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1.
Molecules ; 28(21)2023 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-37959778

RESUMO

Nitric oxide (NO) production in injured and intact brain regions was compared by EPR spectroscopy in a model of brain and spinal cord injury in Wistar rats. The precentral gyrus of the brain was injured, followed by the spinal cord at the level of the first lumbar vertebra. Seven days after brain injury, a reduction in NO content of 84% in injured brain regions and 66% in intact brain regions was found. The difference in NO production in injured and uninjured brain regions persisted 7 days after injury. The copper content in the brain remained unchanged one week after modeling of brain and spinal cord injury. The data obtained in the experiments help to explain the problems in the therapy of patients with combined brain injury.


Assuntos
Lesões Encefálicas , Traumatismos da Medula Espinal , Humanos , Ratos , Animais , Ratos Wistar , Óxido Nítrico , Medula Espinal , Encéfalo
2.
Sci Rep ; 13(1): 13624, 2023 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-37604841

RESUMO

Chemotherapy is one of the main treatment options for cancer, but it is usually accompanied with negative side effects. The classical drugs combination with synergistic adjuvants can be the solution to this problem, allowing reducing therapeutic dose. Elucidating the mechanism of adjuvant action is of key importance for the selection of the optimal agent. Here we examine the system drug-adjuvant to explain the observed effect in practice. We used the first line drug cisplatin. Morpholinium and 4-methylpiperazinium 4,5-dichloro isothiazol-3-carboxylates were selected as adjuvants. The study of the cisplatin-adjuvant system was carried out by quantum chemical modeling using DFT. It turned out that adjuvants form conjugates with cisplatin that lead to the relocation of frontier molecular orbitals as well as increase of conjugate's dipole moment. It resulted in change of the interaction character with DNA and increase of the bioactivity of the system. The data obtained are the basis for expanding the studies to include other drugs and adjuvants. Oncologists will have opportunity to use "classical" chemotherapy drugs in combination with synergists for those patients who have not been previously recommended to such a treatment because of pronounced toxic side effects.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Neoplasias Neuroepiteliomatosas , Humanos , Cisplatino/uso terapêutico , Adjuvantes Imunológicos , Adjuvantes Farmacêuticos
3.
Oncol Lett ; 15(4): 5098-5104, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29552144

RESUMO

Immunotherapy in the form of anticancer vaccination relies on the mobilization of the patient's immune system against specific cancer antigens. Instead of focusing on an autologous cell lysate, which is not always available in clinical practice, the present study investigates vaccines utilizing xenogeneic foetal tissue that are rich in oncofoetal antigens. Lewis lung carcinoma (LLC)-challenged C57BL/6 mice were treated with either a xenogeneic vaccine made from chicken whole embryo, or a xenogeneic vaccine made from rat embryonic brain tissue, supplemented with a Bacillus subtilis protein fraction as an adjuvant. Median and overall survival, size of metastatic foci in lung tissue and levels of circulating CD8a+ T cells were evaluated and compared with untreated control mice. Following primary tumour removal, a course of three subcutaneous vaccinations with xenogeneic chicken embryo vaccine led to significant increase in overall survival rate (100% after 70 days of follow-up vs. 40% in untreated control mice), significant increase in circulating CD8a+ T cells (18.18 vs. 12.6% in untreated control mice), and a significant decrease in the area and incidence of metastasis foci. The xenogeneic rat brain tissue-based vaccine did not improve any of the investigated parameters, despite promising reports in other models. We hypothesize that the proper selection of antigen source (tissue) can constitute an effective immunotherapeutic product.

