Search

The accepted biological potencies of vitamin E (United States Phamacopeia, 1985) for 1 mg all-rac-??-tocopheryl acetate (synthetic form) is 1??00 IU and that of 1 mg (RRR)-??-tocopheryl acetate (natural form) is 1??36 IU. In the present study, a stable isotopic (2H) technique was employed to evaluate the bioavailability of natural v. synthetic forms of vitamin E and to determine whether the potency of the forms is the stated relationship of 1??36:1??00 (RRR)-??-tocopheryl acetate:all-rac-??-tocopheryl acetate. Sixty female in-bred guinea pigs received either 40 or 80 mg vitamin E/kg diet with equal levels of (RRR)-??-tocopheryl acetate and all-rac-??-tocopheryl acetate throughout gestation and lactation. At late-term pregnancy (day 50 or 60) and during early lactation, dams and their corresponding fetuses or neonates were killed and various tissues collected for subsequent ??-tocopherol analysis. Vitamin E analysis of fetal and neonatal tissues indicated a substantial transfer of 2H-labelled ??-tocopherol across the placenta and through the mammary gland. Total ??-tocopherol concentrations were significantly influenced by tissue type and dose level, but not by stage of gestation or lactation. The relative bioavailability (d3:d6) across fetal and neonatal tissues was on average 1??81:1??00, with a range from 1??62:1??00 to 2??01:1??00. Maternal tissues had a mean ratio of 1??77:1??00. A higher relative bioavailability (P???0??05) was observed with natural compared with synthetic ??-tocopherol as shown by a higher d3:d6 ratio in all tissues examined. Vitamin E was highest in colostrum on day 2 then declined through to day 5. Results from this present experiment further question the accepted biological potencies of natural:synthetic ??-tocopheryl acetate of 1??36:1??00. [ABSTRACT FROM PUBLISHER]

The aim of this study was to assess the impact of three ampicillin dosage regimens on ampicillin resistance among Enterobacteriaceae recovered from swine feces by use of phenotypic and genotypic approaches. Phenotypically, ampicillin resistance was determined from the percentage of resistant Enterobacteriaceae and MICs of Escherichia coli isolates. The pool of ampicillin resistance genes was also monitored by quantification of blaTEM genes, which code for the most frequently produced β-1actamases in gram-negative bacteria, using a newly developed real-time PCR assay. Ampicillin was administered intramuscularly and orally to fed or fasted pigs for 7 days at 20 mg/kg of body weight. The average percentage of resistant Enterobacteriaceae before treatment was between 2.5% and 12%, and blaTEM gene quantities were below 107 copies/g of feces. By days 4 and 7, the percentage of resistant Enterobacteriaceae exceeded 50% in all treated groups, with some highly resistant strains (MIC of >256 μg/ml). In the control group, blaTEM gene quantities fluctuated between 104 and 106 copies/g of feces, whereas they fluctuated between 106 to 107 and 107 to 109 copies/g of feces for the intramuscular and oral routes, respectively. Whereas phenotypic evaluations did not discriminate among the three ampicillin dosage regimens, blaTEM gene quantification was able to differentiate between the effects of two routes of ampicillin administration. Our results suggest that fecal blaTEM gene quantification provides a sensitive tool to evaluate the impact of ampicillin administration on the selection of ampicillin resistance in the digestive microflora and its dissemination in the environment. [ABSTRACT FROM AUTHOR]

