Pharmacokinetic parameters of (R)-(-) and (S)-(+)-flurbiprofen in dairy bovines.

The aim of the study was to evaluate the pharmacokinetics of flurbiprofen (FBP) in different age groups and physiological status groups in dairy cattle. Ten Argentine Holstein bovines were divided into three different groups: 3 cows in early lactation, 3 cows in gestation and 4 newborn calves. Based on previous experience, all the animals received racemic FBP (50:50) at a dose of 0.5 mg/kg by intravenous administration. Blood samples were taken at predetermined times after administration of flurbiprofen. Plasma enantiomer concentrations were measured by HPLC. Total body clearance (ClB) of (S)-(+)-FBP was higher in calves than in cows (114.5, 136.4, 121.4, 128.9 microg/ml vs 22.0, 24.2, 46.5 microg/ml and 27.6, 25.3, 34.6 microg/ml). In calves the disposition kinetics showed stereoselective behaviour. Area under the concentration-time curve (AUC) was higher and Cl(B) and steady-state volume of distribution (V(ss)) were lower for (R)-(-)-FBP than for (S)-(+)-FBP. In cows, stereoselectivity was observed in Cl(B) and elimination half-life (t(1)/2) only in the early lactation group. In this study, enantioselective metabolic behaviour of FBP under the physiological situations studied was found. Hence, it is possible that both enantiomers of flurbiprofen may contribute to the drug's therapeutic effects, but further studies with the administration of separate enantiomers will be required to elucidate their metabolism.

Some pharmacokinetic parameters of R-(-)- and S-(+)-ketoprofen: the influence of age and differing physiological status in dairy cattle.

The pharmacokinetic parameters of ketoprofen have previously been studied in cattle, but no studies have been performed on differing ages and metabolic situations in these animals. The aim of this work was to study the possible modifictions of the pharmacokinetics of ketoprofen enantiomers that may result from age, lactation or gestation in dairy cattle. Three groups of Holando Argentino cattle contained, respectively, 8 cows in early lactation, 8 pregnant cows and 8 newborn calves. Four animals from each group received the enantiomer R-(-)-ketoprofen, the other four animals received the S-(+) enantiomer, all by intravenous injection at a dose of 0.5 mg/kg. Significant differences between the three categories of animals were obtained in elimination half-life (t1/2) (1.52, 0.87 and 0.31 and 1.71, 0.69 and 0.26 in newborn calves, cows in early lactation and cows in gestation, respectively), mean residence time (MRT) (0.45, 1.25, 2.20 and 0.38, 0.99, 2.47 h, in cows in gestation, cows in early lactation and newborn calves, respectively) and area under the plasma concentration-time curve (AUC) (0.87, 2.93, 3.24, and 0.67, 2.78, 5.13 (microg/h)/ml in cows in gestation, cows in early lactation and newborn calves, respectively, for the R-(-) and S-(+) enantiomer, respectively. In calves, there was a significant difference in AUC (3.24 vs 5.13 (microg/h)/ml between R-(-)- and S-(+)-ketoprofen. In view of the differences between calves and adult cattle in the pharmacokinetic results for ketoprofen, the effects of age and physiological status (lactation, gestation) should be taken into account for therapeutic regimens.

Chiral inversion of (R)-ketoprofen: influence of age and differing physiological status in dairy cattle.

The chiral inversion of ketoprofen has been previously demonstrated in cattle, but no studies have been performed on different ages and metabolic situations in the animals. The aim of this work was to study any modifications of the stereoconversion of ketoprofen that occur by reason of age, lactation or gestation in dairy cows. Holando Argentino cattle were divided into three groups: 8 cows in early lactation, 8 pregnant cows and 8 newborn calves. Four animals from each group received the enantiomer R-(-)-ketoprofen by intravenous administration; the other four animals received the S-(+) enantiomer, all at doses of 0.5 mg/kg. Blood samples were collected at standardized times after dosing and assayed for ketoprofen by high-performance reversed-phase liquid chromatography (HPLC). The percentage inversion of R-(-)-ketoprofen to S-(+)-ketoprofen was 50.5% (SD +/- 2.4) in the preruminants, 33.3% (SD +/- 1.7) in cows in early lactation and 26.0% (SD +/- 5.1) in cows in gestation. These results indicate a differing enantioselective metabolic behaviour for one compound in one species under different physiological situations.

Serum leptin levels in cattle with different nutritional conditions.

