Tolerância às metilxantinas e interações com o Sistema Dopaminérgico: possíveis implicações clínicas

Recent studies have suggested that methylxanthines could change neuroleptics efficiency, since haloperidol or chlorpromazine-induced catalepsy is reversed by methylxanthines. However, these studies were made with acute administration of the drugs, disregarding the possible development of tolerance to methylxanthines. In the present mini-review of the literature it was observed that few studies investigated the tolerance to methylxanthines, furthermore there is some controversy between them. In our laboratory we found no tolerance to caffeine in relation to the etfect on the rat locomotor activity and its ability in reversing chlorpromazine-induced catalepsy. These results suggest that well-controled clinical studies with psychiatric patients in current use of both kinds of drugs are necessary to establish if methylxanthines actually change neuroleptics antipsychotic efficacy.Trabalhos recentes sugerem que as metilxantinas poderiam interferir com a eficiência terapêutica dos neurolépticos, uma vez que a catalepsia induzida por haloperidol ou clorpromazina é revertida por metilxantinas. Todavia, estes trabalhos forem feitos através da administração aguda das drogas, o que exclui o possivel desenvolvimento de tolerância as metilxantinas. No presente trabalho fez-se uma revisão da literatura e observou-se que os estudos sobre o desenvolvimento de tolerância ás metilxantinas são poucos e, em alguns casos, controversos. Além disto, em nosso laboratório não encontramos tolerância á cafeína no tocante á estimulação da atividade locomotora e á reversão de catalepsia induzida por clorpromazina. Estes resultados demonstram a necessidade da execução de estudos clínicos bem controlados com pacientes psiquiátricos que usem drogas de ambos os grupos para determinar se as metilxantinas interferem efetivamente com a eficácia antipsicótica dos neurolépticos

EXERCÍCIO FÍSICO E Diabetes mellitus TIPO 2

Um estilo de vida sedentrio deve ser considerado um importante fator de risco capaz de ser modificado para indivduos com diabetes mellitus (DM) tipo 2, j que atividade fsica regular oferece mltiplos benefcios que incluem melhora da sensibilidade insulina e do controle glicmico, aumento do condicionamento cardiorespiratrio e reduo do risco de mortalidade cardiovascular. Entretanto, o estabelecimento de programas de treinamentos e de guias prticos para o manejo adequado na diabetes tipo 2 no tm sido sugeridos num consenso nico. Dessa forma, o presente estudo selecionou publicaes realizadas a partir de dados Pubmed, objetivando discutir informaes que esto sendo descritas na literatura de forma a reforar bases que representem uma resposta adaptativa s demandas do treinamento, apoiando uma positiva funo da atividade fsica no cuidado da diabetes tipo 2

Effects of the flavonoid quercetin and the natural dyes bixin and norbixin on blood parameters of rabbits.

Avaliou-se a a??o terap?utica da quercetina, bixina e norbixina, na dose di?ria de 0,01mol/kg, em coelhos hiperlipid?micos induzidos por colesterol a 0,5% e ?cido c?lico a 0,1%, durante o per?odo de vinte e oito dias, ap?s o qual foram dosados colesterol, colesterol-HDL, triacilglicer?is, ur?ia, creatinina, ?cido ?rico, prote?nas totais, c?lcio, aspartato aminotransferase e alanina aminotransferase. Estes estudos s?o importante para se verificarem os efeitos de flavon?ides e corantes sobre o metabolismo destas subst?ncias, permitindo a interpreta??o de desordens hep?ticas ou renais. Os resultados mostraram que os teores de colesterol foram menores para os animais tratados com bixina (-4,03%) e quercetina (-35,07%), enquanto sua associa??o reduziu o n?vel de ur?ia em 5,73%. Nenhuma das subst?ncias testadas apresentou efeitos delet?rios, todavia, n?o ? poss?vel demonstrar a inocuidade destes compostos.The objective of this study was to evaluate the therapeutic action of quercetin, bixin and norbixin, in the daily dose of 0,01mol/kg, in hyperlipidemic rabbits induced by cholesterol at 0.5% and colic acid at 0.1%, during the period of twenty-eight days, after which they were anesthetized and samples of blood were collected, in order to determine cholesterol, HDL-cholesterol, triacylglycerols, urea, creatinine, uric acid, total proteins, calcium, aspartate aminotransferase and alanine aminotransferase. These researchs are important to verify the effects of flavonoids and natural dyes on the metabolism of these constituents, in order to study hepatic or renal disorders. The results showed that cholesterol was reduced by bixin (-44.03%) and by quercetin (-35.07%), while the association reduced urea in 5.73%. None of the constituents analyzed in this study presented deleterious effects and it was not possible to demonstrate the innocuity of these compounds

