RESUMO
Abstract The present research was made to determine the micronuclei and cytotoxic capacity of the antidepressant venlafaxine in an in vivo acute and subchronic assays in mouse. In the first study, we administered once 5, 50, and 250 mg/kg of the drug, and included a negative and a daunorubicin treated group. Observations were daily made during four days. The subchronic assay lasted 5 weeks with daily administration of venlafaxine (1, 5, and 10 mg/kg) plus a negative and an imipramine administered groups. Observations were made each week. In the first assay results showed no micronucleated polychromatic erythrocytes (MNPE) increase, except with the high dose at 72 h. The strongest cytotoxic effect was found with 250 mg/kg at 72 h (a 51% cytotoxic effect in comparison with the mean control level). In the subchronic assay no MNPE increase was found; however, with the highest dose a significant increase of micronucleated normochromatic erythrocytes was observed in the last three weeks (a mean of 51% respect to the mean control value). A cytotoxic effect with the two high doses in the last two weeks was observed (a polychromatic erythrocyte mean decrease of 52% respect to the mean control value). Results suggest caution with venlafaxine.
Resumo A presente pesquisa foi feita para determinar a capacidade micronuclei e citotóxica do antidepressivo venlafaxina em ensaios agudos e subcrônicos in vivo em camundongos. No primeiro estudo, administramos uma vez 5, 50 e 250 mg/kg do medicamento e incluímos um grupo negativo e um grupo tratado com daunorubicina. As observações foram feitas diariamente durante quatro dias. O ensaio subcrônico durou cinco semanas com administração diária de venlafaxina (1, 5, e 10 mg/kg) mais um grupo negativo e um grupo administrado de imipramina. As observações foram feitas a cada semana. No primeiro ensaio, os resultados não mostraram aumento de eritrócitos policromáticos micronucleados (MNPE), exceto com a dose elevada a 72 h. O efeito citotóxico mais forte foi encontrado com 250 mg/kg a 72 h (um efeito citotóxico de 51% em comparação com o nível médio de controle). No ensaio subcrônico não foi encontrado aumento de MNPE; entretanto, com a dose mais alta, um aumento significativo de eritrócitos normocromáticos micronucleados foi observado nas últimas três semanas (média de 51% em relação ao valor médio de controle). Foi observado um efeito citotóxico com as duas altas doses nas últimas duas semanas (uma diminuição média de 52% em relação ao valor médio de controle dos eritrócitos policromáticos). Os resultados sugerem cautela com a venlafaxina.
Assuntos
Animais , Coelhos , Dano ao DNA , Antineoplásicos , Testes para Micronúcleos , Relação Dose-Resposta a Droga , Eritrócitos , Cloridrato de Venlafaxina/toxicidadeRESUMO
Abstract The present research was made to determine the micronuclei and cytotoxic capacity of the antidepressant venlafaxine in an in vivo acute and subchronic assays in mouse. In the first study, we administered once 5, 50, and 250 mg/kg of the drug, and included a negative and a daunorubicin treated group. Observations were daily made during four days. The subchronic assay lasted 5 weeks with daily administration of venlafaxine (1, 5, and 10 mg/kg) plus a negative and an imipramine administered groups. Observations were made each week. In the first assay results showed no micronucleated polychromatic erythrocytes (MNPE) increase, except with the high dose at 72 h. The strongest cytotoxic effect was found with 250 mg/kg at 72 h (a 51% cytotoxic effect in comparison with the mean control level). In the subchronic assay no MNPE increase was found; however, with the highest dose a significant increase of micronucleated normochromatic erythrocytes was observed in the last three weeks (a mean of 51% respect to the mean control value). A cytotoxic effect with the two high doses in the last two weeks was observed (a polychromatic erythrocyte mean decrease of 52% respect to the mean control value). Results suggest caution with venlafaxine.
