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

FARMACOGENÉTICA CARDIOVASCULAR

The widely acknowledged variability in drug response is partiality due to differences in genetic background. Pharmacogenetics is a branch within the field of Clinical Pharmacology focused on the study of how genetic differences affect drug responses. Genetic variations (called polymorphisms) may change pharmacokinetic parameters (by altering enzymes involved in drug metabolism), and pharmacodynamic parameters (by altering receptor affinity by agonist and antagonist drugs). Presently, pharmacogenetics has been valued as a potentially useful tool in finding better therapeutics. This review is mostly concerned with cardiovascular pharmacogenetics. Clinical cases will be described and their possible pharmacogenetic implications will be briefly commented on.A variabilidade de resposta à droga entre pacientes é parcialmente devida à composição genética única que cada indivíduos apresenta. O ramo da Farmacologia Clínica que estuda tais variabilidades é chamado de farmacogenética. Variações genéticas (chamadas de polimorfismos) podem modificar tanto parâmetros farmacocinéticos (por alterarem a atividade de enzimas importantes no metabolismo de fármacos) quanto parâmetros farmacodinâmicos (por modificar a afinidade de um receptor pelos agonistas ou antagonistas). Atualmente, a farmacogenética vem sendo valorizada como uma ferramenta útil na busca de terapêuticas melhores. Esta revisão enfoca a farmacogenética de drogas de ação cardiovascular. Especificamente, alguns casos clínicos ilustrativos de doenças cardiovasculares serão apresentados e comentados quanto às suas possíveis bases farmacogenéticas

Fatores genéticos que modulam concentrações de chumbo no organismo

O chumbo (Pb) é um metal pesado muito tóxico, mesmo em baixas concentrações. Ainda não foi possível estabelecer uma concentração considerada "segura" para exposições. A toxicidade ao metal é atribuída principalmente a alterações enzimáticas, como a inibição da enzima delta aminolevulínico desidratase (ALAD) e à habilidade de competir com o cálcio. A absorção do chumbo se dá prinicpalmente através das vias respiratórias e gastrointestinal. Uma vez absorvido, o metal é encontrado no sangue, tecidos moles e mineralizados. Cerca de 99% do conteúdo absorvido é encontrado nos ossos, principal reservatório de chumbo. Aproximadamente 1% encontrase livre no plasma e disponível para atravessar membranas biológicas e promover os efeitos tóxicos. Apesar das medidas tomadas no sentido de diminuir as concentrações do metal na natureza, alguns indivíduos podem ser mais susceptíveis aos efeitos prejudiciais causados pela exposição ao chumbo. Fatores genéticos vem sendo estudados e associados a diferentes concentrações sanguíneas e plasmáticas do metal em indivíduos expostos. Portadores de diferentes genótipos podem experimentar maiores ou menores concentrações sanguíneas e plasmáticas de Pb. Reconhecer o indivíduo, ou grupo de indivíduos mais susceptíveis às altas concentrações de chumbo pode ser uma ferramenta útil na prevenção dos efeitos tóxicos do metal. O gene que codifica a ALAD e gene do Receptor da Vitamina D (VDR), os quais estão relacionados a toxicocinética do chumbo foram focos dessa revisão.Lead (Pb) is a highly toxic heavy metal, even at low concentrations. There is no threshold considering "safe" for lead exposure. The toxic effects are due mainly to the enzymatic changes, such as inhibition of the enzyme delta aminolevulinic dehydratase (ALAD) and the ability to compete with calcium. The primary sites for lead absorption are gastrointestinal and respiratory tract. Once absorbed, lead is found in blood, soft tissues and mineralizing systems. Approximately 99% of the total body burden of lead is found in bones, body's major storage site. Around 1% of lead in blood is in plasma, representing the labile and biologically active lead fraction, able to pass the cells membranes and cause toxic effects. Despite the measures taken to reduce the concentrations of metal in nature, some individuals may be more susceptible to adverse effects caused by exposure to lead. Genetic factors has been studied and associated to differences among blood and plasma lead concentrations in subjects exposure. Subjects with different genotypes has proved lower or higher blood concentrations and plasma Pb. Recognize the individual or group of individuals more susceptible to high concentrations of lead can be a useful tool in preventing the toxic effects of metal. The gene coding for ALAD gene and of the Vitamin D Receptor (VDR), which are related to the toxicokinetics of lead have been outbreaks of this review

