Ocorrência de indicações farmacológicas não recomendadas por estágios na endometriose e impacto no quadro de ansiedade por persistência de sintomas / Occurrence of pharmacological indications not recommended by stages in endometriosis and impact on anxiety due to persistence of symptoms / Presencia de indicaciones farmacológicas no recomendadas por etapas en la endometriosis e impacto en la ansiedad por la persistencia de los síntomas

Introdução: Endometriose é uma patologia pélvica crônica de caráter inflamatório e estrogênio-dependente. Manifesta-se em quatro tipos de estágio (EI, EII, EIII e EIV), caracterizados pelos números de lesões. Tem indicações farmacológicas recomendadas se baseadas nos estágios, sendo EI/EII sintomático com AINES e/ou uso de anticonceptivos de uso contínuo; e EIII/EIV com fármacos análogos de GnRH. O estilo de vida dessas mulheres é impactado pela dor, que altera a rotina e vida afetivo/sexual contribuindo para quadros de ansiedade. O presente estudo se norteia pela questão "qual impacto na ansiedade de mulheres com endometriose, quando não ocorrem indicações farmacológicas recomendadas para os estágios que se encontra? Logo, o objetivo deste estudo é avaliar os efeitos do tratamento medicamentoso não recomendado e risco de ansiedade. Metodologia: Levantamento de pacientes com diagnóstico de Endometriose, cadastradas no Banco de Dados do Projeto agrupadas em estágios de tratamentos farmacológicos similares (EI/EII e EIII/EIV). O relato de ansiedade, com diagnóstico médico e pós endometriose foi a variável dependente em estudo. As variáveis independentes (ou influenciadoras) foram [1] Estágio da doença, [2] Farmacoterapia recomendada (FR) ou não (FNR) e [3] esquema medicamentoso empregado (classes e combinações). Estatística feitas por chi quadrado e Fischer. Resultados: Do total de 375 mulheres, 274 apresentavam ansiedade. Destas, 170 estavam no grupo IFR; sendo 141 no agrupamento EI/EII, e 29 mulheres no EIII/EIV. No que se refere ao grupo IFNR, teve se um n=104 mulheres, sendo apenas 1 nos EI/EII e 103 nos EIII/EIV. Os casos de FNR estão mais presentes em EIII/EIV, com 90% dos casos (IC 95%, p<0,05). O esquema terapêutico mais presente foi AINEs em monoterapia, sendo 65% (IC 95%, p<0,05) em Estágio inadequado. Notou-se uma correlação positiva entre FNR e quadros de ansiedade, principalmente quando se empregava a monoterapia com AINEs (IC 95%, p<0,05). Conclusão: Dificuldades de acesso a especialistas para diagnóstico e aos medicamentos do EIII/EIV podem ser as causas, que serão investigadas em estudos futuros.

Introduction: Endometriosis is a chronic pelvic pathology with an inflammatory and estrogen-dependent nature. It manifests itself in four types of stages (EI, EII, EIII and EIV), characterized by the number of lesions. It has recommended pharmacological indications based on the stages, being symptomatic EI/EII with NSAIDs and/or use of continuous contraceptives; and EIII/EIV with GnRH analogue drugs. The lifestyle of these women is impacted by pain, which alters their routine and emotional/sexual life, contributing to anxiety. The present study is guided by the question "what impact on the anxiety of women with endometriosis, when there are no recommended pharmacological indications for the stage they are in?" Therefore, the objective of this study is to evaluate the effects of non-recommended drug treatment and the risk of anxiety. Methodology: Survey of patients diagnosed with Endometriosis, registered in the Project Database grouped into stages of similar pharmacological treatments (EI/EII and EIII/EIV). The report of anxiety, with medical diagnosis and post-endometriosis was the dependent variable under study. The independent (or influencing) variables were [1] Stage of the disease, [2] Pharmacotherapy recommended (FR) or not (FNR) and [3] medication regimen used (classes and combinations). Statistics made by chi square and Fischer. Results: Of the total of 375 women, 274 had anxiety. Of these, 170 were in the IFR group; 141 in the EI/EII group, and 29 women in the EIII/EIV group. Regarding the IFNR group, there were n=104 women, with only 1 in EI/EII and 103 in EIII/EIV. FNR cases are more present in EIII/EIV, with 90% of cases (95% CI, p<0.05). The most common therapeutic regimen was NSAIDs as monotherapy, with 65% (95% CI, p<0.05) in an inadequate stage. A positive correlation was noted between FNR and anxiety, especially when using monotherapy with NSAIDs (95% CI, p<0.05). Conclusion: Difficulties in accessing specialists for diagnosis and EIII/EIV medications may be the causes, which will be investigated in future studies.