Resumo A presente pesquisa foi feita para determinar a capacidade micronuclei e citotóxica do antidepressivo venlafaxina em ensaios agudos e subcrônicos in vivo em camundongos. No primeiro estudo, administramos uma vez 5, 50 e 250 mg/kg do medicamento e incluímos um grupo negativo e um grupo tratado com daunorubicina. As observações foram feitas diariamente durante quatro dias. O ensaio subcrônico durou cinco semanas com administração diária de venlafaxina (1, 5, e 10 mg/kg) mais um grupo negativo e um grupo administrado de imipramina. As observações foram feitas a cada semana. No primeiro ensaio, os resultados não mostraram aumento de eritrócitos policromáticos micronucleados (MNPE), exceto com a dose elevada a 72 h. O efeito citotóxico mais forte foi encontrado com 250 mg/kg a 72 h (um efeito citotóxico de 51% em comparação com o nível médio de controle). No ensaio subcrônico não foi encontrado aumento de MNPE; entretanto, com a dose mais alta, um aumento significativo de eritrócitos normocromáticos micronucleados foi observado nas últimas três semanas (média de 51% em relação ao valor médio de controle). Foi observado um efeito citotóxico com as duas altas doses nas últimas duas semanas (uma diminuição média de 52% em relação ao valor médio de controle dos eritrócitos policromáticos). Os resultados sugerem cautela com a venlafaxina.
RESUMO
The present research was made to determine the micronuclei and cytotoxic capacity of the antidepressant venlafaxine in an in vivo acute and subchronic assays in mouse. In the first study, we administered once 5, 50, and 250 mg/kg of the drug, and included a negative and a daunorubicin treated group. Observations were daily made during four days. The subchronic assay lasted 5 weeks with daily administration of venlafaxine (1, 5, and 10 mg/kg) plus a negative and an imipramine administered groups. Observations were made each week. In the first assay results showed no micronucleated polychromatic erythrocytes (MNPE) increase, except with the high dose at 72 h. The strongest cytotoxic effect was found with 250 mg/kg at 72 h (a 51% cytotoxic effect in comparison with the mean control level). In the subchronic assay no MNPE increase was found; however, with the highest dose a significant increase of micronucleated normochromatic erythrocytes was observed in the last three weeks (a mean of 51% respect to the mean control value). A cytotoxic effect with the two high doses in the last two weeks was observed (a polychromatic erythrocyte mean decrease of 52% respect to the mean control value). Results suggest caution with venlafaxine.
Assuntos
Antineoplásicos , Dano ao DNA , Animais , Relação Dose-Resposta a Droga , Eritrócitos , Camundongos , Testes para Micronúcleos , Cloridrato de Venlafaxina/toxicidadeRESUMO
Kramecyne (KACY), a polymer isolated from Krameria cytisoides Cav, has anti-inflammatory, anti-nociceptive, anti-arthritic and anti-ulcerogenic properties. As a part of standard preclinical safety tests, the present study sought to determine potential developmental toxicity (in female rats) and genotoxicity (in male mice) of KACY. Pregnant female rats were divided into six groups: the negative control (vehicle), the positive control (250â¯mg/kg of acetylsalicylic acid (ASA)), and four experimental groups (50, 250, 500 and 1000â¯mg/kg of KACY). To evaluate genotoxicity by in vivo micronuclei (MN) and sister chromatid exchange (SCE) tests, male mice were divided into five groups: the negative control (vehicle), the positive control (1.5 and 2.5â¯mg/kg of doxorubicin for MN and SCE, respectively), and three experimental groups (50, 500 and 1000â¯mg/kg of KACY). All treatments were administered by oral gavage. A slight maternal toxicity was evidenced by lower weight gain for rats receiving 500 and 1000â¯mg/kg of KACY, but no fetal malformations were found. However, there were less live fetuses/litter and greater post-implantation loss/litter at these two doses. Manifestations of developmental toxicity were limited to a higher rate of skeletal alterations. The MN tests did not evidence genotoxicity or cytotoxicity. KACY caused a slightly but significantly increased frequency of SCE. Although KACY-treated rats had skeletal alterations, these apparently were not caused by a mechanism of genotoxicity. Furthermore, the same administration in adult male mice did not produce genotoxicity. Hence, KACY herein proved to be safe for rats during the period of organogenesis.