FARMACOGENÉTICA: PRINCÍPIOS, APLICAÇÕES E PERSPECTIVAS

Multiple factors may affect drug responses. These factors include disease state, environmental factors and genetic background. Pharmacogenetics is a new branch within the field of Clinical Pharmacology with a main focus on how intersubject genetic differences may affect drug responses. In this regard, many polymorphisms in the genes involved in drug metabolism, transport or receptors may contribute to variability in drug responses. This review will focus on the basic principles, clinical implications and new perspectives for this new discipline. Clinically relevant new findings will be used as examples of important contributions resulting from translational research potentially leading to improved therapeutics.As respostas às drogas são influenciadas por múltiplos fatores, incluindo-se estado de saúde, influências ambientais e características genéticas. A farmacogenética é uma área da farmacologia clínica que estuda como diferenças genéticas entre indivíduos podem afetar as respostas às drogas. Neste sentido, polimorfismos genéticos em enzimas metabolizadoras, transportadores ou receptores contribuem para as variações nas respostas a medicamentos. Esta revisão objetiva introduzir alguns princípios, aplicações clínicas e perspectivas da farmacogenética, enfatizando alguns importantes achados clínicos e aplicações que podem contribuir para a melhoria da terapêutica

Pharmacogenetic Implications Of The Enos Polymorphisms For Cardiovascular Action Drugs.

The pharmacogenetics is one of the most promising fields of medicine. The conclusion of the Genome Project allowed this field to start discovering complex factors modulating the response to drugs, and new technologies are close a great expansion of the area. The cardiovascular diseases are currently among the major causes of hospitalizations and death, and have been the target of a large part of genetic studies of complex diseases. Parallel to the susceptibility to disease markers identification, it is necessary to investigate how different genetic profiles can change the responses to the currently used drugs. The biological system that controls the endothelial production of the nitric oxide has been one of the greatest targets in the pharmacological responses to the drugs used in the cardiovascular diseases therapy. This review aims at approaching the current knowledge on interaction among the genetic variations of eNOS and the pharmacological responses to the drugs used in the cardiovascular system.96e27-3

Hemodynamic effects of aortic occlusion during inhalational anesthesia with isoflurane and sevoflurane: experimental study in dogs

