.04.2011.
[008] Camundongos knockout para Apolipoproteína E (ΑροΕ-/-) são frequentemente utilizados como modelo experimental da aterosclerose para a avaliação da atividade anti-aterosclerótica de substâncias testadas.[008] Apolipoprotein E knockout mice (ΑροΕ - / -) are often used as an experimental model of atherosclerosis for the evaluation of the anti-atherosclerotic activity of tested substances.
[009] Esta invenção é direcionada para o tratamento de aterosclerose pela diminuição da área total e volume de lesões ateroscleróticas.[009] This invention is directed to the treatment of atherosclerosis by decreasing the total area and volume of atherosclerotic lesions.
[0010] A inibição da progressão da lesão é conseguida através de tratamento com 3-carbóxi-N-etil-N,N-dimetilpropan-1-amínio seus sais farmaceuticamente aceitáveis: fumarato de hidrogênio de 3-carbóxi-N-etil-N,N-dimetilpropan-1-amínio ou fosfato de dihidrogênio de 3-carbóxi-N-etil-N,N-dimetilpropan-1-amínio, possivelmente, por meio da alteração do metabolismo do colesterol e do lipídeo.[0010] Inhibition of lesion progression is achieved through treatment with 3-carboxy-N-ethyl-N, N-dimethylpropan-1-amine and its pharmaceutically acceptable salts: 3-carboxy-N-ethyl-N hydrogen fumarate , N-dimethylpropan-1-amine or 3-carboxy-N-ethyl-N, N-dimethylpropan-1-amine dihydrogen phosphate, possibly by altering cholesterol and lipid metabolism.
[0011] Uma quantidade terapeuticamente eficaz de 3-carbóxi-N-etil-N,N-dimetilpropan-1-amínio ou seu sal farmaceuticamente aceitável é de cerca de 0,01 a 500 mg/kg/dia, de preferência, 0,1 a 100 mg/kg/dia.[0011] A therapeutically effective amount of 3-carboxy-N-ethyl-N, N-dimethylpropan-1-amine or its pharmaceutically acceptable salt is about 0.01 to 500 mg / kg / day, preferably 0, 1 to 100 mg / kg / day.
[0012] De forma surpreendente e inesperada foi identificado que o 3-carbóxi-N-etil-N,N-dimetilpropan-1-amínio e seus sais farmaceuticamente aceitáveis: fumarato de hidrogênio de 3-carbóxi-N-etil-N,N-dimetilpropan-1-amínio e fosfato de dihidrogênio de 3-carbóxi-N-etil-N,N-dimetilpropan-1-amínio possuem um efeito anti- aterosclerótico pronunciado.[0012] Surprisingly and unexpectedly it was identified that 3-carboxy-N-ethyl-N, N-dimethylpropan-1-amine and its pharmaceutically acceptable salts: 3-carboxy-N-ethyl-N, N hydrogen fumarate -dimethylpropan-1-amine and 3-carboxy-N-ethyl-N, N-dimethylpropan-1-amine dihydrogen phosphate have a pronounced anti-atherosclerotic effect.
[0013] A atividade anti-aterosclerótica de 3-carbóxi-N-etil-N,N-dimetilpropan-1-amínio, fumarato de hidrogênio de 3-carbóxi-N-etil-N,N-dimetilpropan-1-amínio ou fosfato de dihidrogênio de 3-carbóxi-N-etil-N, N-dimetilpropan-1-amínio pode ser determinada por avaliação do efeito destes compostos sobre a porção da superfície aórtica coberta por lesões ateroscleróticas.[0013] The anti-atherosclerotic activity of 3-carboxy-N-ethyl-N, N-dimethylpropan-1-amine, 3-carboxy-N-ethyl-N hydrogen, N-dimethylpropan-1-amine or phosphate of 3-carboxy-N-ethyl-N, N-dimethylpropan-1-amine dihydrogen can be determined by evaluating the effect of these compounds on the portion of the aortic surface covered by atherosclerotic lesions.