4.
Oncol Rep ; 37(1): 171-178, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27878261

RESUMO

Instead of relying on external anticancer factors for treatment, immunotherapy utilizes the host's own immune system and directs it against given tumour antigens. This study demonstrated that it is possible to overcome the documented immunosuppressive properties of tumour cell lysate by supplementing it with appropriate adjuvant. Lewis lung carcinoma (LLC)­challenged C57BL/6 mice were treated with LLC cryo­lysate mixed with either bacterial ghosts (BGs) generated from E. coli Nissle 1917 or B. subtilis 70 kDa protein as adjuvants. Median and overall survival, the size of metastatic foci in lung tissue and levels of circulating CD8a+ T cells were evaluated and compared to the untreated control mice or mice treated with LLC lysate alone. After primary tumour removal, a course of three subcutaneous vaccinations with LLC lysate supplemented with BGs led to a significant increase in overall survival (80% after 84 days of follow­up vs. 40% in untreated control mice), a significant increase in circulating CD8a+ T cells (16.57 vs. 12.6% in untreated control mice) and a significant decrease in metastasis foci area and incidence. LLC lysate supplemented with B. subtilis protein also improved the inspected parameters in the treated mice, when compared against the untreated control mice, but not to a significant degree. Therefore, whole cell lysate supplemented with BGs emerges as an immunostimulatory construct with potential clinical applications in cancer treatment.


Assuntos
Adjuvantes Imunológicos/uso terapêutico , Bactérias/imunologia , Vacinas Anticâncer/uso terapêutico , Carcinoma Pulmonar de Lewis/terapia , Extratos Celulares/uso terapêutico , Vacinação/métodos , Animais , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/uso terapêutico , Bacillus subtilis , Bactérias/química , Carcinoma Pulmonar de Lewis/imunologia , Carcinoma Pulmonar de Lewis/mortalidade , Carcinoma Pulmonar de Lewis/patologia , Extratos Celulares/imunologia , Linhagem Celular Tumoral , Escherichia coli , Feminino , Camundongos , Camundongos Endogâmicos C57BL
5.
Cell Mol Biol Lett ; 19(2): 243-8, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24764142

RESUMO

We used complexes between a fourth generation polyamidoamine (PAMAM) dendrimer and one of two heterocyclic compounds - 1-(6-hydroxyhexyl)-3-(5-phenyl-isoxazole-3-yl)-urea or 5-phenyl-isoxazole-3-carboxylic acid - to reduce oxygen consumption in transverse slices of the hippocampus taken from 4-week old male rats. In vitro electrophysiological experiments revealed that the inhibitory effect of the hypoxic state on the evoked responses was enhanced in the presence of the complexes. The data were analyzed in terms of the potential antitumor effects of these complexes.


Assuntos
Encéfalo/metabolismo , Ácidos Carboxílicos/química , Dendrímeros/farmacologia , Hipocampo/efeitos dos fármacos , Hipóxia , Isoxazóis/química , Ureia/análogos & derivados , Animais , Dendrímeros/química , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Hipocampo/metabolismo , Técnicas In Vitro , Masculino , Oxigênio/metabolismo , Ratos , Ureia/química
6.
PLoS One ; 8(9): e75733, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24069444

RESUMO

Systemic inflammatory response syndrome is associated with either fever or hypothermia, but the mechanisms responsible for switching from one to the other are unknown. In experimental animals, systemic inflammation is often induced by bacterial lipopolysaccharide (LPS). To identify the diencephalic and brainstem structures involved in the fever-hypothermia switch, we studied the expression of c-Fos protein, a marker of neuronal activation, in rats treated with the same high dose of LPS (0.5 mg/kg, intravenously) either in a thermoneutral (30 °C) or cool (24 °C) environment. At 30 °C, LPS caused fever; at 24 °C, the same dose caused profound hypothermia. Both fever and hypothermia were associated with the induction of c-Fos in many brain areas, including several structures of the anterior preoptic, paraventricular, lateral, and dorsal hypothalamus, the bed nucleus of the stria terminalis, the posterior pretectal nucleus, ventrolateral periaqueductal gray, lateral parabrachial nucleus, area postrema, and nucleus of the solitary tract. Every brain area studied showed a comparable response to LPS at the two different ambient temperatures used, with the exception of two areas: the dorsomedial hypothalamic nucleus (DMH), which we studied together with the adjacent dorsal hypothalamic area (DA), and the paraventricular hypothalamic nucleus (PVH). Both structures had much stronger c-Fos expression during LPS hypothermia than during fever. We propose that PVH and DMH/DA neurons are involved in a circuit, which - depending on the ambient temperature - determines whether the thermoregulatory response to bacterial LPS will be fever or hypothermia.