Due to restriction of the use of BPA, several structural analogues such as BPS and BPF have been proposed for its replacement in many consumer products. This has increased the prevalence of BPS and BPF in urine from tested cohorts. However, these substitutes have similar endocrine disrupting properties to BPA, particularly on reproductive and metabolic functions, which suggests that fetal exposure to these analogues could be of concern for human health. Bisphenols (BPs) are mainly metabolized to glucuronides (BP-Gs), which are considered as inactive but provide a relevant marker of fetal exposure during pregnancy. In most instances, these metabolites are indirectly quantified after hydrolysis and measurement of the corresponding native BPs, which may lead to bias due to spurious BPs contamination during blood collection and/or analyses. We have developed a new method for direct quantification of BP-Gs, which has the advantage of not being affected by errors related to the presence of BPs. First, BP-Gs were extracted from plasma by anion exchange solid phase extraction. They were then labelled with dansyl chloride, using experimentally-optimized incubation conditions, after which the dansyl derivatives were injected into an on-line SPE-UHPLC/MS/MS system. The performance of the method, in terms of sensitivity, precision and accuracy, was evaluated in plasma over a concentration range of 0.05-5 ng/mL. The intra- and inter-day CV% precision were lower than 20% with accuracies ranging from 93% to 115%. The limit of quantification was set at 0.05 ng/mL. The method was then applied to measure BP-Gs in forty-four cord plasma samples. Although no BPF-G was found, BPA-G and BPS-G was determined in almost half of the cord plasma samples with concentration ranges nd-0.089 ng/mL and nd-0.586 ng/mL, respectively., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The aim of this study was to assess the impact of three ampicillin dosage regimens on ampicillin resistance among Enterobacteriaceae recovered from swine feces by use of phenotypic and genotypic approaches. Phenotypically, ampicillin resistance was determined from the percentage of resistant Enterobacteriaceae and MICs of Escherichia coli isolates. The pool of ampicillin resistance genes was also monitored by quantification of bla(TEM) genes, which code for the most frequently produced beta-lactamases in gram-negative bacteria, using a newly developed real-time PCR assay. Ampicillin was administered intramuscularly and orally to fed or fasted pigs for 7 days at 20 mg/kg of body weight. The average percentage of resistant Enterobacteriaceae before treatment was between 2.5% and 12%, and bla(TEM) gene quantities were below 10(7) copies/g of feces. By days 4 and 7, the percentage of resistant Enterobacteriaceae exceeded 50% in all treated groups, with some highly resistant strains (MIC of >256 microg/ml). In the control group, bla(TEM) gene quantities fluctuated between 10(4) and 10(6) copies/g of feces, whereas they fluctuated between 10(6) to 10(8) and 10(7) to 10(9) copies/g of feces for the intramuscular and oral routes, respectively. Whereas phenotypic evaluations did not discriminate among the three ampicillin dosage regimens, bla(TEM) gene quantification was able to differentiate between the effects of two routes of ampicillin administration. Our results suggest that fecal bla(TEM) gene quantification provides a sensitive tool to evaluate the impact of ampicillin administration on the selection of ampicillin resistance in the digestive microflora and its dissemination in the environment.

The accepted biological potencies of vitamin E (United States Phamacopeia, 1985) for 1 mg all-rac-alpha-tocopheryl acetate (synthetic form) is 1.00 IU and that of 1 mg (RRR)-alpha-tocopheryl acetate (natural form) is 1.36 IU. In the present study, a stable isotopic (2H) technique was employed to evaluate the bioavailability of natural v. synthetic forms of vitamin E and to determine whether the potency of the forms is the stated relationship of 1.36:1.00 (RRR)-alpha-tocopheryl acetate:all-rac-alpha-tocopheryl acetate. Sixty female in-bred guinea pigs received either 40 or 80 mg vitamin E/kg diet with equal levels of (RRR)-alpha-tocopheryl acetate and all-rac-alpha-tocopheryl acetate throughout gestation and lactation. At late-term pregnancy (day 50 or 60) and during early lactation, dams and their corresponding fetuses or neonates were killed and various tissues collected for subsequent alpha-tocopherol analysis. Vitamin E analysis of fetal and neonatal tissues indicated a substantial transfer of 2H-labelled alpha-tocopherol across the placenta and through the mammary gland. Total alpha-tocopherol concentrations were significantly influenced by tissue type and dose level, but not by stage of gestation or lactation. The relative bioavailability (d3:d6) across fetal and neonatal tissues was on average 1.81:1.00, with a range from 1.62:1.00 to 2.01:1.00. Maternal tissues had a mean ratio of 1.77:1.00. A higher relative bioavailability (P

This study aimed to develop a nonlabeled method for the measurement of cortisol production rate to evaluate adrenal function. The cortisol production rate determination requires that of cortisol clearance, which is not a parameter but a variable resulting from the saturable binding of cortisol to corticosteroid-binding globulin (CBG). Our method is based on evaluation of the plasma clearance of the CBG-free cortisol fraction. This parameter was evaluated from a pharmacokinetic model of total plasma cortisol disposition that takes into account specific binding of the corticoid to CBG in the plasma. We have shown that the CBG-free cortisol kinetics and CBG-binding parameters thus evaluated are not statistically different from those obtained by the radioisotopic method and equilibrium dialysis, suggesting that the plasma CBG-free cortisol clearance is independent of the total plasma cortisol concentrations and represents the actual parameter of cortisol elimination. We validated this modeling approach by using it to calculate the in vivo entry rate of cortisol mimicked by the perfusion of cortisol at a known rate.