The role of leptin as an energetic state indicator in cattle was evaluated correlating different nutritional conditions and serum leptin levels. Two experiments were developed. Experiment I: Polled Hereford heifers were fed in optimum conditions and assigned randomly to one of three treatment diets: grazing, grazing plus supplementation and feedlot. Experiment II: cattle were subjected to feed restriction (R). Serum leptin levels were measured at pre and post-feeding moments. Using serum free fatty acid (FFA), beta-OH Butyrate (beta-OHB) and protein concentration as serum energetic indicators in both experiments. In experiment I leptin values were significantly different between pre and post-feeding moments, similar differences were found among groups when the pre-feeding and post-feeding values were compared. These differences may be considered as changes associated to the control of food intake. In experiment II, the serum leptin levels in Group R were significantly lower. The poor energetic status of animals from group R was demonstrated by the serum FFA, beta-OHB and protein concentrations. These results suggest that the energetic status of animals is correlated with the serum leptin levels, tending to maintain the energetic homeostasis.

Cytochrome c oxidase, Cu,Zn-superoxide dismutase, and ceruloplasmin activities in copper-deficient bovines.

The activity of several cuproenzymes in relation to the immune system was examined in serum and blood cells from bovines with molybdenum-induced copper deficiency. Five female cattle were given molybdenum (30 ppm) and sulfate (225 ppm) to induce experimental secondary copper deficiency. Ceruloplasmin activity was determined in serum. The Cu,Zn-superoxide dismutase and cytochrome c oxidase activities were measured in peripheral blood lymphocytes, neutrophils, and monocyte-derived macrophages. Copper deficiency was confirmed from decreased serum copper levels and the animals with values less than 5.6 micromol/L were considered deficient. The content of intracellular copper decreased between 40% and 70% in deficient cells compared with the controls. In copper-deficient animals, the serum ceruloplasmin activity decreased to half of the control value. Both of them, the Cu,Zn-superoxide dismutase and the cytochrome c oxidase activities, undergo a significant reduction in leukocytes, showing differences among diverse cell populations. We concluded that the copper deficiency alters the activity of several enzymes, which mediate antioxidant defenses and ATP formation. These effects may impair the cell immune functionality, affecting the bactericidal capacity and making the animals more susceptible to infection.

Bovine monocyte-derived macrophage function in induced copper deficiency.

The effect of molybdenum-induced copper deficiency on monocyte-derived macrophage function was examined. Five female calves were given molybdenum (30 ppm) and sulphate (225 ppm) to induce experimental secondary copper deficiency. Oxidant production by bovine macrophages was measured after stimulation with phorbol myristate acetate (PMA) and opsonized zymosan (OpZ). Lipoperoxidative effects inside of macrophage, superoxide dismutase activity, superoxide anion and hydrogen peroxide formation were determined. Copper deficiency was confirmed from decreased serum copper levels, and animals with values less than 5.9 micromol/l were considered deficient. The content of intracellular copper decreased about 40% in deficient cells compared with the controls. The respiratory burst activity determined by nitroblue tetrazolium reduction was significantly impaired with both stimulants used. Superoxide anion formation was less affected than hydrogen peroxide generation. In addition, increased lipid peroxidation was observed. It could be concluded that the effect of these changes may impair the monocyte-derived macrophage function in the immune system.

Levels of progesterone and changes in prostaglandin F(2alpha) release during luteolysis and early pregnancy in llamas and the effect of treatment with flunixin meglumine.

The secretory patterns of progesterone in relation to concentrations of 15-ketodihydro-PGF(2alpha) (PGFM) during the period of luteolysis or of maternal recognition of pregnancy were determined in the blood of llamas mated either with an intact or a vasectomized male. The ability of flunixin meglumine (FM) to postpone luteolysis in non-pregnant llamas was investigated by injecting the drug intravenously every 6 h at a dose of 2.2 mg/kg from days 6 to 12 post-copulation into a group of non-pregnant llamas. A pulsatile pattern of prostaglandin release was recorded during luteolysis in non-pregnant llamas, giving further support to the hypothesis that PGF(2alpha) is the luteolytic agent in llamas. The mean number of peaks per animal rose from 0.3 on day 7 to 3.8 on day 10 and then declined to 1.1 on day 12 with corresponding mean peak amplitude changing from 465 to 1234 and 566 pmol l(-1), respectively. In pregnant llamas, prostaglandin pulsatile release also occurred. The mean number of peaks per animal rose from 0.4 on day 7 to 0.8 on day 10 and then declined to 0.2 on day 11 and 0.6 on day 12, with corresponding mean peak amplitude changing from 494 to 676, 388 and 547 pmol l(-1), respectively. The transient decrease and subsequent recovery in progesterone concentrations was observed to occur in connection with prostaglandin release during early pregnancy. Oestradiol-17beta plasma peak concentrations attained after luteolysis were significantly higher than those recorded in early pregnant animals (around 30 pmol l(-1) and ll pmol l(-1)). Concentrations of PGFM decreased rapidly after the first administration of FM and remained low throughout the first 2 days of treatment. Thereafter, pulsatile release of prostaglandins started, and luteolysis proceeded; but a delay of 1-1.5 days in the progesterone decline was observed. Thus, it might be suggested that a higher dose and/or a more intensive injection schedule is required in llamas than in other ruminants to prevent luteolysis.