[0014] O 3-carbóxi-N-etil-N,N-dimetilpropan-1-amínio pode ser usado em preparações farmacêuticas contendo o composto ou seu sal farmaceuticamente aceitável, em combinação com um veículo ou diluente farmaceuticamente aceitável.[0014] The 3-carboxy-N-ethyl-N, N-dimethylpropan-1-amine can be used in pharmaceutical preparations containing the compound or its pharmaceutically acceptable salt, in combination with a pharmaceutically acceptable carrier or diluent.
[0015] Os veículos farmaceuticamente aceitáveis adequados incluem diluentes ou agentes de enchimento sólidos inertes e soluções orgânicas ou aquosas estéreis. Assim, para administração oral os compostos podem ser combinados com um diluente ou veículo sólido ou líquido adequado para a preparação de cápsulas, comprimidos, pós, xaropes, soluções, suspensões, entre outros. As composições farmacêuticas podem, se desejado, conter componentes adicionais, tais como, flavorizantes, adoçantes, excipientes, entre outros. Para administração parenteral os compostos podem ser combinados com meios orgânicos ou aquosos estéreis para preparar soluções injetáveis ou suspensões. As soluções injetáveis podem ser administradas por vias intravenosa, intraperitoneal, subcutânea ou intramuscular.Suitable pharmaceutically acceptable carriers include inert solid diluents or fillers and sterile organic or aqueous solutions. Thus, for oral administration the compounds can be combined with a diluent or solid or liquid vehicle suitable for the preparation of capsules, tablets, powders, syrups, solutions, suspensions, among others. Pharmaceutical compositions can, if desired, contain additional components, such as flavorings, sweeteners, excipients, among others. For parenteral administration the compounds can be combined with sterile organic or aqueous media to prepare injectable solutions or suspensions. Injectable solutions can be administered intravenously, intraperitoneally, subcutaneously or intramuscularly.
[0016] Camundongos fêmeas ApoE-/- pesando 18 a 20 gramas foram mantidos em um ciclo claro/escuro de 12 horas em ambientes com ar condicionado (22,5±0,5°C, 50±5% de umidade) com acesso ilimitado à comida e água.[0016] ApoE - / - female mice weighing 18 to 20 grams were kept on a 12-hour light / dark cycle in air-conditioned environments (22.5 ± 0.5 ° C, 50 ± 5% humidity) with access unlimited to food and water.
[0017] Os camundongos foram adaptados às condições locais por uma semana antes do início do estudo. Com a idade de oito semanas, os camundongos foram divididos aleatoriamente em cinco grupos de tamanho igual (n = 10). Para induzir a aterosclerose experimental (lesões ateroscleróticas na aorta), os animais de todos os grupos foram alimentados com a dieta WESTERN RD (P) (Cat 82316) a partir dos serviços de dietas especiais (Great Britain) por 4 meses. Durante estes quatro meses, os camundongos de diferentes grupos experimentais receberam seguinte tratamento:
- 1. Grupo controle - água potável;
- 2. Grupo 3-carbóxi-N,N,N-trimetilpropan-1-ammio - 10 mg/kg de 3-carbóxi-N,N,N-1-trimetilpropan-1-ammio em água potável;
- 3. Grupo 3-carbóxi-N-etil-N,N-dimetilpropan-1-ammio - 10 mg/kg de 3-carbóxi-N-etil-N,N-dimetilpropan-1-ammio em água potável;
- 4. Grupo fumarato de hidrogênio do 3-carbóxi-N-etil-N,N-dimetilpropan-1-amínio - 17,5 mg/kg de fumarato de hidrogênio de 3-carbóxi-N-etil-N,N-dimetilpropan-1-ammio em água potável;
- 5. Grupo fosfato de dihidrogênio de 3-carbóxi-N-etil-N,N-dimetilpropan-1-amínio - 16,8 mg/kg de fosfato de dihidrogênio de 3-carbóxi-N-etil-N,N-dimetilpropan-1-ammio em água potável.