Objective: To assess the effects of moderate exercise on plasma creatine kinase (CK) pharmacokinetics and to estimate exercise-induced muscle damage in dogs., Animals: 6 untrained adult Beagles., Procedure: The study was divided into 3 phases. In phase 1, dogs ran for 1 hour at a speed of 9 km/h, and samples were used to determine the area under the plasma CK activity versus time curve (AUC) induced by exercise. In phases 2 and 3, pharmacokinetics of CK were calculated in dogs during exercise and at rest, respectively. Values for AUC and plasma clearance (CI) were used to estimate muscle damage., Results: At rest, values for Cl, steady-state volume of distribution (Vdss), and mean retention time (MRT) were 0.32+/-0.02 ml/kg of body weight/min, 57+/-173 ml/kg, and 3.0+/-0.57 h, respectively. During exercise, Cl decreased significantly (0.26+/-0.03 ml/kg/min), MRT increased significantly, (4.4+/-0.97 h), and Vdss remained unchanged. Peak of plasma CK activity (151+/-58.8 U/L) was observed 3 hours after completion of exercise. Estimated equivalent amount of muscle corresponding to the quantity of CK released was 41+/-29.3 mg/kg., Conclusion and Clinical Relevance: These results revealed that exercise had a minor effect on CK disposition and that the equivalent amount of muscle damaged by moderate exercise was negligible. This study illustrates the relevance for use of the minimally invasive and quantitative pharmacokinetic approach when estimating muscle damage.

Although gastrointestinal complications are common in patients with renal disease, the effects of renal dysfunction on bowel motility and gut transit times are not well known. We assessed gastrointestinal electromyographic activity, gastric emptying rate, orocolonic transit time, oroanal transit time, and xylose absorption before and after surgically inducing a 66% decrease in glomerular filtration rate in dogs. Moderate renal failure induced no gross or microscopic gastrointestinal lesions but caused a 16-42% increase in gastrointestinal motility indexes. We found a 24% decrease in the propagation velocity of the myoelectrical migrating complex in the duodenojejunal segment, a 30% decrease in phase I duration in duodenal and jejunal regions, a 20% increase in the total irregular electrical activity of the small intestine, and a 22% increase in duration of the meal response in the duodenum and jejunum. Renal failure did not change xylose absorption, gastric emptying rate, and orocolonic transit time but decreased colonic transit time by 38%. The mean weight of feces was increased. These results indicate that moderate renal failure alters duodenojejunal motility and decreases colonic transit time.

The pharmacokinetics of benazepril, enalapril, and their active metabolites (benazeprilat and enalaprilat) were compared after a single administration of each product by the oral route at the recommended dosage (0.5 mg/kg for both drugs) in the dog before and after moderate experimental renal impairment. Ten dogs were randomly assigned to 2 groups of 5 animals in a 2-period crossover design for angiotensin-converting enzyme inhibitor administration. Renal failure was surgically induced by right nephrectomy and electrocoagulation of the remaining kidney. Renal mass reduction induced a significant decrease (P < .001) in glomerular filtration rate (GFR) (1.7 +/- 0.3 versus 3.3 +/- 0.7 mL/kg/minute). No significant differences before and after surgery were observed for enalapril and benazepril kinetics. The area under the curve (AUC) for enalaprilat increased after surgery from 23.6 +/- 14.7 to 42.4 +/- 20.9 micrograms.minute/mL (P < .01). Mean peak plasma concentration (Cmax) was increased in the impaired dogs (59.1 +/- 23.3 versus 43.9 +/- 32.9 ng/mL), but this variation was not significant (P > .05). Renal failure had no significant effect on AUC for benazeprilat (13.8 +/- 9.8 versus 14.9 +/- 5.0 micrograms.minute/mL) (P > .05), but Cmax decreased significantly (from 55.0 +/- 26.4 to 31.9 +/- 17.7 ng/mL) (P < .05). Multiple regression analysis showed that both GFR and AUC for enalapril were highly significant variables that explained the variation in AUC for enalaprilat (R2 = .86, P < .001) but not for benazeprilat (R2 = .12, P > .05). The results of this study indicate that exposure to enalaprilat, but not to benazeprilat, is increased in dogs with subclinical renal impairment.

