Quantitative sensory testing in feline osteoarthritic pain - a systematic review and meta-analysis.

Quantitative sensory testing (QST) is a psychophysical test used to quantify somatosensory sensation under normal or pathological conditions including osteoarthritis (OA). OBJECTIVE: This study aimed to conduct a systematic review and meta-analysis of studies using QST in healthy and osteoarthritic cats, registered at Systematic Review Research Facility (#26-06-2017). DESIGN: Hierarchical models with random intercepts for each individual study extracted through the systematic review were fit to subject-level data; QST measures were contrasted between healthy and osteoarthritic cats. Four bibliographic databases were searched; quality and risk of bias assessment were performed using pre-established criteria. RESULTS: Six articles were included; most were of high quality and low risk of bias. Punctate tactile threshold (n = 70) and mechanical temporal summation (n = 35) were eligible for analysis. Cats with OA have lower punctate tactile threshold [mean difference (95%HDI): -44 (-60; -26) grams] and facilitated temporal summation of pain [hazard ratio (95%HDI): 5.32 (2.19; 14) times] when compared with healthy cats. The effect of sex and body weight on sensory sensitivity remained inconclusive throughout all analyses. Due to the correlation between age and OA status, it remains difficult to assess the effect of OA on sensory sensitivity, independently of age. CONCLUSIONS: Clear and transparent reporting using guidelines are warranted. Similar to people, centralized sensitization is a feature of OA in cats. Future studies should try to elucidate the age effect on feline OA. Research with natural OA in cats is promising with potential to benefit feline health and welfare, and improve translatability to clinical research.

Improving the estimation of amino acid requirements to maximize nitrogen retention in precision feeding for growing-finishing pigs.

Precision feeding requires a mathematical model to estimate standardized ileal digestible (SID) lysine (Lys) requirements (SIDLysR) in real time. However, this type of model requires constant calibration updates. The objective of this study was to review the calibration of the model used to estimate the real-time Lys requirements of individual growing-finishing pigs. A digestibility trial (n = 10) was conducted to evaluate amino acids digestibility during the growing and finishing phases. Additionally, 120 pigs were used in two 28-day growth experiments conducted as completely randomized design with growing (25 ± 2.1 kg BW, n = 60; 10 pigs per treatment) or finishing barrows (68.1 ± 6 kg BW, n = 60; 10 pigs per treatment). In each experiment, the pigs were divided into six equal treatment groups and fed 60%, 70%, 80%, 90%, 100% or 110% of their estimated individual SIDLysR. The Lys requirement of each pig was estimated daily using a real-time model. Body composition was measured with dual-energy X-ray densitometry on day 1 and 28 of the experiments. Average daily feed intake increased quadratically (P < 0.05) during both growth phases. Maximum average daily gain (ADG) (0.98 kg) and maximum protein deposition (PD; 170 g/day) were observed in growing pigs fed 100% of the estimated SIDLysR (P < 0.001). During the growing period, PD in BW gain (17% to 19%) and N efficiency (52% to 65%) increased linearly (P < 0.01) with increasing inclusion rates of SID Lys. Finishing pigs had maximum ADG (1.2 kg/day) when they were fed 100% of the requirements. However, the amount of protein in BW gain (13% to 16%) and N efficiency (40% to 55%) increased linearly (P < 0.01) with increasing inclusion rates of SID Lys. In conclusion, the model proposed for precision feeding is correctly calibrated to predict SIDLysR that maximize PD and ADG of average pigs from 25 to 50 kg BW. Still, there is an opportunity to improve the estimation of SIDLysR and N retention in individual pigs by better representing the individual proportion of protein in BW gain and the factors controlling the efficiency of Lys utilization in individual pigs.

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 ß 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.

Pharmacokinetics of liposomal encapsulated buprenorphine suspension following subcutaneous administration to cats.

We investigated the effects of liposome encapsulation at prolonging the systemic exposure of buprenorphine following subcutaneous administration in cats. Seven healthy male cats were dosed intravenously with 0.02 mg/kg buprenorphine solution (STD-BUP), followed 14 days later by a subcutaneous injection of 0.2 mg/kg buprenorphine as a liposomal suspension (SUS-BUP) containing drug molecules both in liposomes and the suspending vehicle. Buprenorphine time plasma concentration data for both dosing routes were analyzed simultaneously with four compartmental models. Goodness of fit was assessed both graphically and with the Akaike information criterion. The time-course of intravenous STD-BUP was biphasic, with a 4.39 h average terminal half-life. The subcutaneous SUS-BUP produced plasma buprenorphine concentrations above 0.5 µg/L for more than 96 h, with three distinct peaks in the first 15 h. The model with best fit comprised a central and a peripheral compartment, plus three subcutaneous absorption compartments: one of dissolved drug molecules that were absorbed through a first-order process, and two of liposome-encapsulated drug molecules that were transferred to the solution compartment through separate zero-order processes. Liposomes effectively prolonged the systemic exposure of buprenorphine in cats.

Assessing experimental visceral pain in dairy cattle: A pilot, prospective, blinded, randomized, and controlled study focusing on spinal pain proteomics.

