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1.
Res Vet Sci ; 167: 105113, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38141570

ABSTRACT

The anthelmintic fenbendazole (FBZ) undergoes hepatic S­oxygenation by monooxygenases belonging to the cytochrome P450 (CYP) and flavin-monooxygenase (FMO) families. The in-feed medication with FBZ induced CYP1A-dependent metabolism in pig liver. This fact may alter the metabolism of the anthelmintic itself, and of CYP1A substrates like aflatoxin B1 (AFB1). This work evaluated the effect of the in-feed administration of FBZ on CYP1A-dependent metabolism, on its own pattern of hepatic S­oxygenation, and on the metabolism of AFB1. Landrace piglets remained untreated (n = 5) or received a pre-mix of FBZ (n = 6) in feed for 9 days. Pigs were slaughtered for preparation of liver microsomes used for: CYP content determination; monitoring the CYP1A-dependent enzyme activities, 7-ethoxyresorufin O-deethylase (EROD) and 7-methoxyresorufin O-demethylase (MROD); measurement of FBZ (50 µM) S­oxygenation, and AFB1 (16 nM) disappearance from the incubation medium. In microsomes of FBZ-treated animals, EROD and MROD increased 19-fold (p = 0.002) and 14-fold (p = 0.003), respectively. An enhanced (3-fold, p = 0.004) participation of the CYP pathway in FBZ S­oxygenation was observed in the liver of piglets treated with the anthelmintic (210 ± 69 pmol/min.nmol CYP) compared to untreated animals (68 ± 34 pmol/min.nmol CYP). AFB1 metabolism was 93% higher (p = 0.009) in the liver of FBZ-treated compared to untreated pigs. Positive and significant (p < 0.05) correlations were observed between CYP1A-dependent enzyme activities and FBZ or AFB1 metabolism. The sustained administration of FBZ caused an auto-induction of the CYP1A-dependent S­oxygenation of this anthelmintic. The CYP1A induction triggered by the anthelmintic could amplify the production of AFB1 metabolites in pig liver, including the hepatotoxic AFB1-derived epoxide.+.


Subject(s)
Anthelmintics , Cytochrome P-450 CYP1A1 , Humans , Animals , Swine , Cytochrome P-450 CYP1A1/metabolism , Cytochrome P-450 CYP1A1/pharmacology , Fenbendazole/pharmacology , Fenbendazole/metabolism , Cytochrome P-450 Enzyme System/metabolism , Anthelmintics/pharmacology , Microsomes, Liver/metabolism , Drug Interactions
2.
Acta Neurol Scand ; 139(2): 199-203, 2019 Feb.
Article in English | MEDLINE | ID: mdl-30256381

ABSTRACT

OBJECTIVES: To investigate the significance of "subtherapeutic" vs "therapeutic" antiepileptic drug (AED) plasma levels with respect to treatment adherence. MATERIAL AND METHODS: One hundred and seventy patients with refractory temporal lobe epilepsy who underwent video-EEG monitoring in view of a surgical indication had their AEDs (carbamazepine, phenobarbital, phenytoin, and valproate) rapidly withdrawn following a standardized schedule. Plasma levels were measured at admission, and during the 2 days of drug withdrawal. Adherence and nonadherence were identified by the development of plasma levels from day 1 through day 3. Frequencies of an initial level below the reference range in both groups were compared. RESULTS: Adherence was found in 73.2% of cases, and nonadherence in 26.8%. Low levels were seen equally often (about 1/4 of cases) in adherent and nonadherent cases. The vast majority (73.7%) of low levels had another explanation than nonadherence (eg low-dose treatment or enzyme induction). Of 42 nonadherent cases, the vast majority of 76.2% had unsuspicious plasma levels at admission. CONCLUSIONS: "Subtherapeutic" AED plasma levels only rarely are caused by nonadherence whereas levels in the "therapeutic range" by no means prove that the patient is adherent to treatment. For meaningful interpretation, any level needs to be compared with other levels of the same patient. Our findings strongly emphasize the principle of individualized therapeutic AED monitoring as promoted by the Therapeutic Strategies Commission of the ILAE.