Introducción: La endometriosis es una patología pélvica crónica de naturaleza inflamatoria y estrógeno-dependiente. Se manifiesta en cuatro tipos de estadios (EI, EII, EIII y EIV), caracterizados por el número de lesiones. Tiene indicaciones farmacológicas recomendadas según los estadios, siendo EI/EII sintomática con AINE y/o uso de anticonceptivos continuos; y EIII/EIV con fármacos análogos de GnRH. El estilo de vida de estas mujeres se ve impactado por el dolor, lo que altera su rutina y su vida emocional/sexual, contribuyendo a la ansiedad. El presente estudio se guía por la pregunta "¿qué impacto tiene en la ansiedad de las mujeres con endometriosis, cuando no existen indicaciones farmacológicas recomendadas para las etapas en las que se encuentra? Por tanto, el objetivo de este estudio es evaluar los efectos del tratamiento farmacológico no recomendado y el riesgo de ansiedad. Metodología: Encuesta a pacientes diagnosticadas de Endometriosis, registradas en la Base de Datos del Proyecto agrupadas en etapas de tratamientos farmacológicos similares (EI/EII y EIII/EIV). El reporte de ansiedad, con diagnóstico médico y post-endometriosis fue la variable dependiente en estudio. Las variables independientes (o influyentes) fueron [1] Estadio de la enfermedad, [2] Farmacoterapia recomendada (FR) o no (FNR) y [3] régimen de medicación utilizado (clases y combinaciones). Estadística realizada por chi cuadrado y Fischer. Resultados: Del total de 375 mujeres, 274 presentaron ansiedad. De ellos, 170 estaban en el grupo IFR; 141 en el grupo EI/EII y 29 mujeres en el grupo EIII/EIV. En cuanto al grupo IFNR, hubo n=104 mujeres, siendo sólo 1 en EI/EII y 103 en EIII/EIV. Los casos de FNR están más presentes en EIII/EIV, con un 90% de los casos (IC 95%, p<0,05). El régimen terapéutico más común fue el de AINE en monoterapia, con un 65% (IC 95%, p<0,05) en estadio inadecuado. Se observó una correlación positiva entre la FNR y la ansiedad, especialmente cuando se utilizaba monoterapia con AINE (IC del 95%, p<0,05). Conclusión: Las dificultades para acceder a especialistas para el diagnóstico y a los medicamentos EIII/EIV pueden ser las causas, que serán investigadas en futuros estudios.

Protective effect of Myrcia pubipetala Miq. against the alterations in oxidative stress parameters in an animal model of depression induced by corticosterone.

Depression is a debilitating disorder in humans that significantly affects quality of life. As such, alternative therapies are highly sought after by patients seeking treatment for depression. Experimentally, the chronic administration of corticosterone (CORT) in rodents has been reported to promote depressive-like behaviors. Herein, animals received saline or CORT for 21 days and, during the last 7 days, they were treated with the crude hydroalcoholic extract (CHE) of Myrcia pubipetala Miq (50, 100 or 150 mg/Kg), or vehicle (distilled water), by oral route. After 24 h, animals were subjected to the open field (OFT) and forced swimming tests (FST), and then sacrificed for the removal of the hippocampus and cerebral cortex for biochemical analysis. Results showed enhanced catalase (CAT) and superoxide dismutase (SOD) activities, as well as an elevated formation of thiobarbituric acid reactive substances (TBARS), in the cerebral cortex of CORT-treated mice. The chronic administration of the CHE (100 and 150 mg/Kg) reduced TBARS and the increased total sulfhydryl content, and also reversed the increase in TBARS induced by CORT. In the hippocampus, CORT increased CAT and SOD activities and reduced glutathione peroxidase (GSH-Px) (C) activity, while Myrcia pubipetala Miq. CHE (100 and 150 mg/Kg) increased GSH-Px activity when administered alone and reversed decreased GSH-Px (100 and 150 mg/Kg) activity when given during CORT administration. Neither CORT administration nor CHE treatment significantly altered the immobility time of the animals in FST and no changes were observed in the locomotor activity of the animals in the OFT. Findings indicate that the CHE of Myrcia pubipetala Miq. exerts antioxidant effects in the cerebral cortex and hippocampus of mice induced to depression by CORT. Since phenolic compounds are reported to have antioxidant effects in this species, the effects of the CHE may be, at least in part, mediated by the presence of these compounds in Myrcia extract.