RESUMO
BACKGROUND: The long-term efficacy of corticosteroids to prevent atopic dermatitis (AD) relapses has partially been addressed in children. This study compared an intermittent dosing regimen of fluticasone propionate (FP) cream 0.05% with its vehicle base in reducing the risk of relapse in children with stabilized AD. METHODS: A randomized controlled, multicentric, double-blind trial was conducted. Children (2-10 years) with mild/moderate AD (exclusion criteria: >30% affected body surface area and/or head) were enrolled into an Open-label Stabilization Phase (OSP) of up to 2 weeks on twice daily FP. Those who achieved treatment success entered the Double-blind Maintenance Phase (DMP). They were randomly allocated to receive FP or vehicle twice-weekly on consecutive days for 16 weeks. The primary study endpoint was relapse rate; time to relapse and severity of disease were also studied. Kaplan-Meier estimates were calculated. RESULTS: Fifty-four patients (29 girls) entered the OSP (23 mild AD) and 49 (26 girls) continued into the DMP. Mean age was 5.5 (SD: 2.8) and 5.1 (SD: 2.3) yrs for FP and vehicle groups, respectively. Four patients withdrew from the DMP (two in every group). Patients treated with FP twice weekly had a 2.7 fold lower risk of experiencing a relapse than patients treated with vehicle (relative risk 2.72, SD: 1.28; p=0.034). FP was also superior to vehicle for delaying time to relapse. Both treatment therapies were well tolerated. CONCLUSION: This long-term study shows that twice weekly FP provides an effective maintenance treatment to control the risk of relapse in children with AD.
Assuntos
Anti-Inflamatórios/uso terapêutico , Dermatite Atópica/tratamento farmacológico , Fluticasona/uso terapêutico , Prevenção Secundária/métodos , Criança , Pré-Escolar , Método Duplo-Cego , Feminino , Humanos , MasculinoRESUMO
By means of the comet assay we demonstrated a strong effect by hydrogen peroxide (HP) and no damage by grapefruit juice (GJ) in human lymphocytes. Cells exposed to HP and treated with three concentrations of GJ (10-90 min) showed an increase of DNA damage by HP over the control level, and a decrease of such damage by GJ. With the comet assay plus formamidopyrimidine-DNA-glycosylase we found the strongest increase of DNA damage by HP over the control level, and the strongest reduction of such damage by GJ. By applying the comet/FISH method we determined 98% of the p53 gene signals in the comet head of control cells along the experiment (10-90 min), in contrast with about 90% signals in the comet tail of cells exposed to HP. Cells treated with both agents showed a significant, concentration/time dependent return of p53 signals to the head, suggesting enhancement of the gene repair. Finally, with the annexin V assay we found an increase in apoptosis and necrosis by HP, and no effect by GJ; when GJ was added to HP treated cells no modification was observed in regard to apoptosis, although a decrease of necrosis was observed.
Assuntos
Bebidas , Citrus paradisi , Dano ao DNA/efeitos dos fármacos , Peróxido de Hidrogênio/toxicidade , Linfócitos/efeitos dos fármacos , Adulto , Anexina A5 , Reparo do DNA , Relação Dose-Resposta a Droga , Feminino , Humanos , Adulto JovemRESUMO
We determined the capacity of grapefruit juice (GJ) to inhibit the rate of micronucleated polychromatic erythrocytes (MNPE) in mice treated with benzo(a)pyrene (BaP), an environmental contaminant that is biotransformed by Cyp1a1 and is a strong genotoxic agent. For this study, we administered 4.1, 20.8, and 41.6 µl/g body weight (b.w.) of GJ to BaP-treated mice (340 mg/kg). We found a significant decrease in the frequency of MNPE at 48 and 72 h compared to BaP-only treated animals. In turn, no prevention of the cytotoxic damage induced by BaP was found. We next explored whether GJ's antigenotoxic mechanism of action was related to an inhibitory effect on the activity of the Cyp1a1 enzyme. A reduction in microsomal hepatic and intestinal ethoxyresorufin-O-deethylase (EROD) activity of 20% and 44%, respectively, was found in mice treated with BaP and GJ compared to BaP-only treated animals. Furthermore, when EROD inhibition was tested in vitro, we found a concentration-dependent EROD inhibition by GJ, which reached 85% of the maximum level. Together, these results suggest that the protective effect of GJ against the genotoxicity of BaP may be related to the inhibition of Cyp1a1 enzyme activity.
