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Item Planejamento, síntese e avaliação da atividade tipo ansiolítica e do perfil antioxidante de novo candidato a protótipo de fármaco LQFM 180(Universidade Federal de Goiás, 2016-08-26) Braga, Patrícia Caixeta Castro Souza; Costa, Elson Alves; http://lattes.cnpq.br/2607893423583912; Costa, Elson Alves; http://lattes.cnpq.br/2607893423583912; Lião, Luciano Morais; Carvalho, Flávio Silva de; Menegatti, RicardoFaced with the high and increasing number of people suffering from some form of mental illness in the world, it is necessary to develop additional therapeutic options for patients not helped by existing treatments and also to address medical / famacológicas unmet needs. Given this panorama, this paper proposes the design, synthesis and evaluation of pharmacological type anxiolytic activity and antioxidant profile of a new drug candidate prototype 4- (3,5-ditert-butyl-4-hydroxybenzyl) piperazine-1 carboxylate acetate (LQFM180 (8)). The new prototype was designed by molecular hybridisation strategy of prototypes from 4 - ((1-phenyl- 1H-pyrazol-4-yl) methyl) piperazine-1-carboxylate Ethyl (LQFM008 (5)) and 2,6-di- tertbutyl-phenol (BHT (9)). LQFM180 (8) The compound was synthesized by the Mannich reaction, in 92% yield, which was chemically characterized by infrared spectroscopy (IR) and nuclear magnetic resonance dimensional and two-dimensional (1H, HSQC and HMBC). Evaluation of antioxidant status was carried out by cyclic voltammetry, which confirmed that the compound has antioxidant activity. For evaluation central pharmacological activity of the compound were worked four behavioral models in animals, with treatment with LQFM180 at doses of 25, 50 and 100 mmol / kg V.O. In the test of sleep induced by sodium pentobarbital, the LQFM180 (8) reduced latency and increased barbiturate sleep duration, indicating a central depressant activity. Treatment with LQFM180 (8) in different doses did not alter the number of self-cleaning, dung, total and raised intersections, behavioral parameters observed in the open field test; there is no impairment of exploratory activity. Also in the open field test, the compound LQFM180 (8) indicated anxiolytic type activity, demonstrated by the increase in length of stay, and the entrance in the center of the field. LQFM180 (8) treatment did not alter the motor activity test in the chimney, which was evidenced by the animal climbing time. The compound LQFM180 (8) evaluated the maze test in high cross, possess anxiolytic activity type; evidenced by the increase in time and entering the open arms and the time reduction in the central platform. At the end of this work we can see that the synthetic route proposed for obtaining LQFM180 (8) compound was effective, given the high yields obtained, little laborious steps and cost. Finally, we conclude that the employee structural planning was ratified before the success of the structural characterization of the compound and the results obtained from the central pharmacological evaluation in animal models. As perspective, it is necessary to establish the mechanism of action of the molecule as well as the continuation of in vivo evaluations.Item Avaliação da atividade tipo antidepressiva do óleo essencial das folhas de Spiranthera odoratissima A. St.-Hil. e de seu componente majoritário, β-cariofileno(Universidade Federal de Goiás, 2016-03-31) Oliveira, Danillo Ramos de; Costa, Elson Alves; http://lattes.cnpq.br/2607893423583912; Costa, Elson Alves; Bara, Maria Teresa Freitas; Carvalho, Pablinny Moreira Galdino deSpiranthera odoratissima A. St.-Hil., popularly known as “manacá”, is a vegetal specie found in Cerrado regions. The chemical composition of essential oil of “manacá” (OEM) by gas chromatography and mass spectrometry (GC/MS) identified -caryophyllene (BCP) as the majority constituent. Pre-clinical studies indicated the anxiolytic like effect of OEM is associated with serotonergic system. Some data revealed that depression and anxiety disorders often coexist together instead only one in the patient and some drugs are effective for both disturbs. In this context, we created the hypothesis that OEM and BCP should present antidepressant like effect. This study was conducted for evaluate