From antidoping controls to medication controls in horses: the European approach

Antidoping control is undergoing major changes on a European level. Equestrian authorities now recognize two types of molecules (xenobiotics) subject to two different control strategies. The most sensitive techniques will be used to track the slightest presence (exposure) of substances prohibited in sports (anabolic steroids, amphetamines…). On the other hand, for molecules used legitimately as medication, such as anti-inflammatories, only concentrations which are above a value able to compromise the competition fairness will be reported i.e. residual plasma and urinary levels of these substances will be interpreted in terms of their biological activity. Consequently, assay techniques are or will be chosen to guarantee a lack of effect rather than the evidence of exposure. These changes in antidoping control concerning medications control required the development of a systematic approach, to define effective plasma levels as well as plasma and urinary concentrations considered as devoid of biological activity. This approach is part of a more general concept of risk analysis, which includes two stages: scientific risk evaluation to define critical drug levels, and risk management by the Authorities that set the final values to implement.La mise en oeuvre du contrôle antidopage connaît une profonde évolution qui se développe dans un cadre européen. Les autorités hippiques reconnaissent aujourd'hui deux types de molécules (xénobiotiques) pour lesquelles elles adopteront des stratégies différentes pour en contrôler l'usage. Pour les molécules qui n'ont pas leur place dans un contexte sportif (anabolisants, amphétamines...), les techniques analytiques les plus performantes seront mises en oeuvre pour traquer la moindre présence (exposition) chez le cheval. En revanche, pour des molécules utilisées légitimement comme médicament, tels les anti-inflammatoires, on ne souhaite pas gêner leur usage médical en détectant, longtemps après la fin du traitement, des traces résiduelles d'exposition. Pour ces molécules, un jugement biologique est désormais porté sur les niveaux de concentration plasmatique et urinaire détectés. Il en résulte que les techniques analytiques ont (ou auront) des performances adaptées aux enjeux, afin de garantir une absence d'effet et non une simple exposition. Cette évolution du contrôle antidopage vers un contrôle des médications a exigé le développement d'une approche systématisée, pour établir les concentrations plasmatiques efficaces et déterminer les concentrations plasmatiques et urinaires considérées comme sans signification biologique. Cette démarche s'inscrit dans un cadre plus général d'une analyse de risque avec une étape d'appréciation scientifique du risque pour établir les concentrations critiques et une étape de gestion du risque, menée par les Autorités qui auront à décider des valeurs finales à retenir et à mettre en oeuvre

Paw Inflammation Model in Dogs for Preclinical Pharmacokinetic/Pharmacodynamic Investigations of Nonsteroidal Anti-Inflammatory Drugs

The goal of the present study was to develop and validate a new canine model of inflammation. The motivation was to make available a scientifically appropriate and ethically acceptable model to conduct pharmacokinetic/pharmacodynamic investigations for testing nonsteroidal anti-inflammatory drugs in dogs. A kaolin-induce paw inflammation model previously developed in cats was adapted to the dog. The paw inflammation developed within a few hours, reached maximum values 24 h and up to 3 days after kaolin administration, and then progressively resolved over 2 months. Five end points of clinical interest (body temperature, creeping time under a tunnel, paw withdrawal latency to a standardized thermal stimulus, lameness score, and vertical force developed during walking on a force plate) were measured regularly over the next 24 h and beyond to characterize the time development of the inflammation either in control conditions (placebo period) or after the administration of meloxicam (test period) according to a crossover design. Pharmacodynamic data were modeled using an indirect response pharmacokinetic/pharmacodynamic model. This model described three effects of meloxicam, namely, classic anti-inflammatory, analgesic, and antipyretic effects. The mean plasma meloxicam IC(50) values were 210 ng/ml for the antipyretic effect, 390 ng/ml for the analgesic effect, and 546 ng/ml for the vertical force exerted by the paw on the ground as measured by force plates. These in vivo IC(50) values require approximately 80 (antipyretic effect) to 90% (all other effects) cyclooxygenase-2 inhibition as calculated ex vivo whole-blood assay data

A bibliometric study of scientific research in the french veterinary schools from 2000 to 2010

L’objet de cet article a été d’évaluer l’impact de la réforme du statut des enseignants-chercheurs de 1992 sur le bilan scientifique des Écoles vétérinaires françaises. Pour cela, un bilan quantitatif des recherches menées dans les ENV a été établi. À partir de la base de données ‘Web of Knowledge’, les performances collectives et individuelles ont été quantifiées par différents indices bibliométriques dont le h-index. Il a été conclu que la réforme de 1992 a en grande partie atteint ses objectifsL’objet de cet article a été d’évaluer l’impact de la réforme du statut des enseignants-chercheurs de 1992 sur le bilan scientifique des Écoles vétérinaires françaises. Pour cela, un bilan quantitatif des recherches menées dans les ENV a été établi. À partir de la base de données ‘Web of Knowledge’, les performances collectives et individuelles ont été quantifiées par différents indices bibliométriques dont le h-index. Il a été conclu que la réforme de 1992 a en grande partie atteint ses objectif

Impact of three ampicillin dosage regimens on selection of ampicillin resistance in Enterobacteriaceae and excretion of blaTEM genes in swine feces