Assuntos
Antimutagênicos/farmacologia , Bebidas , Citrus paradisi , Sistema Enzimático do Citocromo P-450/metabolismo , Dano ao DNA , Intestinos/enzimologia , Fígado/enzimologia , Animais , Benzo(a)pireno/toxicidade , Masculino , CamundongosRESUMO
Imipramine (IMI) and desipramine (DES) are two drugs widely used for the treatment of depression as well as for other diseases. In the present study, we determined their capacity to induce chromosomal aberrations in mouse bone marrow cells. Three doses of each compound were tested and their results were compared with the frequency of chromosomal aberrations obtained in a control group as well as with a group treated with cyclophosphamide. Our results showed a significant increase in chromosome damage with the doses tested for each compound: 7, 20, and 60 mg/kg in the case of IMI, and 2, 20, and 60 mg/kg as regards DES. This last drug induced stronger chromosomal damage than IMI. Our results agree with previous studies regarding the induction of micronuclei and sister chromatid exchanges by the drugs in mouse and suggest caution with respect to their use in long-term treatments.
Assuntos
Antidepressivos Tricíclicos/toxicidade , Células da Medula Óssea/efeitos dos fármacos , Aberrações Cromossômicas/induzido quimicamente , Ciclofosfamida/toxicidade , Desipramina/toxicidade , Imipramina/toxicidade , Animais , Células da Medula Óssea/patologia , Relação Dose-Resposta a Droga , Masculino , CamundongosRESUMO
Beta-sitosterol (BS) is a compound that has shown various activities potentially useful for human health. In the present study, we determined its antigenotoxic capacity and lymphocyte induction potential in mouse as well as its capacity to trap free radicals in vitro. BS, in doses from 200 to 1,000 mg/kg, was able to significantly reduce the frequency of sister chromatid exchanges induced by 10 mg/kg of doxorubicin (DX) in bone marrow cells. The same range of BS doses also gave rise to a strong reduction in the rate of micronucleated, polychromatic erythrocytes induced by DX. In addition, we determined an increase in the production of lymphocytes in mice administered with BS. By means of the DPPH assay, the compound was shown to trap free radicals in a concentration dependent manner as high as 78.12% using 250 mug/ml. Our research established three relevant biological activities of BS which show its potential as a chemopreventive agent.
Assuntos
Antimutagênicos , Antioxidantes/farmacologia , Linfócitos/efeitos dos fármacos , Substâncias Protetoras , Sitosteroides/farmacologia , Animais , Antibióticos Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/farmacologia , Sequestradores de Radicais Livres/farmacologia , Contagem de Linfócitos , Masculino , Camundongos , Testes para Micronúcleos , Troca de Cromátide Irmã/efeitos dos fármacosRESUMO
Aflatoxin B(1) (AFB(1)) is a potent mutagenic and carcinogenic agent found in numerous agricultural and dairy products consumed by humans. Therefore, we evaluated the capacity of mannan to cope with its genotoxic potential. We prepared a diet constituted of corn (90%) plus the recommended amount of other nutrients, as well as with the tested compounds (mannan and/or AFB(1)). Mice were fed this diet during 4 weeks as follows: one group with AFB(1)-contaminated corn (0.25 mg/kg of corn), three groups with mannan (50, 250, and 500 mg/kg of corn) plus AFB(1) (0.25 mg/kg), another group with only mannan (500 mg/kg), and the last group with an uncontaminated diet and no mannan added. We determined the weight, the micronucleated normochromatic erythrocyte rate (MNNE), the polychromatic/normochromatic index, and the sister chromatid exchange rate (SCE). We also examined the recovery response of mice during 4 additional weeks, when they were fed only the normal diet without AFB(1) or mannan. The results in the first period revealed the following: a) mice fed with mannan alone presented values in the range determined for the control group; b) mice fed AFB(1) had a significant weight decrease, as well as a significant increase in the rate of MNNE and SCE; and c) animals fed the combined regimen (AFB(1) plus mannan) presented a 25% weight increase with respect to the animals treated with AFB(1) alone, as well as a significant reduction in the level of MNNE and SCE with the two high doses tested. In the second (recovery) period, the control and the mannan fed groups maintained values similar to those exhibited in the previous phase, and the AFB(1) group as well as the groups fed the regimen combined with mannan showed an improvement in all evaluated parameters; the best response was that found in mice fed AFB(1) plus 500 mg/kg of mannan. Our study established an antigenotoxic effect of mannan that could be due to its adsorbent capacity.