Acute Administration of Diazepam Provokes Redox Homeostasis Imbalance in the Rat Brain: Prevention by Simvastatin.

We investigated the effects of acute diazepam (DZP) administration on thiobarbituric acid-reactive substance (TBARS) levels, protein carbonyl content, and on the activities of the antioxidant enzymes catalase, glutathione peroxidase, and superoxide dismutase in the brain of rats. Additionally, we investigated the antioxidant role of chronic pretreatment with simvastatin on the effects provoked by DZP. Simvastatin was administered (1 or 10 mg/kg by oral gavage) for 30 days. On the 30th day of treatment, groups were randomized and DZP was administered (0.5 or 1.0 mg/kg by intraperitoneal injection). Control groups received saline. Results showed that DZP enhanced TBARS levels and protein carbonyl content and altered enzymatic activity in the brain of rats. Simvastatin prevented most of the alterations caused by DZP on the oxidative stress parameters. Data indicate that DZP administration causes an oxidative imbalance in the brain areas studied; however, in the presence of simvastatin, some of these alterations in oxidative stress were prevented.

Ferulic acid chronic treatment exerts antidepressant-like effect: role of antioxidant defense system.

Oxidative stress has been claimed a place in pathophysiology of depression; however, the details of the neurobiology of this condition remains incompletely understood. Recently, treatments employing antioxidants have been thoroughly researched. Ferulic acid (FA) is a phenolic compound with antioxidant and antidepressant-like effects. Herein, we investigated the involvement of the antioxidant activity of chronic oral FA treatment in its antidepressant-like effect using the tail suspension test (TST) and the forced swimming test (FST) in mice. The modulation of antioxidant system in blood, hippocampus and cerebral cortex was assessed after stress induction through TST and FST. Our results show that FA at the dose of 1 mg/kg has antidepressant-like effect without affecting locomotor activity. The stress induced by despair tests was able to decrease significantly the activities of superoxide dismutase (SOD) in the blood, catalase (CAT) in the blood and cerebral cortex and glutathione peroxidase (GSH-Px) in the cerebral cortex. Thiobarbituric acid-reactive substances (TBA-RS) levels were increased significantly in the cerebral cortex. Furthermore, the results show that FA was capable to increase SOD, CAT and GSH-Px activities and decrease TBA-RS levels in the blood, hippocampus and cerebral cortex. These findings demonstrated that FA treatment in low doses is capable to exert antidepressant-like effect with the involvement of the antioxidant defense system modulation.

Differential in vitro effects of homoarginine on oxidative stress in plasma, erythrocytes, kidney and liver of rats in the absence and in the presence α-tocopherol, ascorbic acid or L-NAME.

