Pharmacokinetic/pharmacodynamic modelling of robenacoxib in a feline tissue cage model of inflammation

Pelligand, L., King, J. N., Toutain, P. L., Elliott, J., Lees, P. Pharmacokinetic/pharmacodynamic modelling of robenacoxib in a feline tissue cage model of inflammation. J. vet. Pharmacol. Therap.  35 , 19–32. Robenacoxib is a novel nonsteroidal anti‐inflammatory drug developed for use in cats. It is a highly selective COX‐2 inhibitor. Results from previous feline studies showed that, despite a short half‐life in blood, the effect of robenacoxib persisted for 24 h in clinical studies. A tissue cage model of acute inflammation was used to determine robenacoxib’s pharmacokinetics and its ex vivo and in vivo selectivity for COX‐1 and COX‐2 using serum TxB₂ and exudate PGE₂ as surrogate markers for enzyme activity, respectively. After intravenous, subcutaneous and oral administration (2 mg/kg), the clearance of robenacoxib from blood was rapid (0.54–0.71 L·h/kg). The mean residence time (MRT) in blood was short (0.4, 1.9 and 3.3 h after intravenous, subcutaneous and oral administration, respectively), but in exudate MRT was approximately 24 h regardless of the route of administration. Robenacoxib inhibition of COX‐1 in blood was transient, occurring only at high concentrations, but inhibition of COX‐2 in exudate persisted to 24 h. The potency ratio (IC₅₀ COX‐1: IC₅₀ COX‐2) was 171:1, and slopes of the concentration–effect relationship were 1.36 and 1.12 for COX‐1 and COX‐2, respectively. These data highlight the enzymatic selectivity and inflamed tissue selectivity of robenacoxib and support the current recommendation of once‐daily administration.     

MAGNETIC RESONANCE IMAGING FINDINGS OF EQUINE SOLAR PENETRATION WOUNDS

The magnetic resonance (MR) imaging features, signalment, clinical history and outcome of 55 horses with a penetrating sole injury were evaluated. Our aim was to describe MR imaging findings within the hoof capsule, assess the utility of the technique and give recommendations for the optimal MR imaging protocol to evaluate such injuries. Data from five equine hospitals were analyzed retrospectively. The tract was more likely to be visualized in animals scanned within the first week postinjury. There was no significant predisposition based on breed, age, or gender. T2*W transverse sequences were the most useful for assessment of solar penetrations due to their orientation perpendicular to the deep digital flexor tendon, the reduced scanning time, and the T2* capability of enhancing magnetic susceptibility caused by hemorrhage.     

Effect of Preoperative Erythromycin or Dexamethasone/Vitamin C on Postoperative Abomasal Emptying Rate in Dairy Cows Undergoing Surgical Correction of Abomasal Volvulus

Objective— To determine the effects of preoperative erythromycin or combined dexamethasone/vitamin C treatment on postoperative abomasal emptying rate in cows undergoing surgical correction of abomasal volvulus (AV).
Study Design— Prospective, controlled, clinical study using a convenience sample.
Animals— Lactating Holstein–Friesian cows (n=45) with AV were alternately assigned to 3 groups (n=15): group C: untreated (control); group E: erythromycin (10 mg/kg intramuscularly [IM]); group D: dexamethasone (0.02 mg/kg intravenously [IV]) and vitamin C (10 mg/kg IV).
Methods— Drugs were administered 1 hour before surgical correction of AV. d -xylose solution (50%, 0.5 g/kg body weight) was injected into the abomasal lumen during surgery. Jugular venous blood samples for determination of serum d -xylose concentration were periodically obtained. Time to maximal serum d -xylose concentration (T_max-model) was pharmacokinetically determined.
Results— Abomasal emptying rate was significantly ( P <0.05) faster in group E (T_max-model=182±69 min; mean±SD) than in group C cows (T_max-model=237±64 min). Abomasal emptying rate was similar in group D (T_max-model=196±47 min) and group C. Both treatments improved postoperative milk yield within 1 day after surgery.
Conclusion— Preoperative injection of erythromycin (10 mg/kg IM) is an effective method for ameliorating postoperative abomasal hypomotility in cows with AV.
Clinical Relevance— Parenteral erythromycin can be recommended for preoperative treatment of cows with AV.     