the antidepressant like activity of OEM and the phytoconstituent β-caryophyllene and verified the possible mechanisms involved in this activity. Male Albino Swiss mice were used in the open field (OFT), forced swim (FST) and tail suspension test (TST). The animals were treated with increasing doses of OEM (125, 250 and 500 mg/kg) and of BCP (25, 50, 70, 100 and 140 mg/kg). The treatment with OEM at doses of 250 and 500 mg/kg, BCP at doses of 50, 70 and 100 mg/kg reduced the immobility time of animals in the TST without alteration in the exploratory activity in the OFT. The dose of 500 mg/kg of OEM and dose of 100 mg/kg of BCP showed the best effect and were chosen to continue the study. Possible alterations in the levels of serotonin (5 – HT), noradrenaline (NE) and in the brain derived neurotrophic factor (BDNF) were verified in the mechanisms of action. The anti-immobility time of OEM was reverted by the pre-treatment with NAN- 190 (0,5 mg/kg i.p., 30 minutes before – 5-HT1A antagonist), PCPA (100 mg/kg i.p., during 4 days – inhibitor of serotonin synthesis), AMPT (100 mg/kg i.p., 4 h before – inhibitor of catecholamines), ioimbine (1 mg/kg i.p., 15 minutes before - 2 adrenergic antagonist) and propranolol (2 mg/kg i.p., 15 minutes before - adrenergic antagonist), but was not reverted by the pretreatment with prazosin (1 mg/kg i.p., 15 minutes before - α1 adrenergic antagonist), suggesting the involvement of serotonergic and catecholaminergic systems in the antidepressive like activity. About the BCP, the pre-treatment with NAN-190, in the conditions described above, did not block the antidepressive like activity of this compound, suggesting the absence of participation of serotonergic system in this activity. The prazosin did not reverse the effect of BCP. However, the previous administration of AMPT, ioimbine and propranolol in the same conditions described above, prevents the antidepressant like activity of BCP in the FST, suggesting the involvement of catecholamines, specifically of NE, in the antidepressive like effect of the BCP. In relation with the capacity to alter the hipocampal levels of BDNF, BCP showed this activity after 14 days of treatment. In this sense we conclude that OEM and the phytoconstituent (BCP) showed antidepressant like effect with involvement of serotonergic system and of the 5-HT1A receptor in the action of OEM, but not of the BCP. Moreover, a activation of α2 and β-adrenergic receptors, but not of 1, are involved in the activity of OEM and of the BCP found in this study. Additionally, the increase in the hippocampal levels of BDNF, can be the responsible, at least in part, with the antidepressant like activity of BCP.Item Avaliação farmacológica no sistema nervoso central de um novo derivado piperazínico LQFM 104(Universidade Federal de Goiás, 2015-03-13) Rodrigues, Oscar Romero Lopes; Costa, Elson Alves; http://lattes.cnpq.br/2607893423583912; Costa, Elson Alves; Cunha, Luiz Carlos da; Guedini, Paulo CésarThe Laboratório de Química Farmaceutica Medicinal designed and synthesized a new piperazine derivative tert-butyl 4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazine-1-carboxylate (LQFM104) based on molecular framework of clozapine. This study aimed the pharmacological evaluation in the central nervous system of the LQFM104. Treatment with LQFM104 at doses of 25 , 50 or 100 μmol/kg (p.o.) in the open-field test did not alter in animals the number of grooming behavior, the number of fecal boluses, the total number of crossings, immobility time, number of rears, the percentage of crossings in the central area and the time spent in the center. None of groups of doses tested with LQFM104 was able to change the time spent in the chimney test. In pentobarbital-induced sleep test, the treatment with LQFM104 25, 50 or 100 μmol/kg (p.o.) did not affect sleep latency, while the sleep duration has increased by 65%, 64.4% and 78.6% respectively compared to the control group treated orally with vehicle 10 ml/kg (28.8 ± 2.9 minutes). In the standardization of apomorphine-induced climbing test, the treatment with haloperidol at dose of 2.6 μmol/kg was able to reduce the climbing behavior in 97.8%, whereas clozapine at dose of 45 μol/kg, has reduced this behavior in 78 % when