- 1. Control group - drinking water;
- 2. Group 3-carboxy-N, N, N-trimethylpropan-1-ammonium - 10 mg / kg of 3-carboxy-N, N, N-1-trimethylpropan-1-ammonium in drinking water;
- 3. Group 3-carboxy-N-ethyl-N, N-dimethylpropan-1-ammonium - 10 mg / kg of 3-carboxy-N-ethyl-N, N-dimethylpropan-1-ammonium in drinking water;
- 4. 3-carboxy-N-ethyl-N, N-dimethylpropan-1-amine hydrogen fumarate group - 17.5 mg / kg 3-carboxy-N-ethyl-N, N-dimethylpropan- hydrogen fumarate 1-ammonium in drinking water;
- 5. 3-Carboxy-N-ethyl-N, N-dimethylpropan-1-amine dihydrogen phosphate group - 16.8 mg / kg 3-carboxy-N-ethyl-N, N-dimethylpropan- dihydrogen phosphate 1-ammonium in drinking water.
[0018] As doses das substâncias testadas foram ajustadas para serem equimolares com a dose de 10 mg/kg de 3-carbóxi-N-etil-N,N-dimetilpropan-1 -amínio.[0018] The doses of the tested substances were adjusted to be equimolar with the dose of 10 mg / kg of 3-carboxy-N-ethyl-N, N-dimethylpropan-1-amine.
[0019] A dosagem dos compostos de teste foi confirmada através da medição do consumo de água potável a cada 2 dias e o ajuste da concentração das substâncias suplementadas.[0019] The dosage of the test compounds was confirmed by measuring the consumption of drinking water every 2 days and adjusting the concentration of the supplemented substances.
[0020] Após 4 meses, os camundongos foram injetados intraperitonealmente (i.p.) com 1,000 Ul de heparina i.p. e sacrificados sob anestesia (pentobarbital de sódio, 50 mg/kg i.p.).[0020] After 4 months, the mice were injected intraperitoneally (i.p.) with 1,000 IU of heparin i.p. and sacrificed under anesthesia (sodium pentobarbital, 50 mg / kg i.p.).
[0021] O tamanho das lesões ateroscleróticas foi determinado em toda a aorta. As aortas do arco até a bifurcação foram limpas de tecidos circundantes, cortadas e fixadas em formaldeído 4%. Depois, toda aorta foi aberta longitudinalmente, fixa em placas de silicone e impregnadas para lipídios com o Sudan IV. As imagens da aorta foram capturadas utilizando uma câmera digital e a área total da lesão foi calculada usando o software Image-Pro Plus 6.3. A extensão da aterosclerose foi expressa como a porcentagem de superfície aórtica coberta por lesões em comparação com a superfície total da aorta.[0021] The size of the atherosclerotic lesions was determined throughout the aorta. The aortas of the arch until the bifurcation were cleaned of surrounding tissues, cut and fixed in 4% formaldehyde. Then, the entire aorta was opened longitudinally, fixed in silicone plates and impregnated for lipids with Sudan IV. The images of the aorta were captured using a digital camera and the total lesion area was calculated using the Image-Pro Plus 6.3 software. The extent of atherosclerosis was expressed as the percentage of aortic surface covered by lesions compared to the total surface of the aorta.
[0022] Todas as análises foram realizadas por um observador que desconhecia o grupo de tratamento.[0022] All analyzes were performed by an observer who was unaware of the treatment group.
