Mestrado em Ciências Farmacêuticas (FF)
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Navegando Mestrado em Ciências Farmacêuticas (FF) por Por Orientador "Cunha, Luiz Carlos da"
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Item Estudo de farmacocinética comparativa entre o resveratrol e o seu complexo hidroxi-γ-ciclodextrina(Universidade Federal de Goiás, 2019-05-28) Diniz, Juliana Araújo; Cunha, Luiz Carlos da; http://lattes.cnpq.br/6349547031976679; Cunha, Luiz Carlos da; Menegatti, Ricardo; Effting, Cristiane; Oluwagbamigbe, JamesResveratrol is a polyphenol that induces vasodilation, antineoplastic, anti-inflammatory, antioxidant and antiplatelet activities. Despite these beneficial effects, resveratrol is characterized by limited therapeutic performance due to its low oxidation stability and low aqueous solubility. Hence, an improvement in bioavailability may be an interesting outlet for such limitations. In order to increase oral bioavailability, resveratrol was incorporated into hydroxy-γ-cyclodextrin, resulting in resveratrol-hydroxy-γ-cyclodextrin complex (RES-γ-CD). In order to verify the efficiency of the complexation, resveratrol (resveratrol + DMSO) was compared to its complex (RES-γ-CD), determining the pharmacokinetic parameters (Tmax, Cmax, AUCT, t1/2, Vd e CLT), by the oral and intravenous routes, with absolute values (F%) and relative bioavailability (FR%) being obtained. The HPLC-PDA analytical technique was validated and the pharmacokinetic parameters were statistically the same, except for a much higher Cmax of RES-γ-CD. The F% and FR% values of resveratrol were higher for RES-γ-CD formulation, demonstrating better absolute and relative bioavailability than the administered resveratrol dissolved in DMSO. In conclusion, the incorporation of resveratrol into hydroxy-γ-cyclodextrin is promising to increase the bioavailability of resveratrol, which may improve its efficacy.Item Avaliação da toxicidade aguda oral, atividades antinociceptiva e anti-inflamatória da crotamina isolada da peçonha de Crotalus durissus collilineatus em camundongos(Universidade Federal de Goiás, 2017-04-28) Moreira, Lorena Alves; Cunha, Luiz Carlos da; http://lattes.cnpq.br/6349547031976679; Cunha, Luiz Carlos da; Fajemiroye, James Oluwagbamigbe; Rodrigues, Caroline RegoIntroduction: Crotamine is a low molecular weight cationic polypeptide (4.8 kDa), isolated from rattlesnake venom. In the previous study the presence of this toxin in the snake venom Crotalus durissus collilineatus was responsible for anti-edematogenic activity, suggesting its anti-inflammatory properties. Pain and inflammation are present mechanisms in several pathologies, being important the search for new compounds candidates for effective drugs and with less adverse effects than those existing in the market for such treatments. Objective: To determine acute oral toxicity of crotamine isolated from snake venom C. d. collilineatus was evaluated and its effects in experimental models of pain and inflammation in mice was investigated. Methodology: To evaluate acute oral toxicity, the up and down procedure and hippocratic screening was performed. For the nociceptive and inflammation assays, acetic acid-induced abdominal writhing, formalin-induced pain, ear edema induced by croton oil and pleurisy induced by carrageenan were performed. Results and Discussion: Crotamine did not cause lethality or signs of intoxication in the dose range of 0.34 to 10.88 mg/kg. In the abdominal writhing test, treatments at doses of 0.08, 0.16 and 0.32 mg/kg p.o. reduced the number of writhings in relation to the control by 34, 57 and 74 %, respectively, showing a dose-dependent trend. In the formalin-induced pain test it was observed that crotamine (0.16 mg/kg p.o.) reduced reactivity to pain in the neurogenic phase in 44.8% and in the inflammatory phase in 59.7%, suggesting antinociceptive activity. In addition, crotamine (0.16 mg/kg p.o.) was able to reduce ear edema induced by croton oil by 77 %, showing antidematogenic activity and reduced in 52.3 % the number of total leukocytes in the pleurisy test, reducing both neutrophil and mononuclear cells migration, thus exhibiting antimigratory activity. Conclusion: Crotamine did not induce a toxic or lethal effect at the doses tested. The reductions in writhings, reactivity to pain, ear edema and leukocytes migration with administration of crotamine were significant, suggesting that it has antinociceptive and anti-inflammatory activities.Item Estudo do perfil cinético e alométrico do protótipo de fármaco antineoplásico LQFM018 em modelos experimentais por