M.F. Landoni

Pharmacokinetic and pharmacodynamic modelling of marbofloxacin administered alone and in combination with tolfenamic acid in goats.

In a four-period cross-over study, the fluoroquinolone antibacterial drug marbofloxacin (MB) was administered to goats intramuscularly (IM) at a dose rate of 2 mg/kg, both alone and in combination with the non-steroidal anti-inflammatory drug tolfenamic acid (TA), also administered IM at a dose rate of 2 mg/kg. Using a tissue cage model of inflammation, based on the irritant actions of carrageenan, the pharmacokinetics (PK) of MB and MB in combination with TA were determined. MB mean values of area under concentration-time curve (AUC) were similar for serum (5.60 microg h/mL), inflamed tissue cage fluid (exudate; 5.32 microg h/mL) and non-inflamed tissue cage fluid (transudate; 4.82 microg h/mL). Values of mean residence time (MRT) of MB in exudate (15.5 h) and transudate (15.8 h) differed significantly from serum MRT (4.23 h). Co-administration of TA did not affect the PK profile of MB. The pharmacodynamics of MB were investigated using a caprine strain of Mannheimia haemolytica. Integration of PK data with ex vivo bacterial time-kill curve data for serum, exudate and transudate provided AUC(24h)/minimum inhibitory concentration (MIC) ratios of 160, 133 and 121 h, respectively, for the strain of organism used. Modelling of the ex vivo time-kill data to the sigmoid E(max) equation provided AUC(24h)/MIC values required for bacteriostatic and bactericidal actions of MB and for virtual eradication of the organism of 27.6, 96.2 and 147.3 h, respectively. Corresponding values for MB+TA were 20.5, 66.5 and 103.0 h. These data were used to predict once daily dosage schedules of MB for subsequent clinical evaluation.

Pharmacokinetic and pharmacodynamic modelling of marbofloxacin administered alone and in combination with tolfenamic acid in calves.

In a four-period, cross-over study, the fluoroquinolone antibacterial drug marbofloxacin (MB) was administered to calves, alone and in combination with the nonsteroidal anti-inflammatory drug tolfenamic acid (TA). Both drugs were administered intramuscularly (IM) at doses of 2 mg/kg. A tissue cage model of inflammation, based on the actions of the mild irritant carrageenan, was used to evaluate the pharmacokinetics (PK) of MB and MB in combination with TA. MB mean values of area under concentration-time curve (AUC) were 15.1 μg·h/mL for serum, 12.1 μg·h/mL for inflamed tissue cage fluid (exudate) and 9.6 μg·h/mL for noninflamed tissue cage fluid (transudate). Values of C(max) were 1.84, 0.35 and 0.31 μg/mL, respectively, for serum, exudate and transudate. Mean residence time (MRT) of 23.6 h (exudate) and 22.6 h (transudate) also differed significantly from serum MRT (8.6 h). Co-administration of TA did not affect the PK profile of MB. The pharmacodynamics of MB was investigated using a bovine strain of Mannheimia haemolytica. Time-kill curves were established ex vivo on serum, exudate and transudate samples. Modelling the ex vivo serum time-kill data to the sigmoid E(max) equation provided AUC(24 h) /MIC values required for bacteriostatic (18.3 h) and bactericidal actions (92 h) of MB and for virtual eradication of the organism was 139 h. Corresponding values for MB + TA were 20.1, 69 and 106 h. These data were used to predict once daily dosage schedules for a bactericidal action, assuming a MIC(90) value of 0.24 μg/mL, a dose of 2.6 mg/kg for MB and 2.19 mg/kg for MB + TA were determined, which are similar to the currently recommended dose of 2.0 mg/kg.

Current concepts on the use of antimicrobials in cats.

This article reviews the general pharmacological properties of antimicrobial drugs used in feline medicine. It focuses on recent advances in pharmacokinetics, providing an update on indications, drug interactions and adverse reactions or toxicity in the cat. Attention is given to the most used groups, such as cephalosporins and fluoroquinolones, reviewing their basic features and clinical uses, and discusses the pharmacokinetic advantages of the newer members of each group. The older groups (penicillins, aminoglycosides, macrolides and tetracyclines) are also considered with regard to their general features and current uses, and any recent reports on adverse reactions in cats are provided.

Effect of different penetration enhancers on diclofenac permeation across horse skin.

