J.R.E. del Castillo

Effects of feeding a high omega-3 fatty acids diet in dogs with naturally occurring osteoarthritis

The aim of this randomized, placebo-controlled and double-blinded trial was to compare the effect of a veterinary therapeutic diet (VTD) rich in omega-3 fatty acids (omega-3) from fish origin to a regular diet used as control (CTR) over a period of 13 weeks in dogs afflicted by naturally occurring osteoarthritis (OA). Thirty privately owned dogs were selected. Dogs had lameness confirmed by an orthopaedic examination, had stifle/hip OA and had locomotor disability based on the peak of the vertically oriented ground reaction force (PVF) measured using a force platform. At Baseline, all owners were asked to determine 2-5 activities of daily living that were the most impaired. Activities were scores (0-4) in accordance with severity using case-specific outcome measures (CSOM). The PVF was also measured. Dogs (15/group) were then randomly assigned to receive either the CTR or the VTD. The CSOM was completed twice weekly. The recording of PVF was repeated at Week 7 and 13. The VTD-fed dogs showed a significantly higher PVF at Week 7 (p < 0.001) and at Week 13 (p < 0.001) when compared to Baseline. From Baseline to Week 13, VTD-fed dogs had a mean (± SD) change in PVF recording of 3.5 ± 6.8% of body weight (%BW) compared with 0.5 ± 6.1%BW (p = 0.211) in CTR-fed dogs. This change in primary outcome was consistent with an effect size of 0.5. Conversely, dogs fed the CTR did not show significant change in PVF measurements. At the end of the study, the CSOM was significantly decreased (p = 0.047) only in VTD fed dogs. In lame OA dogs, a VTD that contains high level of omega-3 from fish origin improved the locomotor disability and the performance in activities of daily living. Such nutritional approach appears interesting for the management of OA.

Pain Induced by a Minor Medical Procedure (Bone Marrow Aspiration) in Dogs: Comparison of Pain Scales in a Pilot Study

BACKGROUND Bone marrow aspiration (BMA) is a clinical procedure frequently performed in dogs. OBJECTIVE To compare levels of pain intensity induced by 3 different BMA procedures using several pain scoring instruments. ANIMALS Sixteen healthy Beagles. METHODS A prospective experimental pilot study was conducted using blinded observers. Dogs were randomized into 3 groups: iliac BMA under sedation (Iliac-Sed, n = 4), sternum BMA under sedation (Stern-Sed, n = 4), and sternum BMA on conscious dogs without sedation (Stern-No-Sed, n = 8). RESULTS Using the SF-Glasgow pain scale, the overall pain score in the Stern-No-Sed group was lower than that in the Stern-Sed group (P = 0.04). Using the 4A-VET pain scale, the effects of procedures over time on pain scores did not differ between and within groups. An inactivity index indicated that the overall score for the Stern-No-Sed group was significantly lower than the scores for the Stern-Sed and Iliac-Sed groups (P ≤ 0.01). There was a significant association in pain assessment using the SF-Glasgow and 4A-VET pain scales (P = 0.0004). When comparing the SF-Glasgowscale to the 4A-VET pain scale, the scores for the Stern-No-Sed group were lower compared to those of the Stern-Sed scores (P = 0.03). Based on telemetered motor activity, the Iliac-Sed group may have experienced more discomfort during the post-procedural period. CONCLUSIONS AND CLINICAL IMPORTANCE Dogs may experience mild to moderate pain after BMA procedures, and the sternal site should be preferred. The SF-Glasgow pain scale showed better interobserver reliability, but the 4A-VET scale was less biased by sedation.

Assessing pharmacokinetic variability directly induced by drug intake behaviour through development of a feeding behaviour-pharmacokinetic model.

Variability in drug intake is increasingly recognized as a major source of variability in drug response. The non-uniform access to medicated feed, influenced by swine individual feeding behaviour, is a determinant of antibiotic exposure, recalling the intrinsic similarity with human compliance to drug regimens. In this paper, we developed a feeding behaviour-pharmacokinetic (FBPK) model of in-feed chlortetracycline (CTC) and established, in a definite way, the effect of feeding behaviour and its induced pharmacokinetic (PK) variability. Based on reported animal behaviour, we mathematically formulated swine feeding behaviour by incorporating its main characteristics: intense feeding periods that repeat on a daily basis and random feeding periods of free access to feed, along with growth stage factors. This behaviour model was then integrated into a PK model of CTC. Moreover, we analysed the effect of each feeding behaviour component and assessed the corresponding PK variability. We have been able to delineate the impact of different feeding behaviour components and characterize the induced PK variability. We have compared different therapeutic assumptions to our model and shown that random features underlying the feeding behaviour have dramatic influence on the PK variability. A practical tool to adopt the dosing regimen in terms of dose and age has been proposed. The method developed here can be generalized to other therapeutic contexts and incorporated into medical practice, particularly to make long-term projections of drug-intake behaviour, to explain possible treatment failure and guide practitioners in adjusting the dosing regimen.