LC-MS/MS(Universidade Federal de Goiás, 2015-03-31) Rodrigues, Andryne Rego; Cunha, Luiz Carlos da; http://lattes.cnpq.br/6349547031976679; Cunha, Luiz Carlos da; Carneiro, Wilsione José; Teixeira, Leonardo de SouzaLQFM018 is a prototype drug with proven anticancer activity in vitro (cytotoxicity against K-562 cell line, IC50 = 0.07652 mM), which was obtained by molecular simplification from antitumor compounds called nutlins, inhibitors of the interaction MDM2-p53. This study aimed to determine its pharmacokinetic profile, using, to this end, validated bioanalytical method in LC-MS/MS. The parameters used in analytical LC-MS/MS were: ACE® C18 column (100 mm × 4.6 mm, 5 μm), mobile phase buffer 2 mM ammonium acetate with 0.025% formic acid and methanol (50%:50% v/v), flow 1.2 mL/min, temperature of the column 40 °C, internal standard (IS) domperidone, liquid-liquid extraction with methyl tert-butyl ether (MTBE) and injection volume of 3.0 μL. The method was linear from 10 to 15,000 ng/mL (r = 0.9997). Intrarun precision was ranged from 0.6% to 5.5% and interrun from 1.8% to 6.7%. The accuracy found was 99.0% to 107.0% and the average recovery of controls was 74.1% ± 4.9%. The retention times were 3.16 min for LQFM018 and 1.81 min to domperidone. LQFM018 was administered to 3 females Wistar rats at 100 mg/kg, i.p. After administration, 0.5 mL samples of blood were collected by cannulation of the left jugular vein with heparinized syringe, at 1h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h and 9 h. Blood samples were identified and centrifuged to obtain plasma which was frozen at -20 °C until the time of analysis. The pharmacokinetic parameters (mean ± SD) were t½ = 2.89 ± 2.0 h; ClT/F = 22.01 ± 13.5 mL/min/kg; Vd/F = 5.48 ± 3.6 L/kg. The values of Vd/F, t½ and CLT/F extrapolated using allometric scaling for a person weighing 70 kg were 1954.3 L/kg, 12.6 h and 1800.4 mL/min/kg, respectively. The bioanalytical method was suitable for the detection and quantification of LQFM018 from plasma rat. The kinetic profile, extrapolated on allometric scaling, revealed a high value of t½, high Vd and long value of CLT, allowing understand that the studied prototype showed good tissue distribution profile and was extensively eliminated.Item Análise toxicológica por técnicas de triagem aplicada em amostras biológicas post-mortem de casos suspeitos de intoxicação provenientes de Instituto de Criminalítisca(Universidade Federal de Goiás, 2014-02-12) Silva, Maria Augusta Alves; Cunha, Luiz Carlos da; http://lattes.cnpq.br/6349547031976679; Cunha, Luiz Carlos da; Alcântara, Keila Correia de; Effting, CristianeThe toxicological analyzes on various samples are extremely important and can be used for multiple purposes, such as monitoring of drug addicts, forensic analysis, doping control, therapeutic monitoring, analyses of environmental contaminants, etc. The objective of this study was to analyze post - mortem blood samples of the Instituto de Criminalística de Goiás (IC) by immunochromatography and systematic toxicological analysis HPLC - PDA to check the presence or absence of toxic agents. The chromatographic conditions of the method were: mobile phase monobasic potassium phosphate buffer pH 2.3 and acetonitrile, flow rate 1 ml / min, Lichrospher RP8 column, 5μm, 250 x 4.0 mm, scanning range 200-380 nm, the calibration standards were MPPH system, caffeine, benzene and histamine. It was used the database proposed by UVTOX Pragst et al (2001). As part of the partial validation the matrix effect was evaluated by liquid-liquid extraction of whole blood samples contaminated with 8 standards in known concentration. The whole blood samples were extracted at different pH values and analyzed by HPLC -PDA. Through the areas obtained from each standard, it was calculated the standardized factor matrix which showed a coefficient of variation less than 10 %. In order to compare two screening techniques for detection of drugs of abuse, post-mortem blood samples from the IC (n = 35) were also analyzed by immunochromatography, yielding 10 samples positive for amphetamine, 3 for benzoylecgonine and 1 for Δ9THC. The ATS by HPLC – PDA analyses showed only 1 sample positive for benzoylecgonine, 2 samples for amphetamines, and 3 benzodiazepines. In the other samples, no substance toxicological interest was detected. Both immunochromatography as systematic toxicological analysis proved useful tools in screening post-mortem blood.Item Atividade hepatoprotetora do extrato hidroalcólico do resíduo agroindustrial de jabuticaba (Myrciaria cauliflora O. Berg), e do extrato etanólico das folhas de fruta-pão (Artocarpus altilis (Parkinson) Fosberg), em camundongos(Universidade Federal de Goiás, 2015-04-01) Silva, Marina Alves Coelho; Cunha, Luiz Carlos da; http://lattes.cnpq.br/6349547031976679; Cunha, Luiz Carlos da; Valladão, Adryano Augusto; Parente, Leila Maria LealWas evaluated the hepatoprotective effect of hydro alcoholic extract of the agroindustrial waste of jaboticaba-paulista (HEJB (Myrciaria cauliflora O. Berg, Myrtaceae) and ethanolic extract of breadfruit leaves (EEBL) (Artocarpus altilis (Park.) Fosberg, Moraceae) in experimental model of hepatotoxicity carbon tetrachloride (CCl4). The jaboticaba tree is native to Brazil and largely grown. It has a potential antioxidant, with phenolic compounds present primarily in the peel of fruit, which is a waste from the manufacturing process jaboticaba wine. Breadfruit is originating to the Pacific Islands and is distributed throughout the world. Fruits and leaves of this plant species have compounds with pharmacological properties, such as flavonoids. Were used Swiss mice, male, divided in eight groups, with five being the control groups (I: Baseline, received no treatment; II: olive oil, 10 mL/kg, i.p.; III: Propylene glycol 50%, 10 ml/kg, v.o. IV: 0.3% CCl4 in olive oil 10 mL/kg, i.p., negative control; V: Silymarin 200 mg/kg, v.o., positive control) and four treated groups, v.o. (VI: HEJB 250 mg/kg, VII: HEJB 500 mg/kg, VIII: EEBL: 250 mg/kg). Except groups I and II, all others received 0.3% CCl4 in olive oil on the 7th day of treatment, 2 hours after administration v.o. Were monitored the weight gain and no had significant difference between groups. At the end of the treatments, blood and liver of the animals were removed for biochemical analysis, after the animals were submitted to euthanasia and macroscopic evaluation of organs and cavities. The potential hepatoprotective and antioxidant activity of plant extracts were observed through the hepatic enzyme L-alanine aminotransferase (ALT), L-aspartate aminotransferase (AST), glutathione peroxidase (GPx ), glutathione reductase (GR) and catalase (CAT) and the dosage of malondialdehyde (MDA) - which required validation analytical HPLC-PDA. The bioanalytical method has a linear, selective, accurate, precise, and without interfering with LOQ 0.5 nmol/mL and LOD of 0.25 nmol/ml, suitable for the dosage of MDA in plasma and liver. There was a decrease of MDA in liver tissue, for the two extracts, as well as decreased levels of AST / ALT and GR to post-treatment with EHJB. The agroindustrial waste of jaboticaba fruit peel and the ethanolic extract of breadfruit leaves showed antioxidant activity in vivo.Item Validação de técnica analítica em LC-MS/MS para quantificação da ivermectina em plasma canino(Universidade Federal de Goiás, 2022-11-17) Toledo, Ney Ramos; Cunha, Luiz Carlos da; http://lattes.cnpq.br/6349547031976679; Cunha, Luiz Carlos da; Rodriguez Salazar, Vânia Cristina; Rodrigues, Caroline RegoIvermectin is an antiparasitary drug with endectocide activity, which is derived from avermectin, a macrocyclic lactone isolated from actinomycete Streptomyces avermectinus. This study aims to validate a new ivermectin’s analytical methodology, in dog plasma, with pharmacokinetic and bioavailability studies as objectives, regarding the still necessary clinical studies in dogs for veterinary products approval. Moreover, the optimized and developed method had as objective to have analytical benefits over the existent methods. The chosen analytical technique was High Performance Liquid Chromatography coupled to Mass Spectrometry (HPLC-MS/MS) with a Zorbax® C18 column from AgilentTM and, as mobile phase, 90:10 (Methanol:water) with 0,1% formic acid and 5 mM ammonium formate being added to aqueous and organic phases. The internal standard of choice was abamectin due to high similarity with ivermectin. Analytical validation was performed through a calibration curve with 7. Precision and accuracy intra-day and inter-day results were obtained through triplicate concentrations of quality control samples. Intra-day precision had 4,0 – 14,9% CV values and inter-day 6,4 – 11,6%. Intra-day accuracy had values between 95,0 and 114,61% and inter-day 98,1 and 109,0%. Stability studies had values between 88,8 and 98,2%. All results agree with parameters stablished by RDC nº27/2012. The analytical technique was used to determine ivermectin’s p.o. kinetic profile of a 2-year-old female mongrel dog weighting 14 kg, and proved adequate to quantificate typical concentration variations of pharmacokinetic data: Cmáx = 17,85 ng/mL; Tmáx = 1,00 h; AUC0-inf_obs = 2113,21 ng/mL*h; Vd = 41,24 L/Kg. The