Assuntos
Núcleo Hipotalâmico Dorsomedial/metabolismo , Neurônios/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Animais , Regulação da Temperatura Corporal , Núcleo Hipotalâmico Dorsomedial/imunologia , Expressão Gênica , Lipopolissacarídeos/imunologia , Masculino , Neurônios/imunologia , Núcleo Hipotalâmico Paraventricular/imunologia , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Temperatura
7.
Am J Physiol Regul Integr Comp Physiol ; 302(12): R1372-83, 2012 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-22513748

RESUMO

The natural switch from fever to hypothermia observed in the most severe cases of systemic inflammation is a phenomenon that continues to puzzle clinicians and scientists. The present study was the first to evaluate in direct experiments how the development of hypothermia vs. fever during severe forms of systemic inflammation impacts the pathophysiology of this malady and mortality rates in rats. Following administration of bacterial lipopolysaccharide (LPS; 5 or 18 mg/kg) or of a clinical Escherichia coli isolate (5 × 10(9) or 1 × 10(10) CFU/kg), hypothermia developed in rats exposed to a mildly cool environment, but not in rats exposed to a warm environment; only fever was revealed in the warm environment. Development of hypothermia instead of fever suppressed endotoxemia in E. coli-infected rats, but not in LPS-injected rats. The infiltration of the lungs by neutrophils was similarly suppressed in E. coli-infected rats of the hypothermic group. These potentially beneficial effects came with costs, as hypothermia increased bacterial burden in the liver. Furthermore, the hypotensive responses to LPS or E. coli were exaggerated in rats of the hypothermic group. This exaggeration, however, occurred independently of changes in inflammatory cytokines and prostaglandins. Despite possible costs, development of hypothermia lessened abdominal organ dysfunction and reduced overall mortality rates in both the E. coli and LPS models. By demonstrating that naturally occurring hypothermia is more advantageous than fever in severe forms of aseptic (LPS-induced) or septic (E. coli-induced) systemic inflammation, this study provides new grounds for the management of this deadly condition.


Assuntos
Regulação da Temperatura Corporal/fisiologia , Escherichia coli , Febre/fisiopatologia , Hipotermia/fisiopatologia , Inflamação/fisiopatologia , Lipopolissacarídeos , Animais , Temperatura Corporal/fisiologia , Febre/induzido quimicamente , Hipotermia/induzido quimicamente , Inflamação/induzido quimicamente , Masculino , Ratos , Ratos Wistar
8.
PLoS One ; 7(4): e34537, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22509318

RESUMO

The limited specificity of nanoparticle (NP) uptake by target cells associated with a disease is one of the principal challenges of nanomedicine. Using the threshold mechanism of plasmonic nanobubble (PNB) generation and enhanced accumulation and clustering of gold nanoparticles in target cells, we increased the specificity of PNB generation and detection in target versus non-target cells by more than one order of magnitude compared to the specificity of NP uptake by the same cells. This improved cellular specificity of PNBs was demonstrated in six different cell models representing diverse molecular targets such as epidermal growth factor receptor, CD3 receptor, prostate specific membrane antigen and mucin molecule MUC1. Thus PNBs may be a universal method and nano-agent that overcome the problem of non-specific uptake of NPs by non-target cells and improve the specificity of NP-based diagnostics, therapeutics and theranostics at the cell level.


