Alistair I. Webb

Penetration of Cefaclor Into the Interstitial Space Fluid of Skeletal Muscle and Lung Tissue in Rats

AbstractPurpose. To measure and compare the penetration of cefaclor from the plasma compartment into the interstitial space of lung and skeletal muscle in rats and to integrate the data in a pharmacokinetic model. Methods. Unbound interstitial concentrations in muscle and lung were measured by in vivo microdialysis following i.v. bolus doses of 50 and 75 mg/kg cefaclor. Unbound muscle concentrations were also measured after a primed, continuous i.v. infusion at an infusion rate of 0.3 mg/kg/min. Results. The cefaclor half-life in plasma, muscle and lung was approximately 1 h. Unbound cefaclor concentrations in muscle and lung were found to be virtually identical. A 2-compartment body model was fitted to the data with a tissue penetration factor (AUCtissue(unbound)/AUCplasma(unbound)) of approximately 0.26 independent of dose, tissue and mode of administration. Conclusions. Unbound concentrations of cefaclor in the interstitial space fluid of lung and skeletal muscle are of similar magnitude and lower than those in plasma. Using total plasma concentrations would overestimate the antibacterial activity of the drug and therefore its clinical efficacy. Instead, therapeutically active levels of cefaclor at the site of action should be taken into account. Microdialysis allows direct measurement of these unbound concentrations.

A NON-SURFACTANT FORMULATION FOR ALFAXALONE BASED ON AN AMORPHOUS CYCLODEXTRIN : ACTIVITY STUDIES IN RATS AND DOGS

Abstract The steroid anesthetic, alfaxalone, is commercially available for veterinary use in a formulation containing Cremophor-EL® and alfadalone acetate. The allergic sensitivity of some species to this formulation limits its veterinary application and also led to withdrawal of the product for human use. The present studies evaluated alfaxalone formulated as an inclusion complex with a mixture of 2-hydroxypropyl-β-cyclodextrin (HPCD) isomers for anesthetic properties in rats and dogs. Aqueous solutions of alfaxalone-HPCD showed identical anesthetic profiles in rats compared to the commercial formulation. In contrast, the anesthetic response to alfaxalone-HPCD in dogs was not accompanied with massive histamine release and pronounced decrease in respiration and blood pressure seen after the commercial preparation. Anesthesia induction and recovery phases were rapid and uncomplicated after alfaxalone-HPCD. An anaphylactoid-like response did occur in dogs after the same dose of alfaxalone as the commercial preparation. The favorable anesthetic profile of alfaxalone formulated as an HPCD complex together with previous toxicology and stability studies suggest that the steroid may be successfully formulated for intravenous dosing with modified cyclodextrins.

Computed tomographic and nuclear magnetic resonance correlation of canine ceroid-lipofuscinosis with aging ☆

Canine ceroid lipofuscinosis is a degenerative neuronal disorder which has as a distinct pathologic counterpart, neuronal ceroid lipofuscinosis or Battens disease in humans. The disease occurs in English setters and is associated with abnormal accumulation of autofluorescent lipopigments. As such, a study of this animal model may allow insight into the aging process as well. This investigation explores the computed tomographic features of canine ceroid-lipofuscinosis and correlates these findings (progressive atrophy, inherent changes in CT/NMR tissue characteristics) with clinical and pathologic features.

The Food Animal Residue Avoidance Databank (Farad): Past, Present and Future

During the last one-and-one-half decades, FARAD has established an unparalleled compilation of residue and pharmacokinetic information for veterinary species. In order to fulfill its mission, FARAD has become as much a research project as an educational one. Pressing problems, such as disease-altered kinetics, minor-species drug use, and industrial contaminants in livestock, require the new methods of analysis FARAD is developing. The data upon which this work is based can be greatly augmented by participation by other nations. In the United States, it was the cooperation of both academic and regulatory organizations that made the success of FARAD possible. Similar international cooperation can facilitate use of the FARAD model in other countries for the economic benefit of all participants, enhancement of food safety, and promotion of animal welfare.

INTRAVENOUS PHARMACOKINETICS OF PENICILLIN G AND ANTIPYRINE IN OSTRICHES (STRUTHIO CAMELUS) AND EMUS (DROMAIUS NOVAEHOLLANDIAE)

Abstract Penicillin G and antipyrine, which served as model drugs to assess the relative capacities of renal and hepatic elimination pathways, respectively, were each administered intravenously to six ostriches (Struthio camelus) and to six emus (Dromaius novaehollandiae). Drug concentrations in blood samples collected over a period of 12 hr after administration were assayed, and elimination half-life, mean residence time, clearance, and steady-state volume of distribution were calculated. Mean values for elimination half-life and mean residence time of penicillin G were significantly higher in emus than in ostriches; no significant differences in antipyrine pharmacokinetics between species were demonstrated.

The Canine c-Wave: Breed and Anesthetic-Dependent Variations

Understanding of the mammalian c-wave is enhanced by recent clarification of the role of the cells of the pigment epithelium. Profound between and within human variability is reported by Hock and Marmor (1982), while the classical literature exhibits a confusing number of citations to species variation for c-wave amplitude and latency. Among others, the canine eye has been reported to have no c-wave (Rodieck, 1973). We report here that this view is incorrect although DC-recorded canine c-waves are highly breed dependent and exhibit sensitivity to both inhalation and parenteral anesthetics. For example, in the pure breed beagle, normally large c-waves were eliminated by end-tidal halothane concentrations of 2%. More sensitive English setters lost 70% of c-wave amplitude with end-tidal halothane concentrations of 0.1%. Setters also show significant c-wave reductions with graded pentobarbital concentrations up to 10 mg/kg. One mixed breed dog showed potentiation of the c-wave in the presence of 2% halothane. An overview of performance across breeds disclosed moderate or mild a-, b-wave sensitivities, while c-wave reductions up to 100% were recorded. Species, breed, anesthetic and general physiological state probably account for the varied results in the classical c-wave literature.

Anesthetic Activity and Pharmacokinetics of the Neurosteroid Alfaxalone Formulated In 2-Hydroxypropyl-β-Cyclodextrin in the Rat

Alfaxalone (3α-hydroxy-5α-pregnan-11, 20-dione) is a potent steroid hypnotic agent whose poor water solubility has prompted the development of a 2-hydroxypropyl-β-cyclodextrin (HPβCD) formulation. The anesthetic potency of the complex was examined in a rat model using righting reflex as a measure of sleeping time. The data suggested a sex difference in activity with females proving to be more sensitive than male to the effects of the drugs especially at higher doses. Pharmacokinetic properties of alfaxalone were then determined using a novel analytical method in which the steroid was derivatized with dinitrophenylhydrazine to confer a potent and selective chromophore. Analysis of the time-concentrations profiles indicated that alfaxalone was more readily eliminated from males than female suggesting that the difference in activity between the sexes was related to differential clearance.