Comparison of continuous infusion with intermittent bolus administration of cefotaxime on blood and cavity fluid drug concentrations in neonatal foals

Healthy neonatal foals were treated with cefotaxime by bolus (40 mg/kg i.v. q6h for 12 doses; n=10) or by infusion (loading dose of 40 mg/kg i.v. followed by continuous infusion of a total daily dose of 160 mg/kg per 24 h for 3 days; n=5). Population pharmacokinetics was determined, and concentrations in cavity fluids were measured at steady state (72 h). Highest measured serum drug concentration in the bolus group was 88.09 μg/mL and minimum drug concentration (C(min)) was 0.78 μg/mL at 6-h postadministration (immediately before each next dose), whereas infusion resulted in a steady-state concentration of 16.10 μg/mL in the infusion group. Mean cefotaxime concentration in joint fluid at 72 h was higher (P=0.051) in the infusion group (5.02 μg/mL) compared to the bolus group (0.78 μg/mL). Drug concentration in CSF at 72 h was not different between groups (P=0.243) and was substantially lower than serum concentrations in either group. Insufficient data on pulmonary epithelial lining fluid were available to compare the methods of administration for cefotaxime in this cavity fluid. Results support continuous drug infusion over bolus dosing in the treatment for neonatal foal septicemia to optimize time that cefotaxime concentration exceeds the minimum inhibitory concentration of common equine pathogens.

Patlak plot analysis CT‐GFR for the determination of renal function: comparison of normal dogs with autologous kidney transplant dogs

Glomerular filtration rate (GFR) can be determined using Patlak plot analysis with single-slice dynamic computed tomography (CT). Acute autologous graft failure has several causes, all of which induce a measurable decrease in glomerular filtration rate. This study demonstrated in an experimental model of canine autologous renal transplant that CT-derived renal plasma clearance was significantly lower (p = 0.002) in dogs having undergone transplant (0.077 +/- 0.058 ml min(-1) ml renal tissue(-1)) compared with control dogs (0.396 +/- 0.139 ml min(-1) ml renal tissue(-1)). A significant negative curvilinear relationship was seen between serum creatinine and total renal plasma clearance (R(2) = 0.84, p = 0.0001). Alterations in renal time attenuation curve shape in dogs having undergone transplant may have been related to increased renal vascular resistance related to tubular necrosis. CT-GFR may be a useful experimental tool in the evaluation of renal dysfunction in transplant models.

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.

Anticoagulant activity of oral rivaroxaban in healthy dogs

Rivaroxaban is an oral, direct factor Xa inhibitor used in human thrombotic disorders. In view of the in vitro concentration dependent anticoagulant effects of rivaroxaban in dogs, the time course of its anticoagulant effects was characterized in healthy dogs. Twenty-four healthy Beagles were randomized into three groups (n = 8 per group) and received orally either a placebo or 20 mg rivaroxaban once or twice at an 8 h interval. Fifteen blood samples were collected over a 30 h period, and blindly assayed for prothrombin time (PT), activated partial thromboplastin time (aPTT), tissue factor induced thrombin generation (TG) and anti-factor Xa activity. Thromboelastography (TEG) was evaluated at 0, 1, 4, 8 and 24 h. Peak/baseline anticoagulant effect ratios were analyzed with generalized linear models using β distributions and times to return to baseline with survival analyses (α = 0.05). Peak/baseline anticoagulant effect ratios of PT, aPTT, anti-factor Xa activity, TG and R (TEG) differed significantly between placebo and both rivaroxaban groups (P <0.0001). The peak anticoagulant effect of rivaroxaban occurred 1.5 to 2 h after dosing. The median return to baseline occurred significantly sooner (P <0.01) with 20 mg rivaroxaban administered once (7.9-18.7 h) versus twice (17.5-26.8 h). The inter-individual variability differed amongst assays, but overall was moderate to large. No adverse effects were recorded. Twice oral administration of 2 mg/kg rivaroxaban at an 8 h interval maintained 24 h anticoagulant activity, but larger studies are needed to establish guidelines for the use of rivaroxaban in dogs.