Assuntos
Ouro/química , Ouro/metabolismo , Nanopartículas Metálicas , Nanocápsulas , Transporte Biológico , Linhagem Celular , Humanos , Fenômenos Ópticos , Especificidade de Órgãos , Especificidade por Substrato
9.
Med Chem ; 8(1): 22-32, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22420547

RESUMO

Neuroepithelial tumor cells were cultured in vitro. The biopsy material was taken from 93 children at removal of the brain tumors during neurosurgical operations. The individual features of the cells sensitivity of primary cultures in respect to protocol-approved chemotherapy drugs and changes in the Interleukin-6 (Il-6) level in the culture medium after the application of chemotherapy were established. The initial level of Il-6 exceeded 600.0 pg/ml in the cultural medium with histologically verified pilomyxoid astrocytoma cells, and ranged from 100.0 to 200.0 pg/ml in the medium at cultivation of ganglioneuroblastoma and pilocytic astrocytoma. A decrease in the Il-6 level in the medium culture of primary tumors cells was observed after the application of chemotherapeutic agents on the cells of pilomyxoid astrocytoma, astrocytomas, and pilocytic desmoplastic/nodular medulloblastoma. The production of Il-6 increased after application of cytostatic drugs on the cells of oligoastrocytomas. A decrease in Il-6 level after application of Cisplatin and Methotrexate and a 5-10 fold increase in the level of Il-6 after application of Etoposide, Carboplatin, Cytarabine, and Gemcitabine were registered in the medium with ganglioneuroblastoma. To improve the cytotoxic action of chemotherapeutic agents, the combined application of cytostatics with heterocyclic compounds was carried out. A computer modeling of ligand-protein complexes of carbamide using the Dock 6.4 and USF Chimera program packages was performed with molecular mechanics method. Special attention was drawn to the ability of several isoxazole heterocycles and isothiazolyl to inhibit the tyrosine kinase. It was proved in vitro that the joint application of chemotherapeutic agents and heterocyclic compounds could reduce the concentration of the cytostatic factor by 10 or more times, having maintained the maximum cytotoxic effect. It was assumed that the target amplification of cytotoxic action of chemotherapeutic agents had prospects for reducing toxic side effects of chemotherapy in vivo, which would be carried out only after the preclinical studies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/patologia , Compostos Heterocíclicos/farmacologia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/síntese química , Protocolos de Quimioterapia Combinada Antineoplásica/química , Neoplasias Encefálicas/cirurgia , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Sistema Nervoso Central/cirurgia , Criança , Pré-Escolar , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Humanos , Lactente , Interleucina-6/análise , Cultura Primária de Células , Células Tumorais Cultivadas
10.
Eur J Appl Physiol ; 111(9): 2229-37, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21327795

RESUMO

Immersion is a useful tool for studying fluid-volume homeostasis. Natriuretic peptides play a vital role in renal, humoral, and cardiovascular regulation under changing environmental conditions. We hypothesized that dry immersion would rapidly induce a new steady state for water and sodium metabolism, and that serum NT-proBNP levels, a proxy measure for brain natriuretic peptide (BNP), would decrease during long-term dry immersion and increase during recovery. Eight healthy young men were studied before, during, and after 7 days of dry immersion. Body weight, water balance, and plasma volume changes were evaluated. Plasma and serum samples were analyzed for active renin, NT-proBNP, aldosterone, electrolytes, osmolality, total protein, and creatinine. Urine samples were analyzed to determine levels of electrolytes, osmolality, creatinine, and free cortisol. A stand test was performed before and after dry immersion to evaluate cardiovascular deconditioning. Long-term dry immersion induced acute changes in water and sodium homeostasis on day 1, followed by a new steady state. Plasma volume decreased significantly during dry immersion. The serum levels of NT-proBNP increased significantly in recovery (10 ± 3 ng/L before dry immersion vs. 26 ± 5 ng/L on the fourth recovery day). Heart rate in the standing position was significantly greater after immersion. Results suggest that chronic dry immersion rapidly induced a new level of water-electrolyte homeostasis. The increase in NT-proBNP levels during the recovery period may be related to greater cardiac work and might reflect the degree of cardiovascular deconditioning.