BACKGROUND AND OBJECTIVES: Aortic flow suppression and release during aortic procedures promote major hemodynamic disorders. This study aimed at evaluating these disorders in dogs anesthetized with isoflurane or sevoflurane. METHODS: This study involved 41 dogs divided in two groups according to the anesthetic agent used for maintenance with 1 MAC: GI (n = 21) isoflurane; GS (n = 20) sevoflurane. Aorta was occluded by intra-arterial infra-diafragmatic cuff inflation for 30 minutes. Hemodynamic parameters were observed in moments M1 (control), M2 and M3, 15 and 30 minutes after aortic occlusion, M4 and M5, 15 and 30 minutes after cuff deflation. RESULTS: During aortic occlusion there has been increased mean blood pressure (MBP), central venous pressure (CVP), pulmonary artery pressure (PAP), pulmonary capillary wedge pressure (PCWP) and systemic vascular resistance (SVR), without increase in pulmonary vascular resistance (PVR) and cardiac output (CO). CO was more stable with isoflurane as compared to sevoflurane where it has decreased after occlusion. Heart rate has initially decreased followed by increase during occlusion, being more expressive in GS as compared to GI, however without statistically significant difference between groups. Systolic volume was not importantly changed; left and right ventricular function have similarly increased after occlusion for both groups. With flow release, MBP, CVP, PAP, PCWP and SVR have decreased, and PVR has increased for both groups; ventricular function has abruptly decreased. CONCLUSIONS: This study has shown that isoflurane is a better indication for such interventions for promoting less hemodynamic changes.JUSTIFICATIVA E OBJETIVOS: A supressão do fluxo aórtico e sua posterior liberação em intervenções cirúrgicas da aorta ocasionam importantes distúrbios hemodinâmicos. O objetivo deste estudo foi avaliar essas alterações em cães anestesiados com isoflurano ou sevoflurano. MÉTODO: Foram estudados 41 cães, divididos em dois grupos segundo o anestésico empregado na manutenção com 1 CAM: GI (n = 21) isoflurano; GS (n = 20) sevoflurano. Foi realizada a oclusão aórtica por insuflação de balão intra-arterial infradiafragmático por 30 minutos. Os parâmetros hemodinâmicos foram observados nos momentos M1 (controle), M2 e M3, 15 e 30 minutos após a oclusão aórtica, M4 e M5, 15 e 30 minutos após a desinsuflação do balão. RESULTADOS: Durante a oclusão da aorta, observou-se aumento da pressão arterial média (PAM), da pressão venosa central (PVC), da pressão de artéria pulmonar (PAP), da pressão de capilar pulmonar (PCP) e da resistência vascular sistêmica (RVS) sem aumento da resistência vascular pulmonar (RVP) e do débito cardíaco (DC). O DC manteve-se mais estável com o isoflurano comparado com o sevoflurano, com o qual apresentou diminuição após a oclusão. A freqüência cardíaca teve diminuição inicial seguida de aumento durante a oclusão sendo em GS mais expressiva do que em GI, porém sem diferença significativa entre os grupos. O volume sistólico não teve grandes alterações; o trabalho sistólico dos ventrículos esquerdo e direito aumentou após a oclusão de forma semelhante nos dois grupos. Com a liberação do fluxo PAM, PVC, PAP, PCP e RVS diminuíram, a RVP aumentou nos dois grupos; o trabalho ventricular diminuiu abruptamente. CONCLUSÕES: O estudo demonstrou ser o isoflurano mais bem indicado nessas intervenções cirúrgicas por causar menores alterações hemodinâmicas.JUSTIFICATIVA Y OBJETIVOS: La supresión del flujo aórtico y su posterior liberación en intervenciones quirúrgicas de la aorta, ocasionan importantes disturbios hemodinámicos. El objetivo de este estudio fue el de evaluar esas alteraciones en perros anestesiados con isoflurano o sevoflurano. MÉTODO: Se estudiaron 41 perros, divididos en dos grupos según el anestésico empleado en el mantenimiento con 1 CAM: GI (n = 21) isoflurano; GS (n = 20) sevoflurano. Se realizó la oclusión aórtica por insuflación de globo intraarterial infradiafragmático por 30 minutos. Los parámetros hemodinámicos fueron observados en los momentos M1 (control), M2 y M3, 15 y 30 minutos después de la oclusión aórtica, M4 y M5, 15 y 30 minutos después de la desinsuflación del globo. RESULTADOS: Durante la oclusión de la aorta, se observó el aumento de la presión arterial promedio (PAM), de la presión venosa central (PVC), de la presión de arteria pulmonar (PAP), de la presión de capilar pulmonar (PCP) y de la resistencia vascular sistémica (RVS) sin aumento de la resistencia vascular pulmonar (RVP) y del débito cardíaco (DC). El DC se mantuvo más estable con el isoflurano comparado al sevoflurano, con el cual presentó disminución después de la oclusión. La frecuencia cardiaca tuvo disminución inicial que después aumentó durante la oclusión, siendo en GS más expresiva que en GI, sin embargo, sin diferencia significativa entre los grupos. El volumen sistólico no tuvo grandes alteraciones; el trabajo sistólico de los ventrículos izquierdo y derecho aumentó después de la oclusión de forma similar en los dos grupos. Con la liberación del flujo PAM, PVC, PAP, PCP y RVS bajaron, la RVP aumentó en los dos grupos; el trabajo ventricular disminuye abruptamente. CONCLUSIONES: El estudio demostró que el isoflurano es el más indicado en esas intervenciones quirúrgicas por causar menores alteraciones hemodinámicas.23925

Activation of the TRKB receptor mediates the panicolytic-like effect of the NOS inhibitor aminoguanidine

