M. I. San Andrés

Pharmacokinetics of marbofloxacin in mature horses after single intravenous and intramuscular administration

The pharmacokinetic behaviour of marbofloxacin, a new fluoroquinolone antimicrobial agent developed exclusively for veterinary use, was studied in mature horses (n = 5) after single-dose i.v. and i.m. administrations of 2 mg/kg bwt. Drug concentrations in plasma were determined by high performance liquid chromatography (HPLC) and data obtained were subjected to compartmental and noncompartmental kinetic analysis. This compound presents a relatively high volume of distribution (V(SS) = 1.17 +/- 0.18 l/kg), which suggests good tissue penetration, and a total body clearance (Cl) of 0.19 +/- 0.042 l/kgh, which is related to a long elimination half-life (t(1/2beta) = 4.74 +/- 0.8 h and 5.47 +/- 1.33 h i.v. and i.m. respectively). Marbofloxacin was rapidly absorbed after i.m. administration (MAT = 33.8 +/- 14.2 min) and presented high bioavailability (F = 87.9 +/- 6.0%). Pharmacokinetic parameters are not significantly different between both routes of administration (P>0.05). After marbofloxacin i.m. administration, no adverse reactions at the site of injection were observed. Serum CK activity levels 12 h after administration increased over 8-fold (range 3-15) compared with pre-injection levels, but this activity decreased to 3-fold during the 24 h follow-up period. Based on the value of surrogate markers to predict clinical success, Cmax/MIC ratio or AUC/MIC ratio, single daily marbofloxacin dose of 2 mg/kg bwt may not be effective in treating infections in horses caused by pathogens with an MIC > or = 0.25 microg/ml. However, if we use a classical antimicrobial efficacy criteria, marbofloxacin can reach a high plasma peak concentration and maintain concentrations higher than MICs determined for marbofloxacin against most gram-negative veterinary pathogens throughout the administration period. Taking into account the fact that fluoroquinolones are considered to have a concentration-dependent effect and a long postantibiotic effect against gram-negative bacteria, a dose of 2 mg/kg bwt every 24 h could be adequate for marbofloxacin in horses.

Pharmacokinetics, Toxicities, and Efficacies of Sodium Stibogluconate Formulations after Intravenous Administration in Animals

ABSTRACT The pharmacokinetics and toxicities of free sodium stibogluconate (SSG) and two vesicular formulations of this drug (a nonionic surfactant vesicular formulation of SSG [SSG-NIV] and SSG-NIV-dextran) were determined after treatment with a single intravenous dose in healthy dogs and were related to their antileishmanial efficacies in mice. Analysis of the curves of the concentrations in plasma after intravenous administration of SSG and SSG-NIV in dogs showed that both formulations produced similar antimony (Sb) pharmacokinetics. In contrast, treatment with SSG-NIV-dextran significantly modified the pharmacokinetics of the drug. The elimination half-life was four times longer (280 min) than that observed after administration of SSG (71 min) (P = 0.01), and the volume of distribution at steady state (VSS) was also increased (VSS for SSG, 0.21 liters/kg; VSS for SSG-NIV-dextran, 0.34 liters/kg [P = 0.02]), thus indicating that drug encapsulation favors the distribution of Sb into organs and increases its residence time in tissues. This would explain the superior antileishmanial efficacy of this formulation compared to those of the free drug in mice. No signs of toxicity were found in dogs after SSG and SSG-NIV administration. However, SSG-NIV-dextran treatment was associated with short-term toxicity, demonstrated by the development of chills and diarrhea, which cleared by 24 h postdosing, and hepatic dysfunction at 24 h postdosing (P < 0.05). The levels of all the biochemical parameters had returned to normal at 1 month postdosing. No signs of toxicity were observed in mice treated with all three formulations.