Phytotoxic sites of action for molecular design of modern herbicides (Part 1): The photosynthetic electron transport system

A bird's eye review was tried to select the bio‐rational targets from known and novel plant‐specific ones for the molecular design of modern herbicides, which exhibit efficient phytotoxicity at a low‐use rate and preserve a good environment in the 21st century. In phytotoxic sites in the photosynthetic electron transport (PET) system discussed in the present article (Part 1), the generally called bleaching herbicides interfering with the biosynthesis of photosynthetic pigments, chlorophylls and carotenoids, and the biosynthesis of plastoquinone, were considered to be good models for the molecular design of modern herbicides. The PET itself was still considered as an interesting target site for new herbicides, although they need to exert their action in all green leaves of weeds to achieve herbicidal efficacy. Because these herbicides never form a tight binding with D1‐protein, their use‐rate cannot be expected to be as low as the herbicides inhibiting chlorophyll or branched amino‐acid biosynthesis. Other herbicidal targets found in chloroplasts, namely ATP and NADPH formations, have already been omitted from the worldwide biorational molecular design program of herbicides targeting the PET system.     

Connectivity of lobster (Homarus americanus) populations in the coastal Gulf of Maine: part II. Coupled biophysical dynamics

We used a coupled biophysical model to investigate larval transport and connectivity patterns in the Gulf of Maine lobster ( Homarus americanus ) population. Biological 'particles' were released at over 21 000 locations every 10 days over a 4-month hatching period, and were followed from hatching through late postlarval stage. In addition to circulation and dispersion, model calculations included spatial patterns of egg production, temporal patterns of hatching, temperature-dependent development, vertical distribution and mortality. We ran the model for three larval production seasons using the same hatching patterns and individual-based modeling parameters but different flow patterns in the coastal current system. Model results gave distribution and abundance patterns of competent postlarvae that closely resembled observed, alongshore patterns of lobster settlement density. We evaluated the relative contribution of all source regions to the total number of competent postlarvae in a series of medium-size zones along the coastal shelf, many of which are used in lobster management. Connectivity depended on many factors, including patterns of egg production and transport, and the location and size of the receiving zones. Self recruitment ranged from a few percent to >90% of competent postlarvae. Although it was common for postlarvae to come from many, often distant, sources, most of the competent postlarvae in a zone originated within one to two zones in the prevailing 'up-stream' direction, forming shorter connections along the coast than the energetic currents might otherwise suggest. Inshore migrations during summer hatching may contribute to these shorter patterns of connectivity. Transport in the prevailing 'upstream' direction was also indicated.     

Differential inhibition of cyclooxygenase isoenzymes in the cat by the NSAID robenacoxib

Robenacoxib is a new nonsteroidal anti-inflammatory drug (NSAID) developed for use in companion animal medicine. The objectives of this study were: to quantify the inhibitory actions of robenacoxib on cyclooxygenase (COX) isoenzymes in feline whole blood assays; to establish blood concentration–time profiles of robenacoxib after intravenous and subcutaneous dosing in the cat and; to predict the time courses of inhibition of COX isoforms by robenacoxib. COX-1 and COX-2 activities in heparinized feline whole blood samples were induced with calcium ionophore and lipopolysaccharide, respectively. Inhibition of thromboxane B₂ provided a marker of both COX-1 and COX-2 activities and a nonlinear parametric mixed effects modelling approach was used to establish the pharmacodynamic parameters describing this inhibition. Mean values (and prediction intervals) of IC₅₀ were 28.9 (16.4–51.1) μ m (COX-1) and 0.058 (0.010–0.340) μ m (COX-2). These parameters were used to compute several selectivity indices. Selectivity IC ratios (COX-1:COX-2) were 502.3 (IC₅₀/IC₅₀), 451.6 (IC₉₅/IC₉₅) and 17.05 (IC₂₀/IC₈₀). Based on a clinically recommended dosage regimen of 2 mg/kg, it was predicted that the corresponding mean robenacoxib blood concentration over the first 12 h after drug administration corresponded to 5% inhibition of COX-1 and 90% inhibition of COX-2.     

