Considerations for extrapolating in vivo bioequivalence data across species and routes

The purpose of this article is to discuss the numerous species-specific and route-specific factors that can influence the peak and extent of exposure of an active pharmaceutical ingredient as they relate to the demonstration of bioequivalence between veterinary drug products (test and reference formulations). Evaluation of potential circumstances when species-to-species or route-to-route extrapolations of bioequivalence data could be considered is provided, together with suggestions for alternative statistical analysis. It is concluded that further research is much needed in this area to establish an appropriate scientific basis for across-species and across-route comparisons.     

Demonstrating bioequivalence using clinical endpoint studies

For drug products not amenable to blood level studies, clinical endpoint studies have been used as an indirect measure of formulation difference in bioavailability between test and reference products. However, clinical endpoint studies are not as sensitive in detecting formulation differences as blood level studies and offer numerous challenges to both regulatory authorities and sponsors. The objective of this article is not to suggest new regulatory policies, but to explore new methodologies and alternative solutions to clinical endpoint bioequivalence (BE) studies, which are used when a blood level study is not considered to be appropriate. To achieve this objective, this article identifies situations where a clinical endpoint study might be appropriate, lists the advantages and disadvantages of this type of study design, and discusses possible alternative solutions. It is concluded that future evidence-based research is needed to explore new methodologies such as clinical trial simulations of various study designs, new statistical methods, and new in vitro methods to demonstrate BE.     

The Functional Role of Oxytocin in the Induction of Oocyte Meiotic Resumption in Cattle

The aim of the present study was to examine the role of oxytocin (OT) in the progesterone (P4) and prostaglandins (PGs) pathway to induce oocyte meiotic resumption. Cumulus–oocyte complexes were co‐cultured with follicular hemisections for 15 h to determine the effects of different doses of OT or atosiban (ATO; oxytocin receptor antagonist) on oocyte meiotic resumption. In another experiment, we examined the effect of the interaction between P4, OT and PGs on the regulatory cascade of the oocyte meiotic resumption. Oxytocin at 1 μm was effective in inducing meiotic resumption in oocytes co‐cultured with follicular cells (84.0%), not differing from the positive control group (74.4%). Atosiban inhibited in a dose‐dependent manner the positive effect of OT on the meiotic resumption (27.6% metaphase I with 10 μm of ATO, which did not differ from the 25.5% of the negative control group). Furthermore, a third experiment showed that P4 was able to induce oocyte meiotic resumption, which was inhibited by ATO. However, the OT positive effect was not blocked by mifepristone (P4 antagonist), but was inhibited by indomethacin (a non‐selective PTGS2 inhibitor). Collectively, these data suggest a sequential role of P4, OT and PGs in the induction of oocyte meiotic resumption.     

Qualitative and quantitative ultrasound attributes of maternal‐foetal structures in pregnant ewes

The aim of this study was to examine foetal organs and placental tissue to establish a correlation between the changes in the composition of these structures associated with their maturation and the ultrasonographic characteristics of the images. Twenty‐four pregnant ewes were included in the study. Ultrasonography assessments were performed in B‐mode, from the ninth gestational week until parturition. The lungs, liver and kidneys of foetuses and placentomes were located in transverse and longitudinal sections to evaluate the echogenicity (hypoechoic, isoechoic, hyperechoic or mixed) and echotexture (homogeneous and heterogeneous) of the tissues of interest. For quantitative evaluation of the ultrasonographic characteristics, it was performed a computerized image analysis using a commercial software (Image ProPlus^®). Mean numerical pixel values (NPVs), pixel heterogeneity (standard deviation of NPVs) and minimum and maximum pixel values were measured by selecting five circular regions of interest in each assessed tissue. All evaluated tissues presented significant variations in the NPVs, except for the liver. Pulmonary NPVmean, NPVmin and NPVmax decreased gradually through gestational weeks. The renal parameters gradually decreased with the advancement of the gestational weeks until the 17th week and later stabilized. The placentome NPVmean, NPVmin and NPVmax decreased gradually over the course of weeks. The hepatic tissue did not show echogenicity and echotexture variations and presented medium echogenicity and homogeneous echotexture throughout the experimental period. It was concluded that pixels numerical evaluation of maternal‐foetal tissues was applicable and allowed the identification of quantitative ultrasonographic characteristics showing changes in echogenicity related to gestational age.     