compared to control (16.87 ± 2.8). The LQFM104 50 or 200 μmol/kg (p.o.) was not able to reduce the climbing behavior. In the forced swimming test just LQFM104 50 μmol/kg (p.o.) was able to reduce the immobility time in 19.8% compared to the control group ( 263.2 ± 6.7 seconds) and increased the latency to immobility in 43%, compared with the control ( 70.6 ± 6.5 seconds). Similarly, in the tail suspension test, only the LQFM104 50 μmol/kg (p.o.) increased immobility time (32.1%) compared to the control (216.1 ± 13.2 seconds). The LQFM104 50 μmol/kg (p.o.) had their antidepressant-like effects completely reversed by blocking treatment with PCPA and NAN-190. And the quantification of brain-derived neurotrophic factor the LQFM104 50 μmol/kg (p.o.) did not change these levels. The results with LQFM104 in the open-field test indicated no changes in spontaneous locomotor activity and showed no anxiogenic activity. The chimney test did not reveal impairment in motor coordination. The pentobarbital-induced sleep test increased sleep duration without reducing the latency, thus suggesting a sedative action. The forced swimming test and the tail suspension test confirmed for LQFM104 50 μmol/kg (p.o.) an antidepressant activity in mice. The blockade with NAN-190 and PCPA suggests the involvement of serotonergic system and 5-HT1A receptor.Item Avaliação da atividade gastroprotetora do extrato etanólico das raízes da Me-mora nodosa (Silva Manso) Miers (Bignoniaceae) e de seu fitoconstituinte – Alantoína(Universidade Federal de Goiás, 2015-07-10) Silva, Dayane Moreira da; Costa, Elson Alves; http://lattes.cnpq.br/2607893423583912; Costa, Elson Alves; Paula, José Realino de; Ghedini, Paulo CésarMemora nodosa (Silva Manso) Miers (Bignoniaceae) is a Cerrado plant popularly known as caroba. In traditional medicine leaves and roots are used by the wound healing properties and the roots for abdominal pain. From ethanolic root extract of Memora nodosa (EERMN) was extracted a purinic derivative, allantoin, that is founded in products for topical use by the wound healing properties. Previous works revealed anti-inflammatory and antinociceptive properties with EERMN and allantoin. In this context, we seek evidence of whether, in addition to antiinflammatory action, there would be some gastric damaging effect. However, after the initial results obtained, this work sought to evaluate the antiulcerogenic effect of the extract and the allantoin and elicit the mechanisms involved in this activity. Albino Swiss mice, weighing 30-35g, maintained on standard conditions of temperature (23 1C) and illumination (12-h light/12-h dark cycle) were used. The gastroprotective activity was designed in different experimental gastric ulcers models induced by food restriction, indomethacin, stress, ethanol, ethanol acidity and acetic acid. Seven days after food restriction the animals treated with EERMN (300 mg/kg p.o.) showed reduction in the index of lesion from 15.01 2.92 to 5.20 1.44. In indomethacin induced gastric lesion, different EERMN doses (100, 300 and 1000 mg/kg p.o.) reduced the index of lesion from 12.70 1.70 (control) to 7.20 0.35; 6.37 0.41 and 5.71 0.47 respectively. Seven days after food restriction the animals treated with EERMN (300 mg/kg p. o.) showed reduction in the lesion index from 15.01 2.92 to 5.20 1.44. When the gastric ulcers were induced by ethanol 75%, the EERMN reduced the ulcerated area in 69%. The gastric acid secretion parameters (volume, pH and total acidity) did not alter by the treatment with the plant extract. However, the treatment with EERMN was capable to avoid the gastric mucus barrier depletion when compared to control lesion group, although it was not able to alter the glutathione levels. In the ethanol acidity model, the treatment with allantoin in doses of 30, 60 and 120 mg/kg reduced ulcerated area from 67.08 3.07% to 51.53 4.67; 42.32 4.93 and 43.18 4.90% respectively. When the lesions were induced by ethanol, allantoin (60 mg/kg p.o.) reduced ulcerated area in 80%. In models of acute lesions induced by stress and indomethacin, this same allantoin dose reduced the index of lesion from 11.90 0.93 to 6.62 0.49 and from 15.35 0.81 to 7.09 0.96 respectively. In the chronic model, allantoin demonstrated an