D-alpha-Tocopherol in an emulsible base was administered i.p. to four groups of five sheep each at doses of 0, 1250, 2500, and 5000 IU. Blood was sampled regularly until slaughter at 7 d after administration. Plasma and tissue concentrations of D-alpha-tocopherol were measured by HPLC. Pharmacokinetic analysis of plasma concentrations, for the three tested doses, showed an absence of significant difference for lag time to absorption (.9 to 2.5 h), half-time of absorption (15 to 30 h), plasma half-life (31 to 42 h), and time of maximal concentration (18 to 31 h). In contrast, dose had a significant effect on area under the tocopherol plasma curve and on the maximal concentration. For both parameters, statistical evidence indicated nonlinearity for disposition of D-alpha-tocopherol, but without biological significance; by 7 d after dosing, amounts of residue of tocopherol were highest in the pancreas and adrenal glands (approximately 65 and 47 micrograms/g, respectively, for the 5000 IU dose) and lowest in neck muscle (approximately 4 micrograms/g for the 5000 IU dose). Kidney had an intermediate level of tocopherol. The intraperitoneal route is an efficient route for tocopherol administration in sheep.

A chronic inflammation model in dogs was induced by intraarticular injection of Freund's Complete Adjuvant in the stifle. After a primary, acute response during the first 24 hr, a secondary subacute response was observed after a delay of approximately 3 weeks and persisted for several weeks. To evaluate the time course of the inflammatory process quantitatively, we tested more than 100 different parameters. Finally, only four parameters were selected based on practicability and metrological properties, namely, the body temperature, difference in skin temperature, difference in stifle diameter and vertical force exerted by arthritic hind limb measured using a force plate. The main results of the experimentation were the demonstration that these four parameters were sufficiently repeatable, reproducible, and appropriate to be used for quantitative evaluation of the inflammatory process, and that training of both animals and investigators was required. Finally, it was illustrated that an adjuvant periarthritis in dogs can be used to carry out a pharmacokinetic/pharmacodynamic modelling of an antiinflammatory drug.

A qualitative impairment of natural killer (NK) function and the presence of circulating DNA have been independently reported in clinical situations such as cancer and lupus. The existence of receptors for chromatin fragments at the leukocyte membrane raised the question of the relation between the presence of chromatin fragments in the extracellular medium and the impairment of NK function. The present study shows that plasmas from patients with metastatic cancer and with pathological DNA concentrations inhibited significantly the NK activity of normal lymphocytes as compared to cancer plasmas with DNA concentrations in the normal range. In vitro, it was demonstrated that chromatin fragments inhibited the NK-mediated cytotoxicity in a dose-dependent manner. Inhibitory concentrations of nucleosomes (2.5-10 micrograms/ml) were lower than those of DNA and histones alone (100 micrograms/ml). Inhibitory effects of nucleosomes, DNA and histones differed also according to the effector population used: nucleosomes were effective whatever the CD56+ cell enrichment of the effector population, while DNA inhibition needed T cells, and histone inhibition probably resulted from a subtoxic effect, prevented by the presence of adherent cells. Finally we found that nucleosomes could inhibit the NK function only when they were present in the extracellular medium. Taken together, these data suggest that the persistence of nucleosomal DNA at sites of cell death or in the blood might be responsible, at least partly, for the NK activity impairment observed in pathological circumstances characterized by a high rate of cell death phenomena such as cancer.