Anaphylactic response to topical fluorescein 2% eye drops: a case report

<p>Abstract</p> <p>Introduction</p> <p>The intravenous use of fluorescein 10% during retinal angiography can cause severe systemic reactions including, on rare occasions, anaphylaxis. Fluorescein 2% eye drops are used extensively for clinical examination and diagnosis, but to the best of our knowledge, they have only been reported as being responsible for a systemic anaphylactic response on two previous occasions.</p> <p>Case presentation</p> <p>We report the case of a 51-year-old woman who developed an anaphylactic reaction when she was administered fluorescein sodium 2% eye drops after cataract surgery. This was the second time she had been exposed to fluorescein. She had brittle asthma and a history of anaphylaxis following exposure to a variety of drug and food allergens. She was successfully resuscitated and recovered completely over a period of two days.</p> <p>Conclusions</p> <p>Fluorescein 2% drops are universally used in general practice, ophthalmology, optometry, and casualty departments. Our case report reveals the potential for this benign eye drop to cause a life-threatening systemic reaction and emphasises the importance of considering this consequence when administering topical fluorescein 2% to a patient with a history of anaphylaxis to other allergens.</p

Effect of flavonoids on the arachidonic acid metabolism

The products of the ciclooxigenase and lipoxigenase action’s on the arachidonic acid are: prostaglandins, tromboxans and leucotriens, which are denominated eicosanoids. These compounds are homeostatic agents. They are involved in the integrity of the inflammatory, cardiovascular and renal systems. It has been demonstrated that flavonoids shows several pharmacological activities among them antiinflamatory and hipocholesterolemic properties. They reduce the risk of cardiovascular diseases and one of its principal action mechanism involve the inhibition of the enzymes which are involved in the final metabolism of the arachidonate.Os produtos da ação das enzimas ciclooxigenase e lipoxigenase sobre o ácido araquidônico são prostaglandinas, tromboxanos e leucotrienos, também denominados eicosanóides. Tais compostos são agentes homeostáticos, envolvidos na manutenção da integridade dos sistemas inflamatório, cardiovascular e renal. Vários pesquisadores têm demonstrado que flavonóides apresentam inúmeras propriedades farmacológicas, entre elas atividade antiinflamatória e hipocolesterolêmica, reduzindo, assim, o risco de doenças cardiovasculares e um dos principais mecanismos de ação propostos é a inibição das enzimas, envolvidas no metabolismo final do araquidonato. Este trabalho mostra uma revisão sobre o metabolismo do ácido araquidõnico e os efeitos farmacológicos de flavonóides nessa rota metabólica

Fenebrutinib in H1 antihistamine-refractory chronic spontaneous urticaria: a randomized phase 2 trial

Bruton’s tyrosine kinase (BTK) is crucial for FcεRI-mediated mast cell activation and essential for autoantibody production by B cells in chronic spontaneous urticaria (CSU). Fenebrutinib, an orally administered, potent, highly selective, reversible BTK inhibitor, may be effective in CSU. This double-blind, placebo-controlled, phase 2 trial (EudraCT ID 2016-004624-35) randomized 93 adults with antihistamine-refractory CSU to 50 mg daily, 150 mg daily and 200 mg twice daily of fenebrutinib or placebo for 8 weeks. The primary end point was change from baseline in urticaria activity score over 7 d (UAS7) at week 8. Secondary end points were the change from baseline in UAS7 at week 4 and the proportion of patients well-controlled (UAS7 ≤ 6) at week 8. Fenebrutinib efficacy in patients with type IIb autoimmunity and effects on IgG-anti-FcεRI were exploratory end points. Safety was also evaluated. The primary end point was met, with dose-dependent improvements in UAS7 at week 8 occurring at 200 mg twice daily and 150 mg daily, but not at 50 mg daily of fenebrutinib versus placebo. Asymptomatic, reversible grade 2 and 3 liver transaminase elevations occurred in the fenebrutinib 150 mg daily and 200 mg twice daily groups (2 patients each). Fenebrutinib diminished disease activity in patients with antihistamine-refractory CSU, including more patients with refractory type IIb autoimmunity. These results support the potential use of BTK inhibition in antihistamine-refractory CSU

Association between matrix metalloproteinase (MMP)-2 polymorphisms and MMP-2 levels in hypertensive disorders of pregnancy