Nitric oxide (NO) triggers escape reactions in the dorsal periaqueductal gray matter (dPAG), a core structure mediating panic-associated response, and decreases the release of BDNF in vitro. BDNF mediates the panicolytic effect induced by antidepressant drugs and produces these effects per se when injected into the dPAG. Based on these findings, we hypothesize that nitric oxide synthase (NOS) inhibitors would have panicolytic properties associated with increased BDNF signaling in the dPAG. We observed that the repeated (7 days), but not acute (1 day), systemic administration of the NOS inhibitor aminoguanidine (AMG; 15 mg/kg/day) increased the latency to escape from the open arm of the elevated T-maze (ETM) and inhibited the number of jumps in hypoxia-induced escape reaction in rats, suggesting a panicolytic-like effect. Repeated, but not acute, AMG administration (15 mg/kg) also decreased nitrite levels and increased TRKB phosphorylation at residues Y706/7 in the dPAG. Notwithstanding the lack of AMG effect on total BDNF levels in this structure, the microinjection of the TRK antagonist K252a into the dPAG blocked the anti-escape effect of this drug in the ETM. Taken together our data suggest that the inhibition of NO production by AMG increases the levels of pTRKB, which is required for the panicolytic-like effect observed.Peer reviewe

Training Status as a Marker of the Relationship between Nitric Oxide, Oxidative Stress, and Blood Pressure in Older Adult Women

The purpose of this study was to evaluate the influence of functional fitness and oxidative capacity on the nitric oxide concentration associated with hemodynamic control in older adult women. The sample consisted of 134 women (65.73 ± 6.14 years old). All subjects underwent a physical examination to assess body mass index, waist-hip ratio, body fat measurement by dual energy X-ray absorptiometry, and blood pressure (BP). Training status (TS) was evaluated by indirect determination of maximal oxygen uptake by a treadmill test using Balke protocol modified for older adults. Functional fitness was also evaluated through a “Functional Fitness Battery Test” to determine the general fitness functional index (GFFI). All participants were separated according to the functional fitness (TS1, very weak and weak; TS2, regular; TS3, good and very good). Plasma blood samples were used to evaluate prooxidant and antioxidant activity and nitrite and nitrate concentrations. The general results of this study showed that good levels of TS were related to lower levels of lipoperoxidation and protein damage, higher levels of antioxidant, and higher concentration of nitrite and nitrate. This combination may be responsible for the lower levels of BP in subjects with better TS

Effects Of Atorvastatin And T-786c Polymorphism Of Enos Gene On Plasma Metabolic Lipid Parameters.

Endothelial nitric oxide synthase (eNOS) activity may be modulated by high-density lipoprotein cholesterol (HDL-C), statins or polymorphisms, such as the T-786C of eNOS. This study aimed at evaluating if the T-786C polymorphism is associated with changes of atorvastatin effects on the lipid profile, on the concentrations of metabolites of nitric oxide (NO) and of high sensitivity C-reactive protein (hsCRP). Thirty male volunteers, asymptomatic, aged between 18 and 56 years were genotyped and classified according to absence (TT, n = 15) or presence (CC, n = 15) of the polymorphism. They were randomly selected for the use of placebo or atorvastatin (10 mg/day/14 days). After each treatment lipids, lipoproteins, HDL2 and HDL3 composition, cholesteryl ester transfer protein (CETP) activity, metabolites of NO and hsCRP were evaluated. The comparisons between genotypes after placebo showed an increase in CETP activity in a polymorphism-dependent way (TT, 12±7; CC, 22±12; p < 0.05). The interaction analyses between treatments indicated that atorvastatin has an effect on cholesterol, LDL, nitrite and lipid-protein ratios (HDL2 and HDL3) (p < 0.001) in both genotypes. Interestingly, we observed genotype/drug interactions on CETP (p < 0.07) and lipoprotein (a) (Lp(a)) (p < 0.056), leading to a borderline decrease in CETP, but with no effect on Lp(a). HsCRP showed no alteration. These results suggest that statin treatment may be relevant for primary prevention of atherosclerosis in patients with the T-786C polymorphism of eNOS, considering the effects on lipid metabolism.10014-2