Genotoxic and cytotoxic evaluation of venlafaxine in an acute and a subchronic assay in mouse

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.

Genotoxic and cytotoxic evaluation of venlafaxine in an acute and a subchronic assay in mouse / Avaliação genotóxica e citotóxica da venlafaxina em ensaio agudo e subcrônico em camundongos

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.

Terapia basada en incretinas para control glucémico de los pacientes hospitalizados con diabetes tipo 2: una revisión sistemática / Incretin-based therapy for glycemic control of hospitalized patients with type 2 diabetes: a systematic review

La terapia basada en incretinas lleva al control glucémico de una manera dependiente de glucosa con un bajo riesgo de hipoglucemia, por lo que resulta atractiva para su uso hospitalario. El objetivo de esta revisión sistemática fue evaluar los beneficios de la terapia basada en incretinas en pacientes con diabetes tipo 2 hospitalizados fuera de la unidad de cuidados intensivos. Se buscaron estudios publicados hasta agosto de 2021 en las bases de datos PubMed y Scopus. Se seleccionaron los ensayos clínicos que comparaban la terapia basada en incretinas (sola o en combinación con insulina) versus el régimen con insulina. Los resultados de los estudios incluidos mostraron que la terapia basada en incretinas registró un promedio de glucosa sanguínea, un porcentaje de registros dentro de meta terapéutica y un porcentaje de falla al tratamiento similar al manejo con insulina, particularmente en pacientes con hiperglucemia leve a moderada. Además, el tratamiento basado en incretinas se asoció con una menor dosis total de insulina y una menor incidencia de hipoglucemia. En conclusión, la terapia basada en incretinas logró un control glucémico similar al tratamiento con insulina en los pacientes con diabetes tipo 2 hospitalizados fuera de la unidad de cuidados intensivos, con la ventaja de disminuir el requerimiento insulínico y con menor riesgo de hipoglucemia (AU)

Incretin-based therapy leads to glycemic control in a glucose-dependent manner with a low risk of hypoglycemia, making it appealing for use in the hospital. The aim of this systematic review was to assess the benefits of incretin-based therapy in patients with type 2 diabetes hospitalized outside of the intensive care unit. We searched for studies published up to August 2021 in the PubMed and Scopus databases. Clinical trials comparing incretin-based therapy (alone or in combination with insulin) versus an insulin regimen were selected. The results of the included studies showed that incretin-based therapy showed mean blood glucose values, a percentage of records within the therapeutic target, and a percentage of treatment failure similar to insulin management, particularly in patients with mild to moderate hyperglycemia. Furthermore, incretin-based treatment was associated with a lower total insulin dose and a lower incidence of hypoglycemia. In conclusion, incretin-based therapy achieved glycemic control similar to insulin treatment in patients with type 2 diabetes hospitalized outside the intensive care unit and has the advantages of reducing the insulin requirement and a lower risk of hypoglycemia (AU)

Incretin-based therapy for glycemic control of hospitalized patients with type 2 diabetes: a systematic review.

Incretin-based therapy leads to glycemic control in a glucose-dependent manner with a low risk of hypoglycemia, making it appealing for use in the hospital. The aim of this systematic review was to assess the benefits of incretin-based therapy in patients with type 2 diabetes hospitalized outside of the intensive care unit. We searched for studies published up to August 2021 in the PubMed and Scopus databases. Clinical trials comparing incretin-based therapy (alone or in combination with insulin) versus an insulin regimen were selected. The results of the included studies showed that incretin-based therapy showed mean blood glucose values, a percentage of records within the therapeutic target, and a percentage of treatment failure similar to insulin management, particularly in patients with mild to moderate hyperglycemia. Furthermore, incretin-based treatment was associated with a lower total insulin dose and a lower incidence of hypoglycemia. In conclusion, incretin-based therapy achieved glycemic control similar to insulin treatment in patients with type 2 diabetes hospitalized outside the intensive care unit and has the advantages of reducing the insulin requirement and a lower risk of hypoglycemia.

Genotoxic and cytotoxic evaluation of venlafaxine in an acute and a subchronic assay in mouse.

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.

Construction of a synthetic protein using PCR with a high essential amino acid content for nutritional purposes.

Ovalbumin is considered a protein of high nutritional value because it contains essential amino acids and is highly digestible. Therefore, it has a high biological value. Currently, the high food demand requires worldwide attention because food production is insufficient. Therefore, other alternatives are necessary to satisfy food demands, such as protein engineering. In this work, a protein with a high essential amino acid content similar to ovalbumin was synthesized by protein engineering, expressed, and digested in vitro. The assembly and sequential overlap extension PCR strategy was used to synthesize a 345-bp gene that encodes a high essential amino acid content protein (HEAAP). The 345-bp product was cloned into the vector pBAD TOPO®, and expressed in Escherichia coli BL21. PCR reactions and sequencing demonstrated the presence, orientation, and correct sequence of the insert. HEAAP expression was induced by L-arabinose and then purified using Ni-NTA affinity chromatography. The expression in E. coli was low and barely detected by Western blot assay. The in vitro multienzyme digestibility of HEAAP was around 79%, which suggests that the protein is potentially nutritious. Virtual analysis classifies the protein as unstable and hydrophilic, with a half-life in E. coli of 10 h. The recombinant HEAAP was successfully synthesized, but it is necessary to improve the digestibility and to optimize expression including selecting other expression models.