Subject(s)
Anticonvulsants/administration & dosage , Drug Monitoring/methods , Epilepsy, Temporal Lobe/drug therapy , Medication Adherence , Adult , Anticonvulsants/blood , Anticonvulsants/therapeutic use , Drug Administration Schedule , Drug Monitoring/standards , Epilepsy, Temporal Lobe/physiopathology , Female , Humans , Male , Middle Aged
3.
Reprod Toxicol ; 63: 114-24, 2016 08.
Article in English | MEDLINE | ID: mdl-27233481

ABSTRACT

Polybrominated diphenyl ether flame-retardants (PBDEs) are thyroid-disrupting environmental chemicals. We investigated the effects of postnatal exposure to DE-71 (a mixture of tetra- and penta-brominated congeners), n-propylthiouracil (PTU) and thyroxine (T4) replacement on open-field (OF) and radial maze (RAM) tests. Wistar rats (5 males/5 females per litter, 32 litters) were treated orally (PND 5-22) with PTU (4mg/kg bw/d), DE-71 (30mg/kg bw/d), with and without co-administration of T4 (15µg/kg bw/d, sc). PTU depressed T4 serum levels and body weight gain and enlarged thyroid gland. Although decreasing T4 levels, DE-71 did not change thyroid and body weights. PTU-treated rats showed hyperactivity (PND 42 and 70), and working and reference memory learning deficits (RAM, PND 100). Although not altering motor activity and working memory, DE-71 caused a reference memory deficit (females only). T4 co-administration averted hypothyroxinemia and long-term cognitive deficits caused by PTU and DE-71.


Subject(s)
Environmental Pollutants/toxicity , Flame Retardants/toxicity , Halogenated Diphenyl Ethers/toxicity , Thyroxine/blood , Animals , Animals, Newborn , Brain/drug effects , Brain/growth & development , Cognitive Dysfunction/chemically induced , Cytochrome P-450 CYP1A1/metabolism , Cytochrome P-450 CYP2B1/metabolism , Female , Glucuronosyltransferase/genetics , Liver/drug effects , Liver/enzymology , Male , Rats, Wistar
4.
Acta sci., Biol. sci ; Acta sci., Biol. sci;37(1): 15-22, jan.- mar. 2015. ilus
Article in English | LILACS | ID: biblio-847977

ABSTRACT

Studies on new microbial sources of cellulase and accurate assessment of the steps that increase cellulase production are essential strategies to reduce costs of various processes using such enzymes. This study aimed at the selection of cellulase-producing filamentous fungi, and at the research of parameters involving cellulase production by submerged fermentation. The first test consisted of selecting the best cellulase-producing microorganisms (FPase) in Erlenmeyer flasks containing 200 mL of specific growth medium. The next test was designed to further investigate the enzyme production in fermentation with four types of soluble sugars: glucose, lactose, sucrose and xylose. In bioreactor tests, three different inoculation strategies were analyzed. The best FPase activity was presented by the strain Trichoderma sp. CMIAT 041 (49.9 FPU L-1) and CMCase by the fungus Lasiodiplodia theobromae CMIAT 096 (350.0 U L-1). Sucrose proved to be the best option among the soluble sugars tested, with higher rates of FPase activity (49.9 FPU L-1) and CMCase (119.7 U L-1). The best inoculation strategy for the bioreactor was a spore suspension obtained from a semi-solid state fermentation of wheat bran for 72h.


