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.     

A Cross‐Sectional Study Examining Campylobacter and Other Zoonotic Enteric Pathogens in Dogs that Frequent Dog Parks in Three Cities in South‐Western Ontario and Risk Factors for Shedding of Campylobacter spp.

An estimated 6 million pet dogs live in Canadian households with the potential to transmit zoonotic pathogens to humans. Dogs have been identified as carriers of Salmonella, Giardia and Campylobacter spp., particularly Campylobacter upsaliensis, but little is known about the prevalence and risk factors for these pathogens in pet dogs that visit dog parks. This study examined the prevalence of these organisms in the faeces of dogs visiting dog parks in three cities in south‐western Ontario, as well as risk factors for shedding Campylobacter spp. and C. upsaliensis. From May to August 2009, canine faecal samples were collected at ten dog parks in the cities of Guelph and Kitchener‐Waterloo, Ontario, Canada. Owners were asked to complete a questionnaire related to pet characteristics and management factors including age, diet and activities in which the dog participates. Faecal samples were collected from 251 dogs, and 189 questionnaires were completed. Salmonella, Giardia and Campylobacter spp. were present in 1.2%, 6.4% and 43.0% of faecal samples, respectively. Of the Campylobacter spp. detected, 86.1% were C. upsaliensis, 13% were C. jejuni and 0.9% were C. coli. Statistically significant sparing factors associated with the shedding of Campylobacter spp. included the feeding of a commercial dry diet and the dog's exposure to compost. Age of dog had a quadratic effect, with young dogs and senior dogs having an increased probability of shedding Campylobacter spp. compared with adult dogs. The only statistically significant risk factor for shedding C. upsaliensis was outdoor water access including lakes and ditches, while dogs >1 year old were at a lower risk than young dogs. Understanding the pet‐related risk factors for Campylobacter spp. and C. upsaliensis shedding in dogs may help in the development of awareness and management strategies to potentially reduce the risk of transmitting this pathogen from dogs to humans.     

Decreased serum apolipoprotein A-I concentrations in cows infected with Salmonella typhimurium.

Serum apolipoprotein A-I concentrations in cows infected with Salmonella Typhimurium were evaluated to assess its relevance in salmonellosis. Apolipoprotein A-I has been shown in rats to be secreted by the intestine as well as the liver. Clinical symptoms such as diarrhea revealed an outbreak of salmonellosis in 22 cows on a farm, and sera were obtained at 6 (acute phase), 16, 28 (convalescent period) and 42 d (postconvalescent period) after the outbreak. Apolipoprotein A-I concentrations (mean +/- SD, mg/mL), determined by ELISA, were 0.598 +/- 0.497 (day 6), 0.111 +/- 0.060 (day 16), 0.432 +/- 0.311 (day 28) and 0.727 +/- 0.516 (day 42). Compared with the concentration at day 42, those at 16 and 28 d were significantly (P < 0.01, P < 0.05) lower, but that at day 6 was not. The serum concentration of apolipoprotein B-100 (of liver origin in cattle) was unaltered during the course of salmonellosis. The concentration of apolipoprotein A-I was positively correlated with those of serum total cholesterol (r = 0.589, P < 0.01) and phospholipids (r = 0.590, P < 0.01). These results suggest that apolipoprotein A-I in cattle is in part of intestinal origin, and also that its decreased serum concentration in salmonellosis can be attributed to the reduced intestinal synthesis or secretion of this apolipoprotein. Moreover, as a potential carrier for dietary lipids such as cholesterol, determination of serum apolipoprotein A-I concentration is suggested to be useful when assessing the nutritional status of the affected cows.     

Isolation of Mycobacterium species from raw milk of pastoral cattle of the Southern Highlands of Tanzania

A study to determine the secretion of Mycobacterium spp. in milk from indigenous cattle was carried out in pastoral cattle reared in the Southern Highlands of Tanzania. The study was aimed at elucidating the dangers associated with milk-borne zoonoses in a society where milk is normally consumed raw. Out of 805 milk samples, 31 (3.9%) were positive for mycobacteria. There was a preponderance of atypical mycobacteria (87%) whereas only two isolates (6.5%) were confirmed as M. bovis. Atypical mycobacteria included: M. terrae (n=7), M. fortuitum (n=2), M. flavescens (n=13), M. gordonae (n=1) and M. smegmatis (n=4). Although the number of M. bovis positive samples was low, the habit of pooling milk may still pose great public health dangers to milk consumers in this part of the world. Moreover, isolation of atypical mycobacteria should also be considered to be a danger to human health in countries such as Tanzania, where the number of people with lowered immunity due to HIV infection is on the increase.     