In the present study, we evaluated the in vitro effects of homoarginine (hArg) at 1, 10 and 20 µM on thiobarbituric acid-reactive substances (TBA-RS), total sulfhydryl content and on the activity of the antioxidant enzymes catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in plasma, erythrocytes, kidney and liver of rats (60 days old). We also investigated the influence of the antioxidants (each at 1 mM) α-tocopherol and ascorbic acid, as well as of the nitric oxide synthase inhibitor N (G)-nitro-L-arginine methyl ester (L-NAME) at 1 mM, on the effects elicited by hArg on the parameters tested. In plasma, hArg at concentrations of 10 and 20 µM decreased moderately the total sulfhydryl content. At 20 µM, hArg enhanced moderately TBA-RS in the plasma. In plasma, the effects of hArg (20 µM) on TBA-RS and total thiol content were abolished by α-tocopherol, ascorbic acid and L-NAME. At all concentrations tested, hArg did not exert any effect on CAT, SOD or GSH-Px activity in the erythrocytes. In the kidney, hArg exerted effects only at 20 µM and in a different manner: TBA-RS levels increased and total thiol content and CAT activity decreased, while SOD and GSH-Px activity increased. In the renal medulla, α-tocopherol and ascorbic acid but not L-NAME abolished the effects of hArg (20 µM) on TBA-RS, while all agents inhibited the hArg-induced increase in SOD activity. In the renal cortex, α-tocopherol, ascorbic acid and L-NAME abolished the effects of hArg (20 µM) on the total sulfhydryl content and GSH-Px activity, but L-NAME did not reverse the inhibitory effects of hArg on CAT activity. In the liver, no effects of hArg were observed of all biomarkers measured. At the pathologically high concentration of 20 µM, as it may occur in plasma in hyperargininemia, hArg may enhance lipid peroxidation and thiol oxidation and inhibit CAT activity, but may increase SOD and GSH-Px activity predominantly in the kidney.

Hypoxanthine induces oxidative stress in kidney of rats: protective effect of vitamins E plus C and allopurinol.

In the present study, we investigated the in vitro effect of hypoxanthine on the activities of antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase, as well as on thiobarbituric-acid-reactive substances (TBA-RS), in the renal cortex and medulla of rats. Results showed that hypoxanthine, at a concentration of 10.0 µM, enhanced the activities of CAT and SOD in the renal cortex of 15-, 30- and 60-day-old rats, enhanced SOD activity in the renal medulla of 60-day-old rats and enhanced TBA-RS levels in the renal medulla of 30-day-old rats, as compared with controls. Furthermore, we also verified the influence of allopurinol (an inhibitor of xanthine oxidase), as well as of the antioxidants, trolox and ascorbic acid on the effects elicited by hypoxanthine on the parameters tested. Allopurinol and/or administration of antioxidants prevented most alterations caused by hypoxanthine in the oxidative stress parameters evaluated. Data suggest that hypoxanthine alters antioxidant defences and induces lipid peroxidation in the kidney of rats; however, in the presence of allopurinol and antioxidants, some of these alterations in oxidative stress were prevented. Our findings lend support to a potential therapeutic strategy for this condition, which may include the use of appropriate antioxidants for ameliorating the damage caused by hypoxanthine.

In vitro stimulation of oxidative stress by hypoxanthine in blood of rats: prevention by vitamins e plus C and allopurinol.

We herein investigated the in vitro effect of hypoxanthine on the activities of antioxidant enzymes such as catalase (CAT), glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD) in erythrocytes, as well as on thiobarbituric acid-reactive substances (TBA-RS), in the plasma of rats. Results showed that hypoxanthine, when added to the incubation medium, enhanced CAT (10.0 µM), GSH-Px and SOD (8.5 µM and 10.0 µM) activities in erythrocytes of 15-day-old rats, reduced CAT activity (10.0 µM) and enhanced GSH-Px activity (10.0 µM) in erythrocytes of 30-day-old rats, reduced CAT activity (10.0 µM) and enhanced GSH-Px activity (8.5 µM and 10.0 µM) in erythrocytes of 60-day-old rats, as compared to controls. In addition, hypoxanthine (10.0 µM) enhanced TBA-RS levels in the plasma of 30- and 60-day old rats. Furthermore, we also tested the influence of allopurinol, trolox, and ascorbic acid on the effects elicited by hypoxanthine on the antioxidant enzymes and TBA-RS. Allopurinol and/or administration of antioxidants prevented most alterations caused by hypoxanthine in the oxidative stress parameters evaluated. Findings suggest that hypoxanthine alters antioxidant defenses and induces lipid peroxidation in the blood of rats; however, in the presence of allopurinol and antioxidants, some of these alterations in oxidative stress caused are prevented. Data indicate that, in humans, antioxidant administration might serve as a potential adjuvant therapy for ameliorating the damage caused by hypoxanthine.