Estudos sobre novas fontes microbianas e análises mais acuradas das etapas que compõem a produção de celulases são essenciais como estratégias para diminuir os custos gerados pelo uso de celulases nos processos de obtenção de açúcares fermentescíveis. O trabalho teve como objetivo a seleção de fungos filamentosos produtores de celulases e a investigação de parâmetros que envolvem a produção enzimática em fermentação submersa. O primeiro teste consistiu em selecionar os melhores fungos produtores de celulases totais em frascos Erlenmeyer contendo 200 mL de meio de cultura específico. O teste subsequente teve o intuito de investigar a produção enzimática com quatro tipos de açúcares solúveis: glicose, lactose, sacarose e xilose. Nos testes em biorreator foram analisados três diferentes estratégias de inoculação. Na etapa de seleção a melhor atividade de FPase foi apresentada por Trichoderma sp. CMIAT 041 (49,9 FPU L-1) e CMCase pelo fungo Lasiodiplodia theobromae CMIAT 096 (350,0 U L-1). O uso de sacarose mostrou-se ser a melhor opção dentre os açúcares solúveis testados, apresentando os maiores valores de atividade de FPase (49,9 FPU L-1) e CMCase (119,7 U L-1). A melhor estratégia de inoculação foi a suspensão de esporos obtidos a partir de fermentação em farelo de trigo, no tempo 72h.


Subject(s)
Brazil , Cellulases , Ecosystem , Fermentation , Fungi
5.
Acta Sci. Biol. Sci. ; 37(1): 15-22, jan.-mar. 2015. graf
Article in English | VETINDEX | ID: vti-691162

ABSTRACT

fermentação submersa utilizando fungos isolados do bioma brasileiro RESUMO. Estudos sobre novas fontes microbianas e análises mais acuradas das etapas que compõem a produção de celulases são essenciais como estratégias para diminuir os custos gerados pelo uso de celulases nos processos de obtenção de açúcares fermentescíveis. O trabalho teve como objetivo a seleção de fungos filamentosos produtores de celulases e a investigação de parâmetros que envolvem a produção enzimática em fermentação submersa. O primeiro teste consistiu em selecionar os melhores fungos produtores de celulases totais em frascos Erlenmeyer contendo 200 mL de meio de cultura específico. O teste subsequente teve o intuito de investigar a produção enzimática com quatro tipos de açúcares solúveis: glicose, lactose, sacarose e xilose. Nos testes em biorreator foram analisados três diferentes estratégias de inoculação. Na etapa de seleção a melhor atividade de FPase foi apresentada por Trichoderma sp. CMIAT 041 (49,9 FPU L-1) e CMCase pelo fungo Lasiodiplodia theobromae CMIAT 096 (350,0 U L-1). O uso de sacarose mostrou-se ser a melhor opção dentre os açúcares solúveis testados, apresentando os maiores valores de atividade de FPase (49,9 FPU L-1) e CMCase (119,7 U L-1). A melhor estratégia de inoculação foi a suspensão de esporos obtidos a partir de fermentação em farelo de trigo, no tempo 72h.(AU)


Studies on new microbial sources of cellulase and accurate assessment of the steps that increase cellulase production are essential strategies to reduce costs of various processes using such enzymes. This study aimed at the selection of cellulase-producing filamentous fungi, and at the research of parameters involving cellulase production by submerged fermentation. The first test consisted of selecting the best cellulase-producing microorganisms (FPase) in Erlenmeyer flasks containing 200 mL of specific growth medium. The next test was designed to further investigate the enzyme production in fermentation with four types of soluble sugars: glucose, lactose, sucrose and xylose. In bioreactor tests, three different inoculation strategies were analyzed. The best FPase activity was presented by the strain Trichoderma sp. CMIAT 041 (49.9 FPU L-1) and CMCase by the fungus Lasiodiplodia theobromae CMIAT 096 (350.0 U L-1). Sucrose proved to be the best option among the soluble sugars tested, with higher rates of FPase activity (49.9 FPU L-1) and CMCase (119.7 U L-1). The best inoculation strategy for the bioreactor was a spore suspension obtained from a semi-solid state fermentation of wheat bran for 72h.(AU)


Subject(s)
Animals , Cellulases/analysis , Fermentation , Fungi/growth & development , Fungi/isolation & purification
6.
Rev. Fac. Cienc. Vet ; 54(2): 108-115, dic. 2013. tab
Article in Spanish | LILACS | ID: lil-705449