Assuntos
Água Corporal/fisiologia , Homeostase/fisiologia , Imersão/fisiopatologia , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Sódio/metabolismo , Adulto , Água Corporal/metabolismo , Dessecação , Saúde , Humanos , Imersão/efeitos adversos , Masculino , Recuperação de Função Fisiológica , Fatores de Tempo , Equilíbrio Hidroeletrolítico/fisiologia , Adulto Jovem
11.
Brain Res ; 993(1-2): 227-9, 2003 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-14642851

RESUMO

Intraperitoneal capsaicin desensitizes sensory fibers traveling within both the vagus and splanchnic nerves. Because capsaicin desensitization blocks the first phase of lipopolysaccharide (LPS) fever, whereas surgical vagotomy does not, splanchnic mediation of the first phase was proposed. However, all phases of the febrile response of splanchnicotomized rats to intravenous LPS (10 microg/kg) were similar to those of sham-operated controls. Hence, the splanchnic nerve is likely uninvolved in LPS fever.


Assuntos
Febre/fisiopatologia , Lipopolissacarídeos , Nervos Esplâncnicos/cirurgia , Animais , Temperatura Corporal/fisiologia , Modelos Animais de Doenças , Febre/induzido quimicamente , Masculino , Ratos , Ratos Long-Evans , Vagotomia/métodos
12.
J Physiol ; 553(Pt 1): 221-8, 2003 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-14565987

RESUMO

Lipopolysaccharide (LPS)-induced systemic inflammation is accompanied by either hypothermia (prevails when the ambient temperature (Ta) is subneutral) or fever (prevails when Ta is neutral or higher). Because platelet-activating factor (PAF) is a proximal mediator of LPS inflammation, it should mediate both thermoregulatory responses to LPS. That PAF possesses hypothermic activity and mediates LPS-induced hypothermia is known. We asked whether PAF possesses pyrogenic activity (Expt 1) and mediates LPS fever (Expt 2). The study was conducted in Long-Evans rats implanted with jugular catheters. A complex with bovine serum albumin (BSA) was infused as a physiologically relevant form of PAF; free (aggregated) PAF was used as a control. In Expt 1, either form of PAF caused hypothermia when infused (83 pmol kg-1 min-1, 60 min, i.v.) at a subneutral Ta of 20 degrees C, but the response to the PAF-BSA complex (-4.5 +/- 0.5 degrees C, nadir) was ~4 times larger than that to free PAF. At a neutral Ta of 30 degrees C, both forms caused fever preceded by tail skin vasoconstriction, but the febrile response to PAF-BSA (1.0 +/- 0.1 degrees C, peak) was > 2 times higher than that to free PAF. Both the hypothermic (at 20 degrees C) and febrile (at 30 degrees C) responses to PAF-BSA started when the total amount of PAF infused was extremely small, < 830 pmol kg-1. In Expt 2 (conducted at 30 degrees C), the PAF receptor antagonist BN 52021 (29 micromol kg-1, i.v.) had no thermal effect of itself. However, it strongly (~2 times) attenuated the febrile response to PAF (5 nmol kg-1, i.v.), implying that this response involves the PAF receptor and is not due to a detergent-like effect of PAF on cell membranes. BN 52021 (but not its vehicle) was similarly effective in attenuating LPS (10 microg kg-1, i.v.) fever. It is concluded that PAF is a highly potent endogenous pyrogenic substance and a mediator of LPS fever.