Nutritional condition affects the hepatic antioxidant systems in steers.

The objectives of this study were to evaluate the activity of antioxidant systems in the hepatic tissues of steers experimentally subjected to a restricted diet. Hence, the activities of superoxide dismutase (SOD) and reduced glutathione (GSH) and lipid peroxide levels were measured. Nine male Holstein steers were used. They were separated in two groups: three steers in group 1 (control) and six steers in group 2, which were subjected to a restricted diet that covered only 60% of the maintenance requirements. After 30 days, the animals in both groups were killed and studies were completed. Both the CuZn-SOD and the glucose-6-phosphate dehydrogenase activities were significantly decreased (p < 0.05) in group 2, reaching 68% and 60%, respectively, of the concentrations found in group 1. The concentration of GSH in group 2 was 6.71+/-0.9 nmol/mg protein, which was significantly lower (p < 0.01) than that of the controls, 25.7+/-2.4 nmol/mg protein. In addition, the lipid peroxide levels were significantly increased (p < 0.01) in group 2, being 50-60% higher than that in group 1. These results showed that the poor nutritional status caused modifications to the enzymatic antioxidant systems, with a lower ability to reduce oxidative compounds and a state of lipid peroxidation.

[Physiologic role of the somatotrophic GH-IGF and others hormones in the domestic animals growth. Influence of the nutritional status]. / Rol fisiológico del eje somatotrófico GH-IGF y otras hormonas en el crecimiento de los animales domésticos. Influencia del estado nutricional.

In this review main hormones involved in development and muscle growth are shown with special emphasis on growth hormone (GH) and insulin-like growth factors (IGF). Chemist composition, synthesis place, action way and main action mechanisms of these hormones are reviewed. Nutritional factors which modified seric metabolites, and their effects on hormone secretion are detailed. It was observed that GH, IGF, thyroid hormones, insulin, glucocorticoids and sexual steroids act in a complex and cordinated way to produce a productive response to different> nutritional strategies.

[Experimental model for the study of molybdenosis in the primary copper deficiency in rats]. / Modelo experimental para el estudio de la molibdenosis y de la deficiencia primaria de cobre en ratas.

An experimental model in rats was evaluated to differentiate the effects between Copper deficiency and Molybdenosis. Sixty weaning rats (30 male and 30 female) received a diet with 70% complete powder milk (1 ppm Cu) and 30% maize meal (0.8-1.5 ppm Cu). Three experimental groups received the following mineral supplementation: copper deficiency (40 ppm Fe), molybdenosis (40 ppm Fe + 40 ppm Cu + 500 ppm Mo) and control (40 ppm Fe + 40 ppm Cu). The animals were weighed each 14 days. At 70 days of treatment were sacrificed. Blood and liver were sampled for analyzing hematocrit, ceruloplasmin activity and Cu and Mo liver concentration. Copper deficiency group had less serum ceruloplasmin activity. Cu and Mo liver concentration were higher in the animals with molybdenosis. We concluded that when Cu levels are higher than minimum requirement, feeding with high Mo, do not affect ceruloplasmin activity. In addition, high Mo liver concentration allows us to elucidate effects "per se" of molybdenosis.

Rol fisiológico del eje somatotrófico GH-IGF y otras hormonas en el crecimiento de los animales domésticos. Influencia del estado nutricional / Physiologic role of the somatotrophic GH-IGF and others hormones in the domestic animals growth. Influence of the nutritional status

En esta revisión se describen las principales hormonas invlolucradas en el desarrollo y crecimiento muscular, haciendo especial énfasis en la hormona de cricimiento (GH) y los factores del crecimiento semejante a insulina (IGF). Se recopila la composición química, el lugar de síntesis y los principales mecanismos de acción de estas hormonas. Se observó que la GH, IGF, las hormonas tiroideas, la insulina, los glucocorticoides y los esteroides sexuales actuán en una forma compleja y coordinada para producir una respuesta productiva a diferentes estrategias nutricionales.