ABSTRACT

Los errores innatos del metabolismo se definen como trastornos genéticos que ocurren en la estructura y/o función de las moléculas proteicas. Uno de estos trastornos, es la fenilcetonuria (PKU, por sus siglas en inglés), la cual se presenta debido a la alteración en la reacción enzimática de la hidroxilación de fenilalanina (F). El tratamiento de la PKU es básicamente nutricional, por lo cual, en Venezuela, se están evaluando nuevas materias primas con bajo contenido de F, de manera que puedan ser incluidas en dietas de niños fenilcetonúricos. Estas materias primas, deben ser validadas a través de pruebas biológicas in vivo usando animales experimentales, antes de suministralos a los humanos. En el presente estudio se evaluó la harina de plátano Musa paradisíaca (como ingrediente único) como coadyudante en el manejo nutricional de ratones fenilcetonuricos inducidos experimentalmente utilizando un bloqueante de la enzima a-metilfenilalanina a una dosis de 24 µM/10 g peso vivo (PV) y el aminoácido D-fenilalanina a una dosis de 52µM/10 g p.v. Se observó que los ratones presentaron solo una elevación de los niveles de F (P≤0,05) alcanzando una hiperfenilalaninemia leve (4-10mg/dL de sangre) durante la etapa predestete. Sin embargo, al ser sometidos a una alimentación postdestete con la harina de plátano, como única fuente nutritiva, se pudo observar una diferencia en el desarrollo del animal (P≤0,05), evidenciándose un marcado deterioro y desnutrición. Se recomienda realizar estudios adicionales, que incorporen junto con la harina de plátano, un glicomacropéptido que supla los requerimientos mínimos nutricionales de los ratones en crecimiento y mantenga bajo los niveles de F.


Inborn errors of metabolism are defined as genetic disturbances that occur in the structure and/or function of protein molecules. Phenylketonuria (PKU) is a good example of this type of disturbance, which is due to an alteration in the enzymatic reaction responsible for phenylalanine (Phe) hydroxylation. Treatment of this disease is basically nutritional. In Venezuela, new raw materials with a low content of Phe are being tested, so that they can be included in the diets of children suffering from PKU. Previous administration to humans, these raw materials should be validated by in vivo biological tests, using laboratory animals. Therefore, the purpose of this study was to assess the plantain (Musa paradisíaca) meal, as the only ingredient, in the nutritional management of experimentally induced PKU in laboratory mice, using a-methyphenylalanine, as the agent responsible for blocking phenylalanine hydroxylase, at a dose of 24 µM/10 of body weight (BW). To help blockade, a dose of D-phenylalanine (52 µM/10g of BW), was also administered. The results of the investigation showed that during the pre-weaning stage, mice exhibited a slight elevation in Phe levels that was statistically significant (P≤0.05), reaching a hyperphenylalalinemia level of 4-10 mg/dL of blood. In contrast, when mice were subjected to a post-weaning diet with plantain meal as the only nutritional source, a difference (P≤0.05) in their development could be observed, which evidenced marked deterioration and malnutrition. It is recommended that additional studies be performed that include a glycomacropeptid along with the plantain meal, so that minimum nutritional requirements can be supplied, keeping low levels of Phe in PKU patients.

7.
Vitae (Medellín) ; 19(3): 280-286, sep.-dic. 2012. ilus, tab
Article in English | LILACS | ID: lil-669353

ABSTRACT

Background: Extracellular lipases are found in the culture broth when the fermentation is at the end of the exponential phase. Lipases can be induced easily since they are produced by the presence of oily sources or other materials as surfactants, fatty acids, some esters, glycerol and biliary salts. Objective: The aim of this work is to study the effect of carbon source concentration and the use of inductors on biomass production, and the lipolytic activity of a bacterium isolated from mature palm oil fruits. Methods: The yield biomass/substrate was evaluated with glucose as carbon source at different concentrations (3, 5, 7, 10, 15 y 20 g/L) by dry weight and OD (600 nm). Lipolytic activity was evaluated by spectrophotometric assay using p-nitrofenilpalmitate at 37°C for 15 min. Results: Gram negative microorganisms with lipolytic activity isolated from palm fruit were identified as Pseudomona aeruginosa. The growth of the bacteria was inhibited when glucose was used at concentrations greater than 5%. The production of lipase was induced by using three inducers (Palm oil, Tween 20 and palm oil:Tween 20 mixture), at three different induction times (0, 11 and 18 hours of fermentation). The highest activity (3,81 µmoles/mL*min) was observed when the palm oil:Tween 20 mixture was added at 11 hours of fermentation. The kinetic of p-nitrophenylpalmitate hydrolysis using the supernatant of a culture induced with palm oil:Tween 20 mixture at 11 hours showed the production of p-nitrophenol beyond 300 minutes, with the greatest hydrolysis rate during the first 7 minutes. Conclusions: The growth of P. aeruginosa was not affected by using glucose as carbon source at concentrations of 3% and 5%. There was a basal level of lipase production without inducer, and greater lipolytic activity was achieved with the addition of inducers.