Assuntos
Febre/fisiopatologia , Fator de Ativação de Plaquetas/fisiologia , Animais , Diterpenos/farmacologia , Meio Ambiente , Ginkgolídeos , Lactonas/farmacologia , Lipopolissacarídeos/farmacologia , Masculino , Glicoproteínas da Membrana de Plaquetas/antagonistas & inibidores , Ratos , Ratos Long-Evans , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Soroalbumina Bovina/metabolismo , Temperatura
13.
J Physiol ; 547(Pt 3): 941-9, 2003 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-12562931

RESUMO

The involvement of the cholecystokinin (CCK)-A receptor in fever was studied. The polyphasic febrile responses to lipopolysaccharide (LPS; 10 microg kg-1, I.V.) were compared between wild-type Long-Evans (LE) rats and the CCK-A-receptor-deficient Otsuka LE Tokushima Fatty (OLETF) rats. The response of the wild-type rats was biphasic, which is typical for LE rats. Phases 1 and 2 of the response of the OLETF rats were similar to those of the LE rats, but the OLETF rats also developed a robust phase 3. This late enhancement of the febrile response could reflect either the absence of the A receptor per se or a secondary trait of the mutant strain. To distinguish between these possibilities, we conducted a pharmacological analysis. We studied whether the normally low phase 3 of LE rats can be enhanced by a CCK-A-receptor antagonist, sodium lorglumide (4.3 microg kg-1 min-1, 120 min, I.V.), and whether the normally high phase 3 of Wistar rats can be attenuated by a CCK-A receptor agonist, sulphated CCK-8 (up to 0.17 microg kg-1 min-1, 120 min, I.V.). The dose of sodium lorglumide used was sufficient to increase food intake (to block satiety), but it did not affect the fever response. In both febrile and afebrile rats, CCK-8 induced dose-dependent skin vasodilatation and decreased body temperature, but it failed to produce any effects specific for phase 3. We conclude that the exaggeration of phase 3 in OLETF rats reflects a secondary trait of this strain and not the lack of the CCK-A receptor per se. None of the three known phases of the febrile response of rats to LPS requires the CCK-A receptor.


Assuntos
Antagonistas de Hormônios/farmacologia , Proglumida/análogos & derivados , Proglumida/farmacologia , Receptores da Colecistocinina/genética , Receptores da Colecistocinina/metabolismo , Sincalida/farmacologia , Animais , Relação Dose-Resposta a Droga , Febre/induzido quimicamente , Febre/fisiopatologia , Deleção de Genes , Lipopolissacarídeos/farmacologia , Masculino , Mutagênese , Ratos , Ratos Endogâmicos OLETF , Ratos Mutantes , Ratos Wistar , Receptor de Colecistocinina A , Resposta de Saciedade/efeitos dos fármacos , Resposta de Saciedade/fisiologia
14.
Auton Neurosci ; 98(1-2): 99-101, 2002 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-12144051

RESUMO

In acute experiments on nembutal-urethan-anaesthetized rats, a slow infusion of subseptic dose of lipopolysaccharide (LPS) Escherichia coli (1 mg/ml) via the right jugular vein immediately led to bradycardia and extrasystoles. Preliminary administration of 20 mg/kg N(G)-nitro-L-arginine methyl ester (L-NAME) or 30 mg/kg aminoguanidine hydrochloride prevented the LPS-induced extrasystoles but did not affect the pattern of bradycardia. We conclude that nitric oxide (NO)-ergic mechanisms are involved in provoking electrical instability of the heart in conditions of endotoxemia.


Assuntos
Escherichia coli , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Lipopolissacarídeos/farmacologia , Óxido Nítrico/fisiologia , Animais , Bradicardia/induzido quimicamente , Complexos Cardíacos Prematuros/induzido quimicamente , Complexos Cardíacos Prematuros/prevenção & controle , Inibidores Enzimáticos/farmacologia , Guanidinas/farmacologia , Injeções Intravenosas , Veias Jugulares , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Ratos , Ratos Wistar
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