Pharmacokinetics of a single intravenous dose of marbofloxacin in adult donkeys

Six donkeys each received 2 mg/kg marbofloxacin as a 10 per cent aqueous solution administered intravenously. Principal pharmacokinetic parameters were determined and two efficacy indices were computed by using pharmacokinetic parameters and selected mic90 values of marbofloxacin against pathogenic equine strains to predict the efficacy of the drug at this dose. The pharmacokinetics of marbofloxacin in donkeys was characterised by a large mean volume of distribution at a steady state (1·15 [0·09] l/kg) and a long mean (sd) elimination half-life of 9·24 (1·96) hours. It was also characterised by a relatively slow total body clearance of 0·10 (0·02) l/kg/hour, slower than in horses. Using mic90 values of marbofloxacin against pathogenic equine strains with a daily dose of 2 mg/kg, appropriate values of efficacy indicators were obtained only for Enterobacteriaceae. Daily intravenous doses of 0·33, 2·62 and 20 mg/kg were calculated for evaluation in clinical trials of infections due to Enterobacteriaceae, Staphylococcus aureus and Streptococci, respectively.

Age-related differences in norfloxacin pharmacokinetic behaviour following intravenous and oral administration in sheep.

The pharmacokinetics of norfloxacin after intravenous (i.v.) and oral (PO) administration in lambs (n = 5) and adult sheep (n = 5) were studied. After i.v. administration (10 mg.kg-1) plasma concentrations were best fitted by a three-compartment open model in both age groups. Distribution volumes were significantly larger in lambs (approximate 4.0 fold difference between 4 week old and adult sheep). There was no significant difference (p < 0.05) between the groups in terms of elimination halflife but plasma clearance was significantly higher in lambs. Norfloxacin was poorly absorbed after oral administration (60 mg.kg-1) in sheep (F = 4.04%). Mean oral bioavailability was 73.51% in lambs (30 mg.kg-1). Norfloxacin elimination was faster in lambs after oral administration. MRTt was significantly prolonged in both age groups when compared with the respective data for i.v. administration.

Toxicokinetics of perfluorooctane sulfonate in birds under environmentally realistic exposure conditions and development of a kinetic predictive model.

This article describes the toxicokinetics of perfluorooctane sulfonate (PFOS) in birds under low repeated dosing, equivalent to 0.085 μg/kg per day, representing environmentally realistic exposure conditions. The best fitting was provided by a simple pseudo monocompartmental first-order kinetics model, regulated by two rates, with a pseudo first-order dissipation half-life of 230 days, accounting for real elimination as well as binding of PFOS to non-exchangeable structures. The calculated assimilation efficiency was 0.66 with confidence intervals of 0.64 and 0.68. The model calculations confirmed that the measured maximum concentrations were still far from the steady state situation, which for this dose regime, was estimated at a value of about 65 μg PFOS/L serum achieved after a theoretical 210 weeks continuous exposure. The results confirm a very different kinetics than that observed in single-dose experiments confirming clear dose-related differences in apparent elimination rates in birds, as described for humans and monkeys; suggesting that a capacity-limited saturable process should also be considered in the kinetic behavior of PFOS in birds. Pseudo first-order kinetic models are highly convenient and frequently used for predicting bioaccumulation of chemicals in livestock and wildlife; the study suggests that previous bioaccumulation models using half-lives obtained at high doses are expected to underestimate the biomagnification potential of PFOS. The toxicokinetic parameters presented here can be used for higher-tier bioaccumulation estimations of PFOS in chickens and as surrogate values for modeling PFOS kinetics in wild bird species.

Some Comparative Aspects of the Pharmacokinetics of Tylosin in Buffaloes and Cattle

The pharmacokinetics of tylosin were compared in cattle (Bos taurus) and buffaloes (Bubalus bubalis). Six animals received each a single dose of 10 mg/kg of tylosin tartrate by the intramuscular route. The serum concentration (Cmax) and the volume of distribution (Vd) presented significant differences between the two species. Cmax was 0.40 ± 0.046 µg/ml for buffaloes and 0.64 ± 0.068 µg/ml for cattle. Vd was 1.91 ± 0.12 L/kg and 1.33 ± 0.09 L/kg for buffaloes and cattle, respectively. However, as the present study did not show considerable differences in the pharmacokinetics of tylosin in buffaloes and cattle, similar dosage regimes of this drug can be recommended for both species.