Subject(s)
Hydrolysis , Fatty Acids
8.
Semina Ci. agr. ; 5(16): 26-30, 1984.
Article in Portuguese | VETINDEX | ID: vti-471221

ABSTRACT

A single dose do DDT (DichlorodiphenyltrichloroethaneJ (50 and 100 mg/kg i.p.) enhanced the hepatic metabolizing activity in rats. The N-demethylation ofaminopyrine showed a 3-4 fold increase when compared with control On the other hand, there was only a 2-fold increase on hydroxyltion of aniline and on the levels of cytochrome PA s 0. The pentobarbital sleeping time decreased 80% in both doses of insecticide. These results revealed a maximal induction in the dose of 50 mg/kg of insecticide. In adition, it was demonstrated that the DDT evokes a diferential effect on the aminopyrine N-demethylase and aniline p-hydroxylase activity. 


Uma única dose de DDT (diclorodifiniltricloroetano) (50 e I00mg/kg) aumentou a atividade metabolizadora de drogas em fígado de ratos. A N-desmetilação da aminopirina aumentou 3 a 4 vezes quando comparada com o controle. Por outro lado, um aumento de 2 vezes foi verificado tanto para a hidroxilação da anilina, como nos níveis de citocromo P4So- O tempo de hipnose barbitúrica provocado pelo pentobarbital sádico foi reduzido em 80% nas duas doses empregadas. Nossos resultados demonstraram que o efeito indutor máximo foi atingido com a dose de 50 mg/kg de DDT. Além disso, revelaram também que DDT exerce um efeito diferencial, na sua capacidade indutora, sobre a atividade da aminopirina N-desmetilase e anilina hidroxilase.  

9.
Semina ciênc. agrar ; 5(16): 26-30, 1984.
Article in Portuguese | LILACS-Express | VETINDEX | ID: biblio-1501995

ABSTRACT

A single dose do DDT (DichlorodiphenyltrichloroethaneJ (50 and 100 mg/kg i.p.) enhanced the hepatic metabolizing activity in rats. The N-demethylation ofaminopyrine showed a 3-4 fold increase when compared with control On the other hand, there was only a 2-fold increase on hydroxyltion of aniline and on the levels of cytochrome PA s 0. The pentobarbital sleeping time decreased 80% in both doses of insecticide. These results revealed a maximal induction in the dose of 50 mg/kg of insecticide. In adition, it was demonstrated that the DDT evokes a diferential effect on the aminopyrine N-demethylase and aniline p-hydroxylase activity.


Uma única dose de DDT (diclorodifiniltricloroetano) (50 e I00mg/kg) aumentou a atividade metabolizadora de drogas em fígado de ratos. A N-desmetilação da aminopirina aumentou 3 a 4 vezes quando comparada com o controle. Por outro lado, um aumento de 2 vezes foi verificado tanto para a hidroxilação da anilina, como nos níveis de citocromo P4So- O tempo de hipnose barbitúrica provocado pelo pentobarbital sádico foi reduzido em 80% nas duas doses empregadas. Nossos resultados demonstraram que o efeito indutor máximo foi atingido com a dose de 50 mg/kg de DDT. Além disso, revelaram também que DDT exerce um efeito diferencial, na sua capacidade indutora, sobre a atividade da aminopirina N-desmetilase e anilina hidroxilase.

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