Diclofenac is a hydrophilic non-steroidal anti-inflammatory drug widely used in humans and animals. Previous reports have shown that this compound has low percutaneous absorption in horses. The effect of five penetration enhancers (10% urea, 15% and 20% oleic acid and 5% and 10% d-limonene) on the percutaneous absorption of diclofenac diethylamine through horse skin was evaluated in vitro using Franz-type diffusion cells. All tested penetration enhancers induced a significant increase in diclofenac diethylamine permeation, with limonene showing the highest enhancing effect at the lowest concentration (5%) applied. The presence of the permeation enhancers did not affect lag-time. This is the first in vitro study of the effects of penetration enhancers on transdermal permeation of diclofenac diethylamine across horse skin. The results suggested that urea, limonene and 5% oleic acid were useful for enhancing the transdermal absorption of diclofenac diethylamine and may assist in the development of a transdermal formulation of diclofenac diethylamine for use in horses.

Pharmacokinetics and bone tissue concentrations of lincomycin following intravenous and intramuscular administrations to cats.

The pharmacokinetic properties and bone concentrations of lincomycin in cats after single intravenous and intramuscular administrations at a dosage rate of 10 mg/kg were investigated. Lincomycin minimum inhibitory concentration (MIC) for some gram-positive strains isolated from clinical cases was determined. Serum lincomycin disposition was best-fitted to a bicompartmental and a monocompartmental open models with first-order elimination after intravenous and intramuscular dosing, respectively. After intravenous administration, distribution was rapid (T(1/2(d)) = 0.22 ± 0.09 h) and wide as reflected by the volume of distribution (V((d(ss)))) of 1.24 ± 0.08 L/kg. Plasma clearance was 0.28 ± 0.09 L/h · kg and elimination half-life (T(1/2)) 3.56 ± 0.62 h. Peak serum concentration (C(max)), T(max), and bioavailability for the intramuscular administration were 7.97 ± 2.31 μg/mL, 0.12 ± 0.05 h, and 82.55 ± 23.64%, respectively. Thirty to 45 min after intravenous administration, lincomycin bone concentrations were 9.31 ± 1.75 μg/mL. At the same time after intramuscular administration, bone concentrations were 3.53 ± 0.28 μg/mL. The corresponding bone/serum ratios were 0.77 ± 0.04 (intravenous) and 0.69 ± 0.18 (intramuscular). Lincomycin MIC for Staphylococcus spp. ranged from 0.25 to 16 μg/mL and for Streptococcus spp. from 0.25 to 8 μg/mL.

Pharmacokinetics of erythromycin after intravenous, intramuscular and oral administration to cats.

The aim of this study was to characterise the pharmacokinetic properties of different formulations of erythromycin in cats. Erythromycin was administered as lactobionate (4 mg/kg intravenously (IV)), base (10mg/kg, intramuscularly (IM)) and ethylsuccinate tablets or suspension (15 mg/kg orally (PO)). After IV administration, the major pharmacokinetic parameters were (mean ± SD): area under the curve (AUC)((0-∞)) 2.61 ± 1.52 microgh/mL; volume of distribution (V(z)) 2.34 ± 1.76L/kg; total body clearance (Cl(t)) 2.1 0 ± 1.37 L/hkg; elimination half-life (t(½)(λ)) 0.75 ± 0.09 h and mean residence time (MRT) 0.88 ± 0.13 h. After IM administration, the principal pharmacokinetic parameters were (mean ± DS): peak concentration (C(max)), 3.54 ± 2.16 microg/mL; time of peak (T(max)), 1.22 ± 0.67 h; t(½)(λ), 1.94 ± 0.21 h and MRT, 3.50 ± 0.82 h. The administration of erythromycin ethylsuccinate (tablets and suspension) did not result in measurable serum concentrations. After IM and IV administrations, erythromycin serum concentrations were above minimum inhibitory concentration (MIC)(90)=0.5 microg/mL for 7 and 1.5h, respectively. However, these results should be interpreted cautiously since tissue erythromycin concentrations have not been measured and can reach much higher concentrations than in blood, which may be associated with enhanced clinical efficacy.