The purpose of this study was to develop a simple and noninvasive method for the quantitative evaluation of neuromuscular blockade in mice. The sciatic nerve in anesthetized animals (etomidate, 50 mg/kg or mephenesin, 250 mg/kg) was stimulated using transcutaneous electrodes; repetitive supramaximal stimulations (3 Hz during 3.3 sec) were applied each minute until recovery or death occurred. Evoked action potentials of the gastrocnemius muscle were recorded. The effect of each pharmacological agent was expressed as the ratio (S5/S1) of the area of the fifth response (S5) to the first one (S1). The performance of the method was tested using neuromuscular blocking agents such as alcuronium, suxamethonium, or alpha-bungarotoxin. It was concluded that the method exhibits the required statistical performances (sensitivity, repeatability, and specificity) to be recommended for in vivo investigation of neuromuscular impairment.

The authors describe the compared pharmacokinetics of triclabendazole in three camels and four sheep which were given orally a single dose of 10 mg/kg liveweight. Plasma concentrations of triclabendazole and its main metabolites were determined by high performance liquid chromatography. No parental drug was detected in the blood plasma due to a hepatic first passage effect. It appeared that there was a major difference between the two species, triclabendazole sulfoxide concentrations being two times lower in camels than in sheep.

The electrical activity of the uterus, greater curvature and lesser curvature, and of the cervix were recorded throughout several oestrous cycles, matings and the entire course of pregnancy in a set of ewes. In cyclic ewes, all electrode sites were active during the periovulatory period, but during the luteal phase only the cervix and lesser curvature continued to present regular activity, i.e. episodes of 6-8 min duration. Matings failed to disrupt the oestrous activity pattern in 5 out of 6 ewes. During the subsequent pregnancy in 4 ewes, activity, when present, consisted of the cyclic occurrence of regular activity episodes in the gravid horn(s) (greater curvature) and in the cervix (and lesser curvature in 1 ewe). Three phases were recognized on the basis of the activity of the greater curvature of the gravid horn(s). The first phase corresponded to quiescence of the horn from Day 5 (Day 0 = mating) to about Day 41. The second phase was marked by the sudden onset of regular activity of the uterus; frequency rapidly increased and maximal values were reached around Day 49, after which frequency progressively decreased until around Day 66. The third phase was characterized by a steady state in genital tract activity until the peripartum period. The cervix and lesser curvature activity followed an almost similar development of regular activity episodes with only slight time differences.

Continuous recordings of the electrical and mechanical activities of the cervix were made. Two basic patterns of electrical signal, short spike bursts and long spike bursts, showed close mechanical relationships with the record of mechanical activity. Electrical activity was organized in myoelectrical complexes including the regular alternation of phases of irregular spiking activity and phases of regular spiking activity. The myoelectrical complexes of the cervix existed independently of the sexual status although the frequency of recurrence did vary. The highest frequency was recorded during the periovulatory period around oestrus when each complex was synchronized with a similar pattern recorded from the uterine horns. At the end of the periovulatory period, the irregular spiking activity decreased, the myoelectrical complex pattern of the cervix and uterine horns consisting mainly of regular spiking activity at a high frequency until metoestrus. During the luteal phase, only the cervix remained active, with myoelectrical complexes formed mainly by phases of regular spiking activity recurring at long intervals. This pattern was also recorded after ovariectomy in the absence of hormonal treatment.

Secretory profiles and production rates of growth hormone (GH) were determined in 6 ruminant lambs during winter. The mean GH concentrations (3.78 +/- 2.17 ng/ml) calculated were based upon blood sampling obtained every 3 min using a withdrawal pump. Body clearance (0.162 +/- 0.031 1/h/kg) was calculated from bolus intravenous oGH administration. The data were analysed by non-linear regression analysis; a bicompartmental model was selected to describe the data. production rate was 14.6 +/- 7.98 micrograms/kg/24 h. It has been emphasized that the experimental design used gave an accurate estimate of GH production rate.

Passage of dexamethasone from plasma to milk in five lactating dairy cows after an intravenous injection was evaluated by a high performance liquid chromatographic technique for measurement of concentrations in blood plasma and milk. The dexamethasone ester was 21-isonicotinate as a solution and was administered at .1 mg/kg bodyweight. The drug was detected in milk postinjection from 15 min to 8 h with a peak concentration of 20.6 ng/ml at the second sample time (30 min). Half-times of dexamethasone in plasma and milk were 4.5 and 3.0 h. The ratio of mean concentration for milk/plasma was .39. It is anticipated that no residues of dexamethasone would be detected in milk if normal dairy practices are followed.