A Novel Pin Distraction Device for Arthroscopic Assessment of the Medial Meniscus in Dogs

Objective— To describe an extra-articular joint distractor for meniscal examination and treatment during canine stifle arthroscopy.
Study Design— Case series.
Animals— Dogs ≥20 kg with suspected cranial cruciate ligament (CrCL) deficiency.
Methods— A custom designed linear side bar was constructed to allow invasive pin distraction of the stifle joint. Its design efficacy for distraction of the medial joint compartment, observation and probing of the medial meniscus, and value during meniscal surgery was evaluated by clinical use.
Results— Application of the stifle distractor medial to the stifle joint using 2 negative threaded pins was easily performed percutaneously without the need of power equipment; however, unintended intra-articular placement of 1 threaded pin occurred in 2 stifles, without appreciable consequence to joint function. Observation as well as thorough probing of the caudal horn of the medial meniscus, even in the presence of a prominent remnant of the CrCL or severe periarticular fibrosis, was possible. Partial meniscectomy was effectively performed as needed without apparent damage to the associated articular surfaces.
Conclusions— Distraction and translation of the medial compartment of the stifle joint using invasive pin distraction allowed observation and palpation of the caudal horn of the medial meniscus so that assessment and treatment were readily accomplished without apparent morbidity.
Clinical Relevance— With careful attention to accurate pin placement, invasive pin distraction of the medial compartment of the canine stifle joint may improve arthroscopic evaluation and treatment of meniscal pathology.     

Mapping of Split-Line Pattern and Cartilage Thickness of Selected Donor and Recipient Sites for Autologous Osteochondral Transplantation in the Canine Stifle Joint

Objective— To characterize donor and recipient sites for autologous osteochondral transplantation in the canine stifle joint with respect to split-line pattern and cartilage thickness.
Study Design— In vitro study.
Sample Population— Stifle joints (n=30) of dogs >20 kg.
Methods— Collagen network orientation of the hyaline cartilage coverage of the distal femur was assessed using split-line technique (n=10). Cartilage thickness was measured radiographically on osteochondral plugs harvested at the abaxial and axial surfaces of the femoropatellar joint (n=15), the most proximal abaxial aspect of the medial condyle (CO; n=5) and at both femoral condyles (n=15).
Results— Cartilage within the femoropatellar joint and both femoral condyles had mostly transversely orientated pattern of split-lines. Abaxial to the femoropatellar joint split-lines were absent. All donor sites had significantly thinner cartilage than the medial condyle (CM). Only the distal trochlea had cartilage thickness comparable to the lateral condyle (CL). The thinnest cartilage was found abaxial to the femoropatellar joint followed by CO, which was ∼2–3 times thinner than the cartilage at both condyles.
Conclusions— None of the investigated donor sites provided transplants of comparable cartilage thickness to CM. Transplants from within the femoropatellar joint should be harvested in priority as they reach cartilage morphology comparable to CL.
Clinical Relevance— Adjusting for cartilage thickness and split-line pattern may improve long-term outcome after autologous osteochondral transplantation. But surface curvature and donor-site morbidity have to be considered as well when choosing the most suitable donor site.     

Immunohistochemical Localization of RANK, RANKL and OPG in Healthy and Arthritic Canine Elbow Joints

Objective— To determine if the receptor activator of nuclear factor-κB–receptor activator of nuclear factor-κB ligand–osteoprotegerin (RANK–RANKL–OPG) system is active in bone remodeling in dogs and, if so, whether differences in expression of these mediators occur in healthy and arthritic joints.
Study Design— Experimental study.
Sample Population— Fragmented processus coronoidei (n=20) were surgically removed from dogs with elbow arthritis and 5 corresponding healthy samples from dogs euthanatized for reasons other than elbow joint disease.
Methods— Bright-field immunohistochemistry and high-resolution fluorescence microscopy were used to investigate the distribution of RANK, RANKL, and OPG in healthy and arthritic joints.
Results— All 3 molecules were identified by immunostaining of canine bone tissue. In elbow dysplasia, the number of RANK-positive osteoclasts was increased. In their vicinity, cells expressing RANKL, a mediator of osteoclast activation, were abundant whereas the number of osteoblasts having the potential to limit osteoclastogenesis and bone resorption via OPG was few.
Conclusions— The RANK–RANKL–OPG system is active in bone remodeling in dogs. In elbow dysplasia, a surplus of molecules promoting osteoclastogenesis was evident and is indicative of an imbalance between the mediators regulating bone resorption and bone formation. Both OPG and neutralizing antibodies against RANKL have the potential to counterbalance bone resorption.
Clinical Relevance— Therapeutic use of neutralizing antibodies against RANKL to inhibit osteoclast activation warrants further investigation.