Assuntos
Aflatoxina B1/toxicidade , Mananas/farmacologia , Zea mays/microbiologia , Animais , Masculino , Camundongos , Micronúcleos com Defeito Cromossômico/efeitos dos fármacos , Troca de Cromátide Irmã/efeitos dos fármacosRESUMO
Grapefruit juice (GJ) is widely consumed in many countries. Several of its constituents possess nutritive value, as well as antigenotoxic and antioxidant effects. Therefore, the aim of this investigation was to evaluate the capacity of GJ to inhibit the micronucleated polychromatic erythrocytes (MNPE) produced by daunorubicin (Dau) in an acute assay in mice, as well as to determine its antioxidant potential in mouse hepatic microsomes, and its capacity to trap free radicals in vitro. In regard to the first point, GJ produced no toxic or genotoxic damage; on the contrary, it generated a significant reduction of the MNPE formed by Dau. The effect was found throughout the examined schedule (from 24 to 96 h). The two high doses produced inhibition of about 60% at 48 h, 86% at 72 h and 100% at 96 h after the treatment. With respect to the GJ antioxidant potential, a 50% decrease in liver microsomal lipid peroxidation produced by Dau was found by quantifying malondialdehyde formation. Finally, a strong GJ scavenging activity evaluated with the 1,1-diphenyl-2-picryl-hydrazyl (DPPH) was observed, giving rise to a concentration-dependent curve with a correlation coefficient of 0.98. Overall, our results established an efficient anticlastogenic potential of GJ, probably related to its antioxidant capacity, or to alterations of Dau metabolism, suggesting the pertinence of extending research on the matter using other mutagens and biological models.
Assuntos
Antibióticos Antineoplásicos/toxicidade , Antioxidantes/farmacologia , Bebidas , Citrus paradisi/química , Daunorrubicina/toxicidade , Radicais Livres/metabolismo , Animais , Relação Dose-Resposta a Droga , Eritrócitos , Peroxidação de Lipídeos , Masculino , Camundongos , Testes para Micronúcleos , Microssomos HepáticosRESUMO
Naringin (Nar) is a flavonone found in high amount in grapefruit. In in vitro studies to determine its antimutagenicity results have been both positive and negative. On the other hand, an increase in the bioavailability of some medicaments have been observed when these are ingested together with grapefruit. It has been suggested that the effect may be related to the inhibition of the human enzyme Cytochrome P450 (CYP) 3A4 by Nar, an enzyme with a high aminoacid sequence homology with the Cyp3a in mouse. The present study was designed for three main purposes: (1) to determine whether Nar has a genotoxic effect in mouse in vivo. This was evaluated by measuring the rate of micronucleated polychromatic erythrocytes (MNPE); (2) to determine its antigenotoxic and its anticytotoxic potential on the damage produced by ifosfamide (Ifos). The first study was done by scoring the rate of MNPE, and the second one by establishing the index polychromatic erythrocytes/normochromatic erythrocytes (PE/NE); and (3) to explore whether its antigenotoxic mechanism of action is related to an inhibitory effect of Nar on the expression of the Cyp3a enzyme, an effect which could avoid the biotransformation of Ifos. A single oral administration was used for all groups in the experiment: three groups were given different doses of Nar (50, 250, and 500 mg/kg), other groups received the same doses of Nar plus an administration of Ifos (60 mg/kg), another group treated with distilled water and another with Ifos (60 mg/kg) were used as negative and positive controls, respectively. The micronuclei and the cell scoring were made in blood samples taken from the tail of the animals at 0, 24, 48, 72, and 96 h. The results showed that Nar was neither genotoxic nor cytotoxic with the doses tested, but Ifos produced an increase in the rate of MNPE at 24 and 48 h. The highest value was 24+/-1.57 MNPE per thousand cells at 48 h. The index PE/NE was significantly reduced by Ifos at 24 and 48 h. Concerning the antigenotoxic capacity of Nar, a significant decrease was observed in the MNPE produced by Ifos at the three tested doses. This effect was dose-dependent, showing the highest reduction in MNPE frequency (54.2%) at 48 h with 500 mg/kg of Nar. However, no protection on the cytotoxicity produced by Ifos was observed. Immunoblot analysis was used to assess the Cyp3a expression in liver and intestinal microsomes from mouse exposed orally to Nar. An induction in the Cyp3a protein was observed in both intestinal and hepatic microsomes from treated mice. This induction correlated with an increase in erythromycin N-demethylase activity. These data suggest that other mechanism(s) are involved in the antigenotoxic action of naringin.