antiulcerogenic effect by the reduction of lesion area from 74.41 4.57 to 24.10 0.89 mm2 in the acetic acid model. In the quantification of gastric mucus, similarly to EERMN, allantoin was able to prevent the mucus depletion (34.77 4.14) when compared with control lesion group (19.75 2.53). Moreover, allantoin was able to restore the activity of catalase enzyme from 403.7 15.1 (control lesion group) to 499.9 16.38 nmol/mg protein after gastric lesion induced by ethanol. These results demonstrate antiulcerogenic activity for EERMN and allantoin throughout different mechanisms.Item Caracterização farmacológica e avaliação da atividade gastroprotetora do extrato etanólico das folhas de Celtis iguanaea (JACQ.) Sargent (Ulmaceae) - Esporão-de-galo(Universidade Federal de Goiás, 2011-06-30) Sousa, Fábio Borges de; Costa, Elson Alves; http://lattes.cnpq.br/2607893423583912; Costa, Elson Alves; Paula, José Realino de; Silveira, Nusa de AlmeidaCeltis iguanaea (Jacq.) Sargent is a small postage plant, it has very flexible branches, armed with spines. The tea obtained through it leaves is popularly used for body pain, rheumatism, chest pain, asthma, cramps, poor digestion and as diuretic. In this study, we evaluated the leaves of Celtis iguanaea, which were collected in Hidrolândia-GO, dried in an ethanolic extract of esporão-de-galo (EEEG). The EEEG was dissolved in water and fractionated by successive liquid-liquid partition with hexane (FH), dichloromethane (FD), ethyl acetate (FAcE) and the aqueous phase (EA). The animals used were Swiss Mice (male, adults, weighing 35–40 mg/kg). After the pharmacological screening, the animals were subjected to analysis of treatment effects with EEEG (100, 300 and 1000 mg/kg p.o.) on the central nervous system (CNS) through the open-field test, “rota-rod” test, and sleep induction by pentobarbital. To evaluate the effects on the gastrointestinal tract, the animals were orally pre-treated with ethanolic extract of esporão-de-galo (EEEG 100, 300 and 1000 mg/kg), vehicle (10 mL/kg) or ranitidine (50 mg/kg) before induction of gastric lesions by indomethacin (30 mg/kg - s. c.), ethanol 75 % (v/v), and stress by contention and hypothermia, and treated intraduodenally in the model of gastric lesions induced by pyloric ligation. The effects of the extract on the volume, pH and total acidity of gastric secretion were evaluated by pyloric ligation method. We also tested if the EEEG and fractions affected the intestinal transit and gastric emptying by the methods of activated charcoal and phenol-red respectively. The hexane fraction (FH 180 mg/kg), dichloromethane fraction (FD 9 mg/kg), ethyl acetate fraction (FAcE 16 mg/kg) and aqueous fraction (FA 360 mg/kg), administered orally, were tested in model of induction of lesions by indomethacin (30 mg/kg s.c.), to elucidate the active fractions of the extract. After determining the active fraction, it was tested in different doses to establish the dose-dependent relationship. A possible action on the intestinal transit was also evaluated. In the evaluation of the EEEG on CNS, we didn’t found any evidence of activity on this system. In models of lesion induction by different ulcerogenic agents (indomethacin, ethanol, stress and pyloric ligation) using EEEG at doses of 100, 300 and 1000 mg/kg, was observed a significant reduction in both the number of ulcers and in the lesions rate caused by these agents. By intraduodenal administration in the model of pyloric ligation, we evaluated volume, free acidity and total acidity, and the animals treated with the EEEG had a reduction in volume, free acidity and total acidity. Only the hexane fraction (FH) showed gastroprotective activity, being effective reducing the number of ulcers and the lesions rate. When we evaluated the parameters of gastric secretion with this fraction (FH), we observed a decrease in volume, increase in pH and decrease in total acidity. Both EEEG and its hexane fraction didn’t alter intestinal motility or gastric emptying. The results of this study suggest that the EEEG has a gastroprotective activity, and this activity involves the active ingredients of the plant with systemic activity, which may justify the popular use of Celtis iguanaea for the treatment of gastritis and gastric ulcers.