optimized and developed method had reduced use of organic solvents in its extraction method, faster analytical run, lower sample volume and can be used in pharmacokinetical studies.Item Avaliação pré-clínica do perfil farmacocinético do protótipo antitumoral lLQFM030 em ratos por LC-MS/MS(Universidade Federal de Goiás, 2013-10-18) Zoghaib, Iury Valentim Jorge; Cunha, Luiz Carlos da; http://lattes.cnpq.br/6349547031976679; Cunha, Luiz Carlos da; Costa, Sérgio Henrique Nascente; Efting, Cristiane; Salazar, Vania Cristina RodríguezThe LQFM030 was obtained by molecular simplification of nutlins (inhibitors of p53-MDM2 interaction) and, having demonstrated excellent antineoplastic activity in vitro (cytotoxicity against K-562 cell line with IC50 = 23 M) and in vivo against Ehrlich ascitic tumor with increased survival in treated animals developed the pharmacokinetic study of p.o. in rats. It was used for LC-MS/MS analytical method (Applied Biosystems MDS Sciex API 3200) previously validated together. O LQFM030 was administered to 3 rats (mean weight 186g) in predetermined dose of 100 mg/kg by gavage. After administration, samples were collected from 1.0 mL of blood by cannulation of the left jugular vein with heparinized syringe, the intervals 0-8 h. The blood samples were identified and centrifuged to obtain plasma which was frozen at -20°C until analysis. The kinetic parameters were calculated in the software WinNonlin 5.0 (Pharsight™). Results (mean ± SD) half-life (t1/2) 3.61 ± 0.68 h, total clearance (CLT) 36.49 ± 2.23 mL/min/kg, volume of distribution (Vd) 11,40 ± 1.58 L/kg. The LQFM030 had low value of t1/2, Vd high and high value of CLT. These values allow us to understand that the prototype study demonstrated a good safety profile of tissue distribution and/or has been extensively eliminated. When compared with the kinetic parameters obtained in other studies, it was observed difference in results is justified by the high interspecies variability, mainly in basal metabolic rate and body weight, once the route of administration, orally and intraperitoneally, are kinetically similar.Item Avaliação pré-clínica do perfil farmacocinético do complexo de rutênio II/ triptofano em ratos por espectrofotometria UV-Vis(Universidade Federal de Goiás, 2015-09-28) Zoghaib, Alarisse Arçari Fachetti; Cunha, Luiz Carlos da; http://lattes.cnpq.br/6349547031976679; Cunha, Luiz Carlos da; Meira, Flávia Neri; Parente, Leila Leal; Oliveira, Stela Ramirez deThe ruthenium (II)/amino acid complex (rutrpII) demonstrated high anticancer activity against murine breast cancer (tumor of Ehrlich) in vitro and in vivo, and increased the median survival of animals. There was then necessary to investigate the pharmacokinetic parameters of the drug prototype as a requirement to pre-clinical knowledge of it. This study aimed to obtain the pharmacokinetic profile of ruthenium (II) / tryptophan administered to rats intraperitoneally in a single dose by quantifying this substance in plasma using validated analytical methodology in UV-VIS spectrophotometer. The methodology consisted of the administration of the prototype rutrpII to 3 rats at a dose of 6 mg/kg, intraperitoneally. Samples of blood 1.0 ml were collected by cannulation of the left jugular vein with heparinized syringe, the intervals from 0 to 9 hr. After centrifugation the plasma was frozen at -20 until the time of analysis. The bioanalytical method to quantify rutrpII was developed and validated in UV-VIS at a wavelength of 417 nm. From the construction of the concentration versus time curve, the kinetic parameters were calculated (Software WinNonlin 5.0 (Pharsight ™) Results were: Tmax = 8 h, Cmax = 169.86 mg/mL, t1/2 = 1.04 ± 0.02 h, ClT/F = 1.32 ± 0.05 mL/min/kg, Vd/F = 1,98 ± 0,05 L/kg. The developed and validated bioanalytical method was suitable for the detection and quantification of RutrpII in rat plasma. The values of pharmacokinetic profiles found, and extrapolated on allometric scaling allow us to understand that the compound studied showed a slow tissue distribution profile and / or was eliminated slowly (Vd low and low value CLT), due to a possible affinity between RutrpII and plasma proteins. This affinity may be explained by the similarity of their chemical structure with iron, enabling it to be transported by biomolecules such as transferrin, albumin or any other, and having as a target the DNA of cancer cells. In general, the compounds of ruthenium (II) / amino acids may be promising drugs for the amino acids present in the complex, may facilitate the recognition of the complex as a whole by DNA, and thus less toxic.