The aim of this study was to assess the impact of three ampicillin dosage regimens on ampicillin resistance among Enterobacteriaceae recovered from swine feces using phenotypic and genotypic approaches. Phenotypically, ampicillin resistance was determined from the percentage of resistant Enterobacteriaceae and MICs of E. coli isolates. The pool of ampicillin resistance genes was also monitored by quantification of blaTEM genes, which code for the most frequently produced β-lactamases in Gram-negative bacteria, using a newly-developed real-time PCR assay. Ampicillin was administered intramuscularly and by oral route to fed or fasted pigs for 7 days at 20 mg/kg. The average percentage of resistant Enterobacteriaceae before treatment was between 2.5% and 12% and blaTEM genes quantities were below 107 copies/g of feces. By days four and seven, the percentage of resistant Enterobacteriaceae exceeded 50% in all treated groups, with some highly resistant strains (MIC>256µg/mL). In the control group, blaTEM genes quantities fluctuated between 104 - 106 copies/g of feces, whereas they fluctuated between 106-108 and 107-109 copies/g of feces for intramuscular and oral routes, respectively. Whereas phenotypic evaluations did not discriminate between the three ampicillin dosage regimens, blaTEM genes quantification was able to differentiate between the effects of two routes of ampicillin administration. Our results suggest that fecal blaTEM genes 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

Prion protein in the cerebrospinal fluid of healthy and naturally scrapie-affected sheep

The aim of this study was to characterize the cerebrospinal fluid (CSF) prion protein (PrP) of healthy and naturally scrapie-affected sheep. The soluble form of CSF PrPC immunoblotted with an anti-octarepeat and an anti-C terminus mAb showed two isoforms of approximately 33 and 26 kDa, corresponding to the biglycosylated and unglycosylated isoforms of brain PrPC. Neither the mean concentration nor the electrophoretic profile of CSF PrP differed between healthy and scrapieaffected sheep, whereas a slightly increased resistance of CSF PrP to mild proteolysis by proteinase K was evident in the CSF of scrapie-affected sheep. No difference in susceptibility to proteolysis was observed between the two ARR and VRQ genetic variants of the purified prokaryote recombinant PrP. It was concluded that the physicochemical properties of PrPC in the CSF could be altered during scrapie and that these changes might reflect the physiopathological process of prion disease

Clinical, electroretinographic and histomorphometric evaluation of the retina in sheep with natural scrapie

Background: The retina is part of the diencephalon in a peripheral location and may be involved in prion diseases. Retinal function and structural changes were assessed in naturally scrapie-affected red face Manech ewes presenting the classical signs of the disease, and clinically healthy age-matched subjects for controls. Ophthalmic examination was done prior to electroretinography (ERG), which was carried out under conditions that allowed photopic and scotopic activities to be assessed. Histomorphometry of the inner and outer retinal layers was performed post-mortem, and retinas were also examined for evidence of abnormal prion protein (PrPSc) accumulation and glial fibrillary acidic protein (GFAP) upregulation as a marker of gliosis. Scrapie status was determined by examination of brain tissue Results: Ocular reflexes and ophthalmoscopy did not reveal any difference between scrapie affected and control animals. Although the light-and dark-adapted ERG responses of both rod-and cone-mediated functions had a similar waveform in scrapie-affected and control sheep, a significant reduction in the amplitude of the ERG a-and b-waves was observed in affected animals compared to controls. These functional alterations were correlated with a substantial loss of cells in the outer nuclear layer (ONL), lengthening and disorganization in photoreceptor segments, and substantial reduction in cellularity and thickness of the inner nuclear layer (INL). The degenerative changes in the INL and ONL were most marked in the central and paracentral areas of the scrapie retinas, and were accompanied in all scrapie retinas by PrPSc deposition in the ganglion cell and synaptic layers. GFAP immunoreactivity was mainly increased in the ganglion cell and inner plexiform layers. Conclusions: No appreciable fundoscopic changes were observed in the scrapie-affected ewes although reproducible changes in retinal function as measured by ERG were observed in these animals. The alterations in the receptoral and post-receptoral pathways corresponded to the degenerative lesions observed in the ONL and INL of the scrapie retinas. The retinal degeneration was associated with prion protein infectivity which presumably spread via the optic nerve

Maternal and Fetal Exposure to Bisphenol A Is Associated with Alterations of Thyroid Function in Pregnant Ewes and Their Newborn Lambs

The putative thyroid-disrupting properties of bisphenol A (BPA) highlight the need for an evaluation of fetal exposure and its consequence on the mother/newborn thyroid functions in models relevant to human. The goals of this study were to characterize in sheep a relevant model for human pregnancy and thyroid physiology, the internal exposures of the fetuses and their mothers to BPA and its main metabolite BPA-glucuronide (Gluc), and to determine to what extent it might be associated with thyroid disruption. Ewes were treated with BPA [5 mg/(kg . d) sc] or vehicle from d 28 until the end of pregnancy. Unconjugated BPA did not appear to accumulate in pregnant ewes, and its concentration was similar in the newborns and their mothers (0.13 +/- 0.02 and 0.18 +/- 0.03 nmol/ml in cord and maternal blood, respectively). In amniotic fluid and cord blood, BPA-Gluc concentrations were about 1300-fold higher than those of BPA. Total T-4 concentrations were decreased in BPA-treated pregnant ewes and in the cord and the jugular blood of their newborns (30% decrease). A similar difference was observed for free T-4 plasma concentrations in the jugular blood of the newborns. Our results show in a long-gestation species with a similar regulatory scheme of thyroid function as humans that BPA in utero exposure can be associated with hypothyroidism in the newborns. If such an effect were to be confirmed for a more relevant exposure scheme to BPA, this would constitute a major issue for BPA risk assessment

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.Facultad de Ciencias Veterinaria

Bisphenol A in Thermal Paper Receipts: Taylor et al. Respond

We agree with Schwartz and Landrigan that there is a need for change in the regulatory system for chemicals used in products in the United States. Bisphenol A (BPA) is one of thousands of chemicals of concern, but it provides a striking example of what happens when there is no requirement for premarket testing

Authors' Reply to Coste et al.: "Levothyrox® New and Old Formulations: Are they Switchable for Millions of Patients?"

"Authors'Reply to Coste et al"International audienc