A procedure to estimate okadaic acid in whole dinoflagellate cells using immunological techniques

A single procedure to detect and estimate okadaic acid in isolated whole cells was developed based on immunofluorescence and microscope photometry. This procedure allows the study of variations in okadaic acid concentration per cell although it is no substitute for HPLC procedures. Cells from mid-log exponential and stationary phase from two different clonal cultures of the okadaic-acid-producing dinoflagellate Prorocentrum lima (PI 5V and PI 7V) were analyzed. The results showed that: (1) cells from saturated phase cultures contain more okadaic acid than those from exponentially-growing mid-log phase; (2) genetic differences exist in okadaic acid production between the clones used; (3) okadaic acid is synthesized continuously during the whole cell cycle.

TRANSMISSION ELECTRON MICROSCOPY APPLIED TO THE STUDY OF WORKS OF ART : SAMPLE PREPARATION METHODOLOGY AND POSSIBLE TECHNIQUES

Technical examination of a work of art is a necessary preliminary stage both for proper conservation/restoration of the work and for purposes of dating and/or authentication. There is a wide variety of methods and procedures, and of these a particularly valuable technique is stratigraphic analysis in view of the data that it furnishes on the composition of the pictorial layers of which a painting is composed. The techniques utilized in this type of analysis to date have been essentially light microscopy and scanning electron microscopy. Transmission electron microscopy can provide new data for characterization of pictorial layers, thanks to the possibility of individually using ultrathin sections of paint sample. This study provides morphological analysis and microanalysis by X‐ray energy dispersion, with determination of the crystalline structure of each particle by electron diffraction. The sample preparation method for producing thin sections from the pictorial layers for examination in the TEM is described. This allows the stratigraphic section to be preserved exactly as applied by the artist. The first results from the examination of three microsamples from actual old works of art are presented. The individual components of each strata were successfully identified in all cases.

Pharmacokinetics of enrofloxacin after multiple subcutaneous and intramuscular administrations in adult ostriches

1. The objective of the study was to evaluate the comparative pharmacokinetic behaviour of enrofloxacin in adult ostriches after single and multiple intramuscular (IM) and subcutaneous (SC) administrations. In addition, tissue tolerance was evaluated. 2. Enrofloxacin was well absorbed, but showed a short permanence after both administration routes. After multiple dose administrations the maximum and minimum peak plasma concentrations were very similar for both routes, obtaining a steady state phase from the second dose that extended until the last evaluated administration. 3. There was no significant accumulation after multiple IM or SC doses; however, there were differences in a fluctuation index after multiple intramuscular administrations that could be related to muscle damage. 4. The different microbiological efficacy indicators (PK/PD indices) obtained, the pharmacokinetic behaviour and CK serum concentrations suggest that subcutaneous enrofloxacin administration of 15 mg/kg every 12 h produce and maintain an efficient concentration of antibiotic that is a safer and more effective therapeutic option than intramuscular administration.

Ivermectin Residue Depletion in Food Producing Species and its Presence in Animal Foodstuffs With a View to Human Safety

From a human safety perspective, the administration of ivermectin to food producing animal species entails potential risks related to the presence of drug residues in edible tissues, milk, and other derived products. The European Medicines Agency has established the maximum residue limits for ivermectin in the European Union, with values of 100 μg·kg(-1) in fat and liver and 30 μg·kg(-1) in kidney for all mammalian food producing species, in order to ensure that the amount of ivermectin that can be found in animal foodstuff is below dangerous levels for the consumers. According to these values, withdrawal periods after subcutaneous injection were recently established in the European Union (2009), in 49 days for products containing ivermectin as a single active substance or in combination with closantel, and in 66 days when combined with clorsulon. The marker residue for ivermectin was found to be H(2)B(1a), which is the major component of the parent compound. The tissue distribution of residues and the overall ratios of marker to total residues were generally similar in most species, and the highest concentrations of ivermectin residues were found in fat and liver with high levels also detected in injection site muscles. Ivermectin is not licensed for use in animals from which milk is produced for human consumption, however its extra-label use should be considered regarding human safety, due to its long persistence in milk and milk-derived products.