Behavioral interactions of simvastatin and fluoxetine in tests of anxiety and depression.

Simvastatin inhibits 3-hydroxy-3-methylglutaryl CoA reductase, the rate-limiting enzyme in the cholesterol biosynthetic pathway, and is widely used to control plasma cholesterol levels and prevent cardiovascular disease. However, emerging evidence indicates that the beneficial effects of simvastatin extend to the central nervous system. The effects of simvastatin combined with fluoxetine provide an exciting and potential paradigm to decreased anxiety and depression. Thus, the present paper investigates the possibility of synergistic interactions between simvastatin and fluoxetine in models of anxiety and depression. We investigated the effects of subchronically administered simvastatin (1 or 10 mg/kg/day) combined with fluoxetine (2 or 10 mg/kg) at 24, 5, and 1 hour on adult rats before conducting behavioral tests. The results indicate that simvastatin and/or fluoxetine treatment reduces anxiety-like behaviors in the elevated plus-maze and open-field tests. Our results showed that simvastatin and/or fluoxetine induced a significant increase in the swimming activity during the forced swimming test (antidepressant effect), with a concomitant increase in climbing time in simvastatin-treated animals only (noradrenergic activation). We hypothesize that anxiolytic and antidepressant effects of simvastatin and/or fluoxetine produce their behavioral effects through similar mechanisms and provide an important foundation for future preclinical research.

Proline alters antioxidant enzyme defenses and lipoperoxidation in the erythrocytes and plasma of rats: in vitro and in vivo studies.

In the present study, we investigated, in vivo (acute and chronic) and in vitro, the effects of proline on the activities of antioxidant enzymes such as catalase (CAT), glutathione peroxidase and superoxide dismutase (SOD) in erythrocytes and also investigated the effect on thiobarbituric acid-reactive substances (TBARS) in the plasma of rats. For the experiments, the number of animals per group ranged from eight to ten. For acute administration, 29-day-old rats received one subcutaneous injection of proline (18.2 µmol/g body weight) or an equivalent volume of 0.9% saline solution (control) and were killed 1 h later. For chronic treatment, buffered proline was injected subcutaneously into rats twice a day at 10 h intervals from the 6th to the 28th day of age. Rats were killed 12 h after the last injection. For in vitro studies, proline (30.0 µM to 1.0 mM) was added to the incubation medium. Results showed that acute administration of proline reduced CAT and increased SOD activities, while chronic treatment increased the activities of CAT and SOD in erythrocytes and TBARS in the plasma of rats. Furthermore, in vitro studies showed that proline increased TBARS in the plasma (0.5 and 1.0 mM) and CAT activity (1.0 mM) in the erythrocytes of rats. The influence of the antioxidants (α-tocopherol plus ascorbic acid) on the effects elicited by proline was also studied. Treatment with antioxidants for 1 week or from the 6th to the 28th day of age prevented the alterations caused by acute and chronic, respectively, proline administration on the oxidative parameters evaluated. Data indicate that proline alters antioxidant defenses and induces lipid peroxidation in the blood of rats.

Protective effect of antioxidants on blood oxidative stress caused by arginine.

In this study, we investigated in vivo and in vitro effect of arginine on parameters of oxidative stress namely thiobarbituric acid-reactive substances (TBA-RS) and total radical-trapping antioxidant parameter (TRAP) in plasma and on the antioxidant enzymes activities catalase (CAT), glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD) in erythrocytes of rats. Results showed that acute administration reduced TRAP and CAT activity and increased TBA-RS. Furthermore, in vitro studies did not alter oxidative parameters studied. The influence of N(ω)-nitro-L-arginine methyl ester (L-NAME) and antioxidants (α-tocopherol plus ascorbic acid) on the effects elicited by arginine was also studied. In addition, simultaneous injection of L-NAME or treatment with antioxidants prevented the alteration on TRAP, TBA-RS, and CAT activity caused by arginine. Data indicate that oxidative stress induction is probably mediated by the generation of NO and/or ONOO(-) and other free radicals, because L-NAME and these antioxidants prevented these effects caused by arginine.