Few studies have verified the validity of behavioral and physiological methods of pain assessment in cattle. This prospective, blinded, randomized controlled experimental study aimed to validate different methods of pain assessment during acute and chronic (up to 21 d postintervention) conditions in dairy cattle, in response to 3 analgesic treatments for traumatic reticuloperitonitis. Cerebrospinal fluid (CSF) biomarkers and mechanical sensitization were measured as indicators of centralized pain. Proteomics in the CSF were examined to detect specific (to pain intensity) and sensitive (responsive to analgesia) markers. Recordings of spontaneous behavior with video analysis, telemetered motor activity, pain scales, electrodermal activity, and plasma cortisol concentration were quantified at regular intervals. Cows were assigned to group 1 (n=4, standard control receiving aspirin), group 2 (n=5, test group receiving preemptive tolfenamic acid), or group 3 (n=3, positive control receiving preemptive multimodal analgesia composed of epidural morphine, plus tolfenamic acid and butorphanol). Rescue analgesia was administered as needed. Generalized estimating equations tested group differences and the influence of rescue analgesia on the measurements. All 3 groups demonstrated a long-term decrease in a CSF protein identified as transthyretin. The decrease in transthyretin expression inversely correlated with the expected level of analgesia (group 1<2<3). Moreover, in group 1, CSF noradrenaline decreased long term, cows were hypersensitive to mechanical stimulation, and they demonstrated signs of discomfort with higher motor activity and "agitation while lying" recorded from video analysis. Decreased "feeding behavior," observer-reported pain scales, electrodermal activity, and plasma cortisol concentration were inconsistent to differentiate pain intensity between groups. In summary, changes in CSF biomarkers and mechanical sensitization reflected modulation of central pain in dairy cows. The spontaneous behavior "agitation while lying" was the only behavioral outcome validated for assessing acute and chronic pain in this visceral pain model.

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.

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.

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.

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.

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.

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.

Interindividual variability in plasma concentrations after systemic exposure of swine to dietary doxycycline supplied with and without paracetamol: a population pharmacokinetic approach.

Anorexigenic substances released during infection may hinder the therapeutic efficacy of in-feed antibiotics. Paracetamol (acetaminophen; PARA) inhibits the anorexia of infection and seems to improve the clinical efficacy of doxycycline (DOX) against bacterial respiratory disease in swine herds. In order to verify whether PARA selectively stimulates intake of DOX-medicated feed in diseased pigs, we documented the pharmacokinetics (PK) of DOX when coadministered with PARA and examined the effect of in-feed PARA on the interindividual variability in plasma concentrations after systemic exposure to in-feed DOX in swine herds with respiratory disease. Systemic exposure to DOX was measured with the area under the curve (AUC) of its plasma concentrations over time. First, a rich-sampling PK study of in-feed and i.v. DOX (10 mg/kg of BW) and PARA (30 and 10 mg/kg of BW, respectively) was performed on 5 pigs. The PK profiles of in-feed DOX were used in mathematical simulations to determine 5 optimal sampling times for the farm-based population PK study. A randomized, blind, parallel PK study was performed in 2 herds with bacterial respiratory disease, where liquid feed was fortified with DOX alone (5 mg x kg of BW(-1) x meal(-1)) or combined with PARA (15 mg x kg of BW(-1) x meal(-1)). Medicated meals were given twice, 12 h apart, to group-housed growing pigs (n > 50 pigs x treatment(-1) x herd(-1), totaling 215 pigs). Plasma concentrations of DOX and PARA were measured with HPLC. At variance with our expectations, PARA decreased (P = 0.069) mean AUC of in-feed DOX and did not decrease its variability (P > 0.34). Mean AUC of DOX increased with feed intake and with initial exposure to DOX, and was greater in sick animals. Therefore, symptomatic PARA-induced improvement in bacterial respiratory disease control with DOX is more likely caused by its analgesic/antipyretic effects than by its orexigenic effect. Interindividual variation in the AUC of DOX was large in pigs given group medication, even when sufficient feeding space was allowed and the amount of feed offered was greater than their requirements. Therefore, future studies to improve the efficacy of group antibiotic therapy should focus on feeding behavior characteristics as well as biopharmaceutical properties of medicated feeds.

The pharmacokinetic-pharmacodynamic approach to a rational dosage regimen for antibiotics.

Pharmacokinetic-pharmacodynamic (PK/PD) surrogate indices (AUIC, AUC/MIC, C(max)/MIC, T>MIC) for measuring antibiotic efficacy are presented and reviewed. As clinical trials are not sufficiently sensitive to establish a dosage regimen which guarantees total bacteriological cure (Pollyanna phenomenon), PK/PD indexes have been proposed from in vitro, ex vivo, and in vivo infection models and subsequently validated in retrospective or prospective human clinical trials. The target value for time-dependent antibiotics (beta-lactams, macrolides) is a time above the MIC (T>MIC) of 50-80% of the dosage interval, while for concentration-dependent antibiotics (quinolones and aminoglycosides), the area under the inhibitory curve (AUIC, or more simply AUC/MIC of about 125h) is the best surrogate indicator of activity. Using the latter drugs, high concentrations achieved early during therapy are desirable to prevent the development of resistance. A C(max)/MIC ratio greater than 10-12 seems to be an appropriate target for aminoglycosides.