Modelo experimental para el estudio de la molibdenosis y de la deficiencia primaria de cobre en ratas / Experimental model for the study of molybdenosis in the primary copper deficiency in rats

Con el objetivo de diferenciar los efectos producidos por la deficiencia primaria cobre y los provocados por el excesso de molibdeno se evaluó un modelo experimental en ratas. Sesenta ratas de destete (30 machos y 30 hembras) recibieron una dieta compuesta por 70 por ciento de leche entera en polvo (1 ppm Cu) y 30 por ciento de harina de maíz (0.8 - 1.5 ppm Cu). Los animales se dividieron en tres grupos conforme a la suplementación mineral recibida: deficiencia primaria de cobre (40 ppm Fe), molibdenosis (40 ppm Fe + 40 ppm Cu + 500 ppm Mo) y controles (40 ppm Fe + 40 ppm Cu). Se pesaron cada 14 días. Al cabo de 70 días de tratamiento se obtuvieron muestras de sangre para determinación de hematocrito y actividad sérica de ceruloplasmina y se sacrificaron para medir concentraciones hepáticas de Cu y Mo. El grupo deficiente en Cu tuvo valores significativamente inferiores en la actividad de ceruloplasmina. Las concentraciones hepáticas de Cu y Mo fueron superiores significativamente en los animales con molibdenosis. Se concluye que con niveles de Cu por encima de los requerimientos mínimos, la alimentación con alto contenido de Mo, no afecta la actividad sérica de ceruloplasmina. Esto sumado a la concentración hepática de Mo lograda, permitirá identificar efectos "per se" de la molibdenosis.

Rol fisiológico del eje somatotrófico GH-IGF y otras hormonas en el crecimiento de los animales domésticos. Influencia del estado nutricional. / [Physiologic role of the somatotrophic GH-IGF and others hormones in the domestic animals growth. Influence of the nutritional status]

In this review main hormones involved in development and muscle growth are shown with special emphasis on growth hormone (GH) and insulin-like growth factors (IGF). Chemist composition, synthesis place, action way and main action mechanisms of these hormones are reviewed. Nutritional factors which modified seric metabolites, and their effects on hormone secretion are detailed. It was observed that GH, IGF, thyroid hormones, insulin, glucocorticoids and sexual steroids act in a complex and cordinated way to produce a productive response to different> nutritional strategies.

Modelo experimental para el estudio de la molibdenosis y de la deficiencia primaria de cobre en ratas. / [Experimental model for the study of molybdenosis in the primary copper deficiency in rats]

An experimental model in rats was evaluated to differentiate the effects between Copper deficiency and Molybdenosis. Sixty weaning rats (30 male and 30 female) received a diet with 70

complete powder milk (1 ppm Cu) and 30

maize meal (0.8-1.5 ppm Cu). Three experimental groups received the following mineral supplementation: copper deficiency (40 ppm Fe), molybdenosis (40 ppm Fe + 40 ppm Cu + 500 ppm Mo) and control (40 ppm Fe + 40 ppm Cu). The animals were weighed each 14 days. At 70 days of treatment were sacrificed. Blood and liver were sampled for analyzing hematocrit, ceruloplasmin activity and Cu and Mo liver concentration. Copper deficiency group had less serum ceruloplasmin activity. Cu and Mo liver concentration were higher in the animals with molybdenosis. We concluded that when Cu levels are higher than minimum requirement, feeding with high Mo, do not affect ceruloplasmin activity. In addition, high Mo liver concentration allows us to elucidate effects [quot ]per se[quot ] of molybdenosis.

Rol fisiológico del eje somatotrófico GH-IGF y otras hormonas en el crecimiento de los animales domésticos. Influencia del estado nutricional / Physiologic role of the somatotrophic GH-IGF and others hormones in the domestic animals growth. Influence of the nutritional status

En esta revisión se describen las principales hormonas invlolucradas en el desarrollo y crecimiento muscular, haciendo especial énfasis en la hormona de cricimiento (GH) y los factores del crecimiento semejante a insulina (IGF). Se recopila la composición química, el lugar de síntesis y los principales mecanismos de acción de estas hormonas. Se observó que la GH, IGF, las hormonas tiroideas, la insulina, los glucocorticoides y los esteroides sexuales actuán en una forma compleja y coordinada para producir una respuesta productiva a diferentes estrategias nutricionales. (AU)

Modelo experimental para el estudio de la molibdenosis y de la deficiencia primaria de cobre en ratas / Experimental model for the study of molybdenosis in the primary copper deficiency in rats