[0023] Após a exposição à dieta RD Western por 4 meses, os camundongos apoE-/- desenvolveram lesões ateroscleróticas marcadas. As análises das aortas impregnadas com Sudan IV mostraram que a área das lesões ateroscleróticas no grupo de controle tinha em média 14 a 16% do total da superfície da aorta. A administração por quatro meses de 3-carbóxi-N-etil-N,N-dimetilpropan-1-amínio na dosagem de 10 mg/kg, fumarato de hidrogênio de 3-carbóxi-N-etil-N,N-dimetilpropan-1-amínio na dose de 17,5 mg/kg, fosfato de dihidrogênio de 3-carbóxi-N-etil-N,N-dimetilpropan-1-amínio na dosagem de 16,8 mg/kg (os dois últimos equimolares a 10 mg/kg de 3-carbóxi-N-etil-N,N-dimetilpropan-1-amínio) induziu uma redução estatisticamente significativa no tamanho das lesões ateroscleróticas. O 3-carbóxi-N,N, N-trimetilpropan-1-amínio (10 mg/kg) não teve efeito sobre o tamanho das lesões ateroscleróticas.[0023] After exposure to the RD Western diet for 4 months, apoE - / - mice developed marked atherosclerotic lesions. Analyzes of aortas impregnated with Sudan IV showed that the area of atherosclerotic lesions in the control group averaged 14 to 16% of the total surface of the aorta. The administration for 4 months of 3-carboxy-N-ethyl-N, N-dimethylpropan-1-amine in the dosage of 10 mg / kg, 3-carboxy-N-ethyl-N, N-dimethylpropan-1 hydrogen fumarate -amination at a dose of 17.5 mg / kg, 3-carboxy-N-ethyl-N dihydrogen phosphate, N-dimethylpropan-1-amine at a dosage of 16.8 mg / kg (the last two equimolar at 10 mg / kg of 3-carboxy-N-ethyl-N, N-dimethylpropan-1-amine) induced a statistically significant reduction in the size of atherosclerotic lesions. 3-carboxy-N, N, N-trimethylpropan-1-amine (10 mg / kg) had no effect on the size of atherosclerotic lesions.
[0024] Os efeitos do tratamento de 4 meses com 3-carbóxi-N,N,N-trimetilpropan-1 -amínio, 3-carbóxi-N-etil-N,N-dimetilpropan-1 -amínio, fumarato de hidrogênio de 3-carbóxi-N-etil-N,N-dimetilpropan-1-amínio e fosfato de dihidrogênio de 3-carbóxi-N-etil-N,N-dimetilpropan-1-amínio sobre a área das lesões ateroscleróticas na aorta dos camundongos apoE_/_estão apresentados na tabela 1.
[0025] Os resultados são apresentados como uma porcentagem em relação ao grupo controle que foi atribuído um valor de 100%.[0025] The results are presented as a percentage in relation to the control group that was assigned a value of 100%.
[0026] Os resultados apresentados na tabela 1 mostram que o 3-carbóxi-N-etil-N,N-dimetilpropan-1-ammio, fumarato de hidrogênio de 3-carbóxi-N-etil-N,N-dimetilpropan-1-amínio e fosfato de dihidrogênio de 3-carbóxi-N-etil-N,N-dimetilpropan-1-amínio apresentaram um efeito protetor sobre a formação de lesões ateroscleróticas na aorta de camundongos apoE_/_ O 3-carbóxi-N,N,N-trimetilpropan-1-ammio, ao contrário, não foi eficaz.[0026] The results shown in Table 1 show that 3-carboxy-N-ethyl-N, N-dimethylpropan-1-ammium, 3-carboxy-N-ethyl-N, N-dimethylpropan-1- hydrogen fumarate amine and 3-carboxy-N-ethyl-N, N-dimethylpropan-1-amine dihydrogen phosphate had a protective effect on the formation of atherosclerotic lesions in the aorta of apoE _ / _ O 3-carboxy-N, N, N mice -trimethylpropan-1-ammium, on the contrary, was not effective.
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| PCT/EP2013/077291 WO2014096133A1 (en) | 2012-12-20 | 2013-12-19 | Use of 3-carboxy-n-ethyl-n,n-dimethylpropan-1-aminium or a pharmaceutically acceptable salt thereof in the treatment of atherosclerosis |
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| WO2010151095A1 (en) * | 2009-06-25 | 2010-12-29 | Tetra, Sia | Novel acetylsalicylic acid salts |
| LV14345B (en) * | 2009-10-22 | 2011-07-20 | Grindeks, A/S | 4-[ethyl(dimethyl)ammonio]butanoate and their use in the treatment of cardiovascular diseases |
| RS55092B1 (en) * | 2011-04-27 | 2016-12-30 | Grindeks Jsc | Use of 3-carboxy-n-ethyl-n,n-dimethylpropan-1-aminium salts in the treatment of cardiovascular disease |
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