We examined whether two functional polymorphisms (g.-1306 C&gt; T and g.-735 C&gt;T) in matrix metalloproteinase (MMP)-2 gene are associated with preeclampsia (PE) or gestational hypertension (GH), and whether they modify MMP-2 or tissue inhibitor of metalloproteinase (TIMP)-2 plasma concentrations in these hypertensive disorders of pregnancy. We studied 130 healthy pregnant (HP), 130 pregnant with GH, and 133 pregnant with PE. Genomic DNA was extracted from whole blood and genotypes for g.-1306 C&gt;T and g.-735 C&gt;T polymorphisms were determined by Real Time-PCR, using Taqman allele discrimination assays. Haplotypes were inferred using the PHASE program. Plasma MMP-2 and TIMP-2 concentrations were measured by ELISA. The main findings were that pregnant with PE have higher plasma MMP-2 and TIMP-2 concentrations than HP (P&lt;0.05), although the MMP-2/TIMP-2 ratios were similar (P&gt;0.05). Moreover, pregnant with GH have elevated plasma MMP-2 levels and MMP-2/TIMP-2 ratios compared to HP (P&lt;0.05). While MMP-2 genotypes and haplotypes are not linked with hypertensive disorders of pregnancy, MMP-2 genotypes and haplotypes are associated with significant alterations in plasma MMP-2 and TIMP-2 concentrations in preeclampsia (P&lt;0.05). Our findings may help to understand the relevance of MMP-2 and its genetic polymorphisms to the pathophysiology of hypertensive disorders of pregnancy. It is possible that patients with PE and the MMP-2 haplotype combining the C and T alleles for the g.-1306 C&gt;T and g.-735 C&gt;T polymorphisms may benefit from the use of MMPs inhibitors such as doxycycline. However, this possibility remains to be determined. (C) 2012 Elsevier Inc. All rights reserved.Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP), BrazilConselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Brazi

Maternal iNOS genetic polymorphisms and hypertensive disorders of pregnancy

Increased expression and activity of inducible nitric oxide synthase (iNOS) may contribute to the pathogenesis of pre-eclampsia (PE) and gestational hypertension (GH). However, no previous study has examined whether genetic polymorphisms in the iNOS gene are associated with PE or GH. We examined whether two functional, clinically relevant iNOS genetic polymorphisms (the C(-1026)A polymorphism, rs2779249, in the promoter region, and the G2087A polymorphism, rs2297518, in exon 16) are associated with GH or with PE. We studied 565 pregnant women: 212 healthy pregnant (HP), 166 pregnant with GH and 187 pregnant with PE. Genotypes were determined by real-time PCR, using the Taqman allele discrimination assay. The PHASE 2.1 program was used to estimate haplotype distributions in the three study groups. We found no significant association between the C(-1026)A polymorphism and PE or GH (P&gt;0.05). However, we found the GA genotype and the A allele for the G2087A polymorphism at higher frequency in PE, but not in GH, compared with HP (P&lt;0.05). The haplotype analysis showed no significant intergroup differences (P&gt;0.05). These findings suggest that iNOS genetic variants may affect the susceptibility to PE, but not to GH. Journal of Human Hypertension (2012) 26, 547-552; doi:10.1038/jhh.2011.65; published online 30 June 2011Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)Coordenadoria de Aperfeicoamento de Pessoal de Nivel Superior (CAPES

Blood transfusions increase circulating plasma free hemoglobin levels and plasma nitric oxide consumption: a prospective observational pilot study

Introduction: The increasing number of reports on the relation between transfusion of stored red blood cells (RBCs) and adverse patient outcome has sparked an intense debate on the benefits and risks of blood transfusions. Meanwhile, the pathophysiological mechanisms underlying this postulated relation remain unclear. The development of hemolysis during storage might contribute to this mechanism by release of free hemoglobin (fHb), a potent nitric oxide (NO) scavenger, which may impair vasodilation and microcirculatory perfusion after transfusion. The objective of this prospective observational pilot study was to establish whether RBC transfusion results in increased circulating fHb levels and plasma NO consumption. In addition, the relation between increased fHb values and circulating haptoglobin, its natural scavenger, was studied. Methods: Thirty patients electively received 1 stored packed RBC unit (n = 8) or 2 stored packed RBC units (n = 22). Blood samples were drawn to analyze plasma levels of fHb, haptoglobin, and NO consumption prior to transfusion, and 15, 30, 60 and 120 minutes and 24 hours after transfusion. Differences were compared using Pearson's chi-square test or Fisher's exact test for dichotomous variables, or an independent-sample t test or Mann-Whitney U test for continuous data. Continuous, multiple-timepoint data were analyzed using repeated one-way analysis of variance or the Kruskall-Wallis test. Correlations were analyzed using Spearman or Pearson correlation. Results: Storage duration correlated significantly with fHb concentrations and NO consumption within the storage medium (r = 0.51, P &lt; 0.001 and r = 0.62, P = 0.002). fHb also significantly correlated with NO consumption directly (r = 0.61, P = 0.002). Transfusion of 2 RBC units significantly increased circulating fHb and NO consumption in the recipient (P &lt; 0.001 and P &lt; 0.05, respectively), in contrast to transfusion of 1 stored RBC unit. Storage duration of the blood products did not correlate with changes in fHb and NO consumption in the recipient. In contrast, pre-transfusion recipient plasma haptoglobin levels inversely influenced post-transfusion fHb concentrations. Conclusion: These data suggest that RBC transfusion can significantly increase post-transfusion plasma fHb levels and plasma NO consumption in the recipient. This finding may contribute to the potential pathophysiological mechanism underlying the much-discussed adverse relation between blood transfusions and patient outcome. This observation may be of particular importance for patients with substantial transfusion requirements.Annadal Foundation of the Maastricht University Medical CenterAnnadal Foundation of the Maastricht University Medical Cente