Identification of Chlamydia gallinacea in a parrot and in free‐range chickens in Australia

Chlamydia gallinacea is a recently described bacterial species in a genus known to infect and cause disease in animals and humans. Our report describes the identification of C. gallinacea infection in free‐range laying chickens (Gallus gallus) in Australia, and the identification of C. gallinacea infection in a parrot, a wild Australian galah (Eolophus roseicapillus). There is currently little knowledge of the effects of C. gallinacea infection on avian hosts, but it has been linked to respiratory disease in humans and could potentially cause similar disease in other species. Our report highlights the need for further study and surveillance of Chlamydia species in both wild and domestic hosts in Australia.     

DYNAMIC COMPUTED TOMOGRAPHY OF THE NORMAL FELINE HYPOPHYSIS CEREBRI (GLANDULA PITUITARIA)

The purpose of this study was to describe normal feline hypophyseal mensuration and contrast enhancement characteristics using dynamic computed tomography (CT) imaging. An intravenous bolus of an ionic iodinated contrast medium was administered to eight cats using a pressure injector while dynamic CT images were obtained every 5 s for five cats and every 7 s for three cats for a total imaging time of 5 min. Each pituitary was measured at its maximum height and width on the peak contrast medium enhancement image. A hand-drawn region of interest was placed around each hypophysis cerebri and time attenuation curves were generated. The specific enhancement pattern of the hypophysis cerebri for each cat was recorded. The mean width and height of the hypophysis cerebri was 5.2 +/- 0.4 (average +/- SD) mm and 3.1 +/- 0.3 mm, respectively. The mean time to maximum contrast enhancement was 28.6 +/- 14.8 s (range 14-50 s) from the onset of contrast medium injection. Four cats had initial dorsal and peripheral contrast enhancement patterns of the hypophysis cerebri, while four cats had an initial central contrast medium enhancement pattern. The hypophysis cerebri had a homogenous appearance in all cats, 28-50 s after contrast medium injection. The average (+/- SD) clearance half-time was 292 (+/- 87) s. Normal hypophysis cerebri mensuration and contrast medium enhancement characteristics will help in clinical evaluation of the feline hypophysis cerebri.     

Pharmacokinetics of enrofloxacin administered intravenously and orally to foals

OBJECTIVE: To determine the pharmacokinetics of enrofloxacin administered IV and orally to foals. ANIMALS: 5 clinically normal foals. PROCEDURE: A 2-dose cross-over trial with IV and oral administration was performed. Enrofloxacin was administered once IV (5 mg/kg of body weight) to 1-week-old foals, followed by 1 oral administration (10 mg/kg) after a 7-day washout period. Blood samples were collected for 48 hours after the single dose IV and oral administrations and analyzed for plasma enrofloxacin and ciprofloxacin concentrations by use of high-performance liquid chromatography. RESULTS: For IV administration, mean +/- SD total area under the curve (AUC0-infinity) was 48.54 +/- 10.46 microg x h/ml, clearance was 103.72 +/- 0.06 ml/kg/h, half-life (t1/2beta) was 17.10 +/- 0.09 hours, and apparent volume of distribution was 2.49 +/- 0.43 L/kg. For oral administration, AUC0-infinity was 58.47 +/- 16.37 microg x h/ml, t1/2beta was 18.39 +/- 0.06 hours, maximum concentration (Cmax) was 2.12 +/- 00.51 microg/ml, time to Cmax was 2.20 +/- 2.17 hours, mean absorption time was 2.09 +/- 0.51 hours, and bioavailability was 42 +/- 0.42%. CONCLUSIONS AND CLINICAL RELEVANCE: Compared with adult horses given 5 mg of enrofloxacin/kg IV, foals have higher AUC0-infinity, longer t1/2beta, and lower clearance. Concentration of ciprofloxacin was negligible. Using a target Cmax to minimum inhibitory concentration ratio of 1:8 to 1:10, computer modeling suggests that 2.5 to 10 mg of enrofloxacin/kg administered every 24 hours would be effective in foals, depending on minimum inhibitory concentration of the pathogen.