Efeito tipo-antidepressivo e antioxidante do Ibuprofeno no modelo da Doença de Parkinson induzido por administração de Rotenona intraperitoneal em ratos

Resumo: A doença de Parkinson idiopática (DP) é uma doença neurodegenerativa, que afeta aproximadamente 1% da população mundial acima de 55 anos, manifestando-se através de sinais motores e sintomas não-motores, como a depressão, decorrentes principalmente da neurodegeneração dos neurônios dopaminérgicos na substância negra pars compacta (SNpc). Dentre os possíveis mecanismos envolvidos nesta patologia, destacam-se a disfunção mitocondrial, neuroinflamação e o estresse oxidativo. Em nosso estudo foi avaliado o efeito do antiinflamatório não esteróide (AINE) ibuprofeno, um inibidor não seletivo da enzima ciclooxigenase, sobre o prejuízo motor e comportamento tipo-depressivo induzidos pela administração intraperitoneal de rotenona em ratos. Nossos resultados demonstram que a administração de rotenona (2,5 mg/kg, por 10 dias, i.p.), foi capaz de reduzir a imunoreatividade da enzima tirosina-hidroxilase na SNpc, enquanto que o pós-tratamento com ibuprofeno (15 mg/kg, por 22 dias, p.o.) bloqueou esta redução. Também demonstramos que a rotenona foi capaz de induzir déficit motor (hipolocomoção) e comportamento tipo-depressivo, sendo ambos revertidos pelo pós-tratamento com ibuprofeno. Além destes parâmetros, foi avaliado o estresse oxidativo induzido por esta toxina. A administração de rotenona promoveu depleção nos níveis de GSH na região do hipocampo, e também reduziu a atividade da catalase em ambas as regiões, hipocampo e estriado. O pós-tratamento com ibuprofeno bloqueou a depleção do GSH induzida pela rotenona, bem como, aumentou os níveis basais deste antioxidante na região do estriado. O ibuprofeno também restaurou a atividade da catalase. Assim, acreditamos que o efeito neuroprotetor do ibuprofeno contra a toxicidade induzida pela rotenona em nosso estudo seja decorrente de suas propriedades antioxidante e inibidora da COX

Synthesis and evaluation of antidiarrheal activity of pyridopyrimidine analogues

Orientador: Gilberto De NucciTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: O aumento dos níveis de nucleotídeos cíclicos (GMPc e AMPc) nos enterócitos, desencadeia mecanismos intracelulares de secreção de íons e líquidos para o lúmen intestinal, caracterizando a diarreia secretória. Neste trabalho, doze novas moléculas derivadas de piridopirimidinas foram sintetizadas e avaliadas quanto seu efeito sob o acúmulo induzido de nucleotídeos cíclicos intracelular. Nossos resultados demonstram que todos os compostos não exercem efeito sob os níveis basais (ausência de estímulo exógeno) de nucleotídeos cíclicos e também em anéis aórticos pré-contraídos de coelhos. Tanto a atividade metabólica e viabilidade nas células, avaliadas pelos testes MTT e LDH, respectivamente, não foram afetadas pela incubação com os compostos (50 ?M). O melhor composto em atividade, composto VI, quase aboliu o acúmulo de GMPc (94% de inibição) induzido pela toxina STa em células T84 e reduziu significativamente (69%) o acúmulo de AMPc induzido por Forscolina em células Jurkat. O composto VI foi avaliado em um modelo in vivo de diarreia em coelhos, onde demonstrou eficácia em inibir o acúmulo de líquidos induzido pela STa e redução nos danos e alterações morfológicas teciduais promovidas pela exposição à esta enterotoxina. O teste de estabilidade in vitro revelou que o composto VI é resistente à oxidação promovida pelo oxigênio atmosféricoAbstract: The increased levels of cyclic nucleotides (cGMP and cAMP) in enterocytes trigger intracellular mechanisms of ion and fluid secretion into the lumen causing secretory diarrhea. Twelve novel pyridopyrimidines derived from 5-(3,5-bistrifluoromethylphenyl)-1,3-dimethyl-5,11-dihydro-1H-indeno[2,1:5,6]pyrido[2,3-d]pyrimidine-2,4,6-trione (FPIPP) were synthesized and evaluated on intracellular cyclic nucleotide accumulation. All compounds had no effect on either cyclic nucleotide basal levels or on pre-contracted aortic rings. The metabolic activity and viability in T84 cells, assessed by MTT and LDH assays respectively were not affected by incubation with the compounds (50 µM). Compound VI almost abolished cGMP accumulation (94% inhibition) induced by STa toxin in T84 cells and significantly decreased (69%) forskolin-induced cAMP accumulation in Jurkat cells. Compound VI was found to be active in an in vivo model for diarrhea in rabbits. In vitro stability test revealed that compound VI is resistant to oxidation promoted by atmospheric oxygenDoutoradoFarmacologiaDoutor em Farmacologia2013/15525-1FAPES