Pharmacokinetics and bioavailability of a long-acting formulation of cephalexin after intramuscular administration to cats

The pharmacokinetic profile and bioavailability of a long-acting formulation of cephalexin after intramuscular administration to cats was investigated. Single intravenous (cephalexin lysine salt) and intramuscular (20% cephalexin monohydrate suspension) were administered to five cats at a dose rate of 10 mg/kg. Serum disposition curves were analyzed by noncompartmental approaches. After intravenous administration, volume of distribution (V(z)), total body clearance (Cl(t)), elimination constant (λ(z)), elimination half-life (t(½)(λ)) and mean residence time (MRT) were: 0.33±0.03 L/kg; 0.14±0.02 L/hkg, 0.42±0.05 h(-1), 1.68±0.20 h and 2.11±0.25 h, respectively. Peak serum concentration (C(max)), time to peak serum concentration (T(max)) and bioavailability after intramuscular administration were 15.67±1.95 μg/mL, 2.00±0.61 h and 83.33±8.74%, respectively.

Pharmacokinetics of cefuroxime after intravenous, intramuscular, and subcutaneous administration to dogs.

Cefuroxime pharmacokinetic profile was investigated in 6 Beagle dogs after single intravenous, intramuscular, and subcutaneous administration at a dosage of 20 mg/kg. Blood samples were withdrawn at predetermined times over a 12-h period. Cefuroxime plasma concentrations were determined by HPLC. Data were analyzed by compartmental analysis. Peak plasma concentration (Cmax ), time-to-peak plasma concentration (Tmax ), and bioavailability for the intramuscular and subcutaneous administration were (mean ± SD) 22.99 ± 7.87 μg/mL, 0.43 ± 0.20 h, and 79.70 ± 14.43% and 15.37 ± 3.07 μg/mL, 0.99 ± 0.10 h, and 77.22 ± 21.41%, respectively. Elimination half-lives and mean residence time for the intravenous, intramuscular, and subcutaneous administration were 1.12 ± 0.19 h and 1.49 ± 0.21 h; 1.13 ± 0.13 and 1.79 ± 0.24 h; and 1.04 ± 0.23 h and 2.21 ± 0.23 h, respectively. Significant differences were found between routes for Ka , MAT, Cmax , Tmax , t½(a) , and MRT. T > MIC = 50%, considering a MIC of 1 μg/mL, was 11 h for intravenous and intramuscular administration and 12 h for the subcutaneous route. When a MIC of 4 μg/mL is considered, T > MIC = 50% for intramuscular and subcutaneous administration was estimated in 8 h.

Impact of the type of catheter on the absorption of tylvalosin (acetylvaleryltylosin) administered orally to broiler chickens

Pharmacokinetic and pharmacodynamic data are useful tointerpret the efficacy and safety of a product. However,information on avian pharmacotherapy is scarce. Most of thepharmacokinetic studies on antimicrobials in chickens are basedon drugs applied orally using oral gavage. However, it is verydifficult to find a clear description of the type of catheter used forthe administration of the antimicrobials.Aivlosin (ECO Animal Health, London, UK), a water-solublepowder for the treatment of mycoplasmosis and other diseases inpoultry and swine production, contains the macrolide tylvalosin(acetylisovaleryltylosin) (Cerda´ et al., 2002, 2006a). During pilotstudies on the pharmacokinetics of tylvalosin in chickens, wefound a high variation in the absorption profile not only betweenindividuals but also within individuals when used on separateoccasions. To investigate the cause of this variation, a study wasdesigned with the objective of analysing the impact of the qualityof the catheter used on the plasma kinetics of tylvalosin.A total of 12, 2-week-old chickens were used. Group A (sixchickens) received tylvalosin orally, through a flexible 25-cm-length catheter (polyvinyl chloride), at a dosage of 20 mg⁄kgbodyweight (b.w.); group B (six chickens) received tylvalosinorally, through a rigid 25-cm-length catheter (stainless steelcannula), at a dosage of 20 mg⁄kg b.w. Blood samples (0.5 ml)were collected from the wing vein in heparinized tubes at thefollowing times: 0, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12and 24 h postadministration.Plasma was separated and frozen at )20 C until analysis. Allsamples were assayed on the week following collection. Tylvalosinplasma concentration was determined using a microbiologicalassay (Bennet et al., 1966) with Micrococcus luteus ATCC 9314as test micro-organism (Cerda´ et al., 2006b,c). The limit ofquantification of the method was 0.05 lg ⁄ml. The method waslinear between 0.025 and 10 lg ⁄ml (r = 0.9974). Inter- andintra-assay coefficients of variation were <10%.Individual birds tylvalosin concentration vs. time curves wereanalysed by nonlinear least square regression analysis using