Evaluation of blueberry juice in mouse azoxymethane-induced aberrant crypts and oxidative damage.

Blueberry is a plant with a number of nutritional and biomedical capabilities. In the present study we initially evaluated the capacity of its juice (BJ) to inhibit the number of aberrant crypts (AC) induced with azoxymethane (AOM) in mouse. BJ was administered daily by the oral route to three groups of animals during four weeks (1.6, 4.1, and 15.0 µL/g), respectively, while AOM (10 mg/kg) was intraperitoneally injected to the mentioned groups, twice a week, in weeks two and three of the assay. We also included two control groups of mice, one administered distilled water and the other the high dose of BJ. A significant increase of AC was observed in the AOM treated animals, and a mean protection of 75.6% was determined with the two low doses of BJ tested; however, the high dose of the juice administered together with AOM increased the number of crypts more than four times the value observed in animals administered only AOM. Furthermore, we determined the antioxidant potential of BJ with an ex vivo DPPH assay and found a dose-dependent decrease with a mean of 19.5%. We also determined the DNA oxidation/antioxidation by identifying 8-hydroxy-2'-deoxyguanosine adducts and found a mean decrease of 44.3% with the BJ administration with respect to the level induced by AOM. Our results show a complex differential effect of BJ related to the tested doses, opening the need to further evaluate a number of factors so as to determine the possibility of a cocarcinogenic potential.

Genotoxic and oxidative damage induced by Helicobacter pylori in Meriones unguiculatus.

Infection with Helicobacter pylori has been shown to be at the origin of various gastric pathologies. However, it has not yet been established whether the etiology of such diseases, particularly of gastric cancer, is related to the production of free radicals or to mutagenesis. The aim of this study was to determine whether a six-month infection with Helicobacter pylori increased the amount of lipid peroxidation, nitric oxide, and DNA damage in Mongolian gerbils (Meriones unguiculatus). H. pylori was characterized genotypically and administered orally to the animals. Four tests were applied to identify the presence of bacteria at one, two, four, and six months after the inoculation, namely, isolation and identification in culture, the urease test, the ELISA assay, and immunohistochemical staining of gastric biopsies. The infection was considered to be successful when three of the above-mentioned tests were positive. The infection occurred in 30% of the animals in the first month after the H. pylori inoculation and in 60-70% of the animals in the later stages. Levels of malondialdehyde, nitric oxide, and DNA damage (using the "comet" assay) were determined in the gastric tissue of the animals at one, two, four, and six months. We found statistically significant increases in malondialdehyde and nitric oxide levels from the second month on. The comet assay in animals infected with H. pylori showed a significant increase in the mean tail length throughout the observation period. We conclude that our results support the assumption that oxidative damage and DNA breakage produced by the infection with H. pylori are some of the initial alterations occurring in the development of gastric diseases.

Inhibitory effect of mannan on the toxicity produced in mice fed aflatoxin B1 contaminated corn.

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.

Antigenotoxic effect of Saccharomyces cerevisiae on the damage produced in mice fed with aflatoxin B(1) contaminated corn.

The potential of Saccharomyces cerevisiae (Sc) was evaluated for reducing the micronucleated normochromatic erythrocytes (MNNE) rate in mice fed AFB(1) contaminated corn. The study included two groups fed AFB(1) contaminated corn (0.4 and 0.8 mg/kg), a control fed uncontaminated corn, another group fed uncontaminated corn and 0.3% of Sc (1 x 10(8) live cells/g), and two groups fed AFB(1) contaminated corn (0.4 and 0.8 mg/kg) plus 0.3% Sc. Weight and MNNE were determined weekly for six weeks. Subsequently, the same determinations were made for another three-week period, but in mice receiving only a normal diet, without AFB(1) and Sc. Results in the first period revealed the following: control and Sc fed mice had similar constant weight increase, and low MNNE rate; mice fed only AFB(1) showed weight decrease and significant MNNE increase; finally, Sc improved weight gain and reduced MNNE produced by AFB(1). In the second period, results exhibited a tendency similar to that of the previous phase in the control and Sc fed mice; the weight and MNNE values improved in the other groups. We also determined the capacity of Sc for adsorbing and modifying the mycotoxin structure. The mixture was filtered to obtain two phases, and AFB(1) content was measured. Sc revealed a potent adsorbent capacity; however, chromatographic determination suggested no structural modification.