Con el objetivo de diferenciar los efectos producidos por la deficiencia primaria cobre y los provocados por el excesso de molibdeno se evaluó un modelo experimental en ratas. Sesenta ratas de destete (30 machos y 30 hembras) recibieron una dieta compuesta por 70 por ciento de leche entera en polvo (1 ppm Cu) y 30 por ciento de harina de maíz (0.8 - 1.5 ppm Cu). Los animales se dividieron en tres grupos conforme a la suplementación mineral recibida: deficiencia primaria de cobre (40 ppm Fe), molibdenosis (40 ppm Fe + 40 ppm Cu + 500 ppm Mo) y controles (40 ppm Fe + 40 ppm Cu). Se pesaron cada 14 días. Al cabo de 70 días de tratamiento se obtuvieron muestras de sangre para determinación de hematocrito y actividad sérica de ceruloplasmina y se sacrificaron para medir concentraciones hepáticas de Cu y Mo. El grupo deficiente en Cu tuvo valores significativamente inferiores en la actividad de ceruloplasmina. Las concentraciones hepáticas de Cu y Mo fueron superiores significativamente en los animales con molibdenosis. Se concluye que con niveles de Cu por encima de los requerimientos mínimos, la alimentación con alto contenido de Mo, no afecta la actividad sérica de ceruloplasmina. Esto sumado a la concentración hepática de Mo lograda, permitirá identificar efectos "per se" de la molibdenosis. (AU)

The effect of copper deficiency on the peripheral blood cells of cattle.

Six female cattle were given molybdenum (30 ppm) and sulphate (225 ppm) to induce experimental secondary copper deficiency. The total and differential leukocyte numbers and lymphocyte subpopulations were counted and the neutrophil activity was assessed by means of nitroblue tetrazolium reduction and phagocytosis of sheep erythrocytes. The serum caeruloplasmin activity and concentration were also determined. Copper deficiency was confirmed from decreased serum copper levels, the animals with values less than 5.9 mumol/L being considered deficient. Total leukocyte numbers were not affected by the copper deficiency. However, differential counts showed a marked increase in monocyte subpopulations, a significant decrease in B lymphocytes and reduced neutrophil activity. The serum caeruloplasmin activity was decreased about 50%, but the total serum protein concentration was less altered. We concluded that the effect of these changes on the animals' immune competence may contribute to a greater incidence of infectious diseases in copper-deficient cattle.

[Oxidative effect of hepatic copper overload]. / Efecto oxidativo de la sobrecarga hepática de cobre.

To explain the cytotoxicity of excessive free radical production in the liver of rats, the lipoperoxidation in subcellular structures and some antioxidants systems were evaluated. We measured Cu-Zn superoxide dismutase (Cu-Zn-SOD) activity, reduced glutathione (GSH) levels and lipid peroxidation in homogenates and subcellular fractions of hepatocytes. Female Wistar rats were given a 0,2 per cent solution of CUSO4 in water, to induce the Cu toxicity. Serum copper levels and acid phosphatase (AP) activity were determined at frequent intervals. Six treated rats were euthanased to the twelfth week of begun the assay. During the sixteenth week, at time of the increase of serum AP activity the others treated rats also were killed. We found high liver Cu content and evidence of lipid peroxidation. In whole homogenate, mitochondrial and microsomal fractions, the thiobarbituric acid reacting substances were increased. This was correlated with an increase in the Cu-Zn-SOD activity and with decrease of the GSH levels. It could be argued that high copper status might have increased the Cu-Zn-SOD activity and induced lowest levels of GSH. Additionally, lipid peroxidation was induced by Cu-overload.

Glucose-6-phosphate dehydrogenase activity in erythrocytes from chronically copper-poisoned sheep.

The present study was undertaken to investigate the capacity to generate reducing equivalents in erythrocytes from experimentally copper-poisoned sheep. Ten ewes were dosed orally with CuSO4 to induce the Cu toxicity. Copper dosing was stopped at the first day of hemolysis. The activity of glucose-6-phosphate dehydrogenase (G6PD) in the erythrocytes, the levels of reduced glutathione (GSH) and glucose (in serum and erythrocytes) was examined at frequent intervals. The copper-poisoned sheep had reduced levels (25-35% less) of glucose in serum and erythrocytes than controls. The activity of G6PD in erythrocytes from sheep was 50-60% of typical levels found in human erythrocytes. Immediately before the hemolytic period, the copper-poisoned sheep showed decreased activity of G6PD, declining to 65% of the initial activity. In addition, we found decreased blood levels of reduced GSH in copper-poisoned sheep. There appears to be a relationship between decreased capacity to generate reducing equivalents and the overload of copper in sheep erythrocytes.