Amiloride relaxes rat corpus cavernosum relaxation in vitro and increases intracavernous pressure in vivo

The antihypertensive effects of thiazide diuretics such as hydrochlorothiazide are commonly associated with erectile dysfunction. The association of hydrochlorothiazide/amiloride is not associated with erectile dysfunction. The hypothesis is that amiloride has beneficial effect in penile erection and, therefore, counterbalances the hydrochlorothiazide-induced disruptive effect. Aim: To investigate the effects of amiloride and its analogues hexamethylamiloride and benzamil on rat isolated corpus cavernosa (CC) and intracavernous pressure (ICP) in anaesthetized rats. Methods: Rat isolated CC were incubated with amiloride, hexamethylamiloride, and benzamil (10 and 100 mu mol/L each), followed by phenylephrine, potassium chloride, and electrical field stimulation (EFS). Their effect on the relaxant responses to EFS and sodium nitroprusside were also determined. Oral (30 mg/kg) and intraperitoneal (3 mg/kg) treatments with amiloride were also investigated on nerve-evoked ICP. Main Outcome Measures: In vitro functional studies and in vivo ICP measurement on rat CC were performed. Additionally, phosphodiesterase type V isoform A1 activity and the mRNA expressions of Na+/H+ pump, epithelial sodium channel exchangers (ENaC) channels (alpha-, beta- and gamma subunits) and Na+/Ca2+ exchangers were evaluated in CC tissues. Results: Amiloride and its analogues significantly reduced the phenylephrine-, potassium chloride-, and EFS-induced CC contractions, which were not changed by nitro-L-arginine methyl ester (100 mu mol/L) or indomethacin (6 mu mol/L). In phenylephrine-precontracted CC tissues, amiloride itself caused concentration-dependent relaxation and significantly increased the EFS-induced relaxation. Oral and intraperitoneal treatment with amiloride significantly increased the ICP. Phosphodiesterase type V isoform A1 activity was not affected by amiloride. Na+/H+ pump, ENaC, and Na+/Ca2+ exchanger mRNA expressions were all detected in rat CC tissues. Clinical Implication: Amiloride analogues may have therapeutic potential for erectile dysfunction. Strength & Limitations: The interesting effect of amiloride in penile erection was observed in both in vitro and in vivo methods. The evidence at the moment is restricted to rat CC. Conclusion: Amiloride reduces in vitro CC contractility and enhances erectile function after oral and intraperitoneal administration, possibly via inhibition of ENaC4500511COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPPNPD20131784 - 33003017051P02007/08440-

Campomanesia adamantium peel extract in antidiarrheal activity: the ability of Inhibition of heat-stable enterotoxin by polyphenols

Campomanesia adamantium (Myrtaceae) is a medicinal plant distributed in Brazilian Cerrado. Different parts of this plant are used in popular medicine for treatment of several diseases like fever, diarrhea, hypercholesterolemia and rheumatism. The aim of this work was to evaluate the inhibition of heat-stable enterotoxin type A (STa) by gallic acid present in the peel of C. adamantium fruit and assays to assess the antidiarrheal activity, anti-inflammatory and cytotoxic properties of peel extract using the T84 cell line model. The possible inhibition exerted by the gallic acid of the peel extract on the STa peptide was inferred by molecular dynamics simulations. The antidiarrheal effects were investigated measuring cGMP accumulation in cells after stimulation by STa toxin and antibacterial activity was assessed. The anti-inflammatory activity was assessed by inhibition of COX-1 and COX-2. MTT and LDH assays were used to evaluate any possible cytotoxic action while the CyQUANT test was used to investigate the effect on cell proliferation. A representation showing how the possible interactions between STa and the gallic acid of the extract might reduce the action of the enterotoxin is presented. C. adamantium peel extract significantly decreased the levels of cGMP in T84 cells. However, no effect on the species of microorganisms was observed. The extract also inhibited COX-1 (IC50 255.70 +/- 0.04 ng/mL) and COX-2 (IC50 569.50 +/- 0.11 ng/mL) enzymes. Cytotoxicity assay have shown significant changes in cells treated with the extract, which inhibited the cell proliferation until 72 hours of treatment. Direct interactions of phenolic compounds present in the extract with the STa toxin may limit its activity. Curative effect in the diarrhea treatment and its anti-inflammatory action is based on the pharmacological properties, mechanism of action of the C. adamantium peel extract, and no toxic effects of the peel extract presented on this work1110CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP470374/2013-62010/16947-9; 2013/05475-7; 2013/08293-

Campomanesia adamantium Peel Extract in Antidiarrheal Activity: The Ability of Inhibition of Heat-Stable Enterotoxin by Polyphenols.

Campomanesia adamantium (Myrtaceae) is a medicinal plant distributed in Brazilian Cerrado. Different parts of this plant are used in popular medicine for treatment of several diseases like fever, diarrhea, hypercholesterolemia and rheumatism. The aim of this work was to evaluate the inhibition of heat-stable enterotoxin type A (STa) by gallic acid present in the peel of C. adamantium fruit and assays to assess the antidiarrheal activity, anti-inflammatory and cytotoxic properties of peel extract using the T84 cell line model. The possible inhibition exerted by the gallic acid of the peel extract on the STa peptide was inferred by molecular dynamics simulations. The antidiarrheal effects were investigated measuring cGMP accumulation in cells after stimulation by STa toxin and antibacterial activity was assessed. The anti-inflammatory activity was assessed by inhibition of COX-1 and COX-2. MTT and LDH assays were used to evaluate any possible cytotoxic action while the CyQUANT test was used to investigate the effect on cell proliferation. A representation showing how the possible interactions between STa and the gallic acid of the extract might reduce the action of the enterotoxin is presented. C. adamantium peel extract significantly decreased the levels of cGMP in T84 cells. However, no effect on the species of microorganisms was observed. The extract also inhibited COX-1 (IC50 255.70 ± 0.04 ng/mL) and COX-2 (IC50 569.50 ± 0.11 ng/mL) enzymes. Cytotoxicity assay have shown significant changes in cells treated with the extract, which inhibited the cell proliferation until 72 hours of treatment. Direct interactions of phenolic compounds present in the extract with the STa toxin may limit its activity. Curative effect in the diarrhea treatment and its anti-inflammatory action is based on the pharmacological properties, mechanism of action of the C. adamantium peel extract, and no toxic effects of the peel extract presented on this work

Additional file 3: Table S3. of Rebamipide does not protect against naproxen-induced gastric damage: a randomized double-blind controlled trial

Individual histopathological scores and H. pylori status before and after treatment for each volunteer. (DOCX 15 kb

Acetylsalicylic Acid Daily Vs Acetylsalicylic Acid Every 3 Days In Healthy Volunteers: Effect On Platelet Aggregation, Gastric Mucosa, And Prostaglandin E2 Synthesis

Substantial platelet inhibition was observed 3 days after a single administration of acetylsalicylic acid 81 mg to healthy volunteers. Here we investigate prostaglandin E2 (PGE2) antrum concentrations and gastrointestinal symptoms in two treatment groups: one receiving losartan and acetylsalicylic acid every day and the other receiving losartan every day and acetylsalicylic acid every 3 days. Twenty-eight healthy volunteers from both sexes received either 50 mg losartan and acetylsalicylic acid 81 mg daily or 50 mg losartan and acetylsalicylic acid 81 every 3 days with placebo on the other days. Therapy was delivered for 30 days for both groups. Gastric endoscopy was performed before and after treatment period. Biopsies were collected for PGE2 quantification. Platelet function tests were carried out before and during treatment and TXB2 release on platelet rich plasma was measured. The every 3 day low-dose acetylsalicylic acid regimen produced complete inhibition of platelet aggregation compared to the daily treatment. Thromboxane B2 release was substantially abolished for both groups during treatment. There was no significant difference on the endoscopic score of both treatment groups after the 30-day treatment (P = .215). There was over 50% suppression of antrum PGE2 content on volunteers receiving acetylsalicylic acid daily (P = .0016), while for the every 3 day dose regimen there was no significant difference between pre and post-treatment antrum PGE2 dosages (P = .4193). Since PGE2 is involved in gastric healing, we understand that this new approach could be safer and as efficient as the standard daily therapy on a long-term basis. © 2015, The American College of Clinical Pharmacology