Hiatal herniation as a complication of chronic diaphragmatic herniation

Three of four cases of chronic diaphragmatic herniation seen over a period of 12 months developed hiatal herniation within five to eight days of corrective surgery for the diaphragmatic herniation. None of the dogs had shown any prior signs referrable to hiatal herniation. The features that developed subsequent to diaphragmatic herniorrhaphy in all cases were dyspnoea, increased intra-abdominal pressure due to decreased abdominal domain and laxity of the oesophageal hiatus as judged subjectively at the time of surgery for hiatal herniation correction. These conditions may be significant underlying factors for the development of hiatal herniation not preceded by diaphragmatic herniation in the dog. Those associated factors accepted as important in humans, including reduced lower oesophageal sphincter tone and gastroesophageal reflux, may not be of similar importance in small animals.     

Efficacy of ceftiofur hydrochloride for treatment of experimentally induced colibacillosis in neonatal swine

Ceftiofur hydrochloride was tested for effectiveness against induced colibacillosis in neonatal swine. In this model, pigs less than 12 hours old were inoculated via stomach tube with a virulent, K99+, nalidixic acid-resistant strain of Escherichia coli. Six hours after challenge exposure, 1 dose of ceftiofur was administered either IM or orally in experiment 1 and orally only in experiment 2. Mortality, shedding of bacteria, fecal consistency scores, and body weight changes were monitored for 10 days. In experiment 1 (n = 383 pigs), all treatments at dosage that ranged between 0.5 and 64.0 mg of ceftiofur/kg of body weight significantly (P less than 0.001) reduced mortality, bacterial shedding, and diarrhea and increased weight gain, compared with findings in untreated controls. There were no detectable differences between oral and IM routes, except that there was greater reduction in bacteria shedding associated with the oral route of administration. In experiment 2 (n = 505 pigs), ceftiofur was administered orally either once at 6 hours after challenge exposure or twice at 6 and at 48 hours after the first dose. Dosage of ceftiofur was 0, 5, 10, 20, 30, or 60 mg/kg administered once, or half the same dose was administered at each of 2 times. At the optimal dosage (10 mg/kg), a single dose was as effective as 2 doses. The single administration at all dosages reduced mortality, bacterial shedding, and diarrhea scores and increased body weight gain, compared with findings in untreated pigs (P less than 0.01). In this induced infection model, the optimal treatment dosage was determined to be 10 mg/kg administered once.     

Evaluation of Transmittance and Reflectance Pulse Oximetry in a Canine Model of Hypotension and Desaturation

Ten, anesthetized dogs were instrumented with three pulse oximeter probes; two lingual transmittance probes and one rectal reflective probe. Arterial oxygen desaturation was produced by decreasing the inspired oxygen concentration. Hypotension was produced with an infusion of nitroprusside. Simultaneous pulse oximeter readings (SpO₂) were compared to co-oximeter measured arterial saturation (SaO₂) collected over a range of SaO₂ (50–100%) and mean arterial pressures (40–100mmHg). Each of the monitors and means of evaluating SpO₂ studied provided accurate SpO₂ measurements over a range of mean arterial pressure from 40–100mmHg. All of the monitors tested tended to overestimate the SaO₂ when the arterial saturation was less than 70%.     

Proteomics: A new tool in bovine claw disease research

Claw horn disruption (CHD) is a common underlying cause of lameness in dairy cattle which leads to compromised animal welfare and production losses. Despite an intense research effort over the last two decades, progress in reducing the prevalence of lameness due to CHD has been limited. In addition to current research strategies there is a need to develop novel approaches and methods that expand understanding of the disease mechanisms involved in CHD. The objectives of the present study were to explore the potential of liquid chromatography tandem mass spectrometry (LC-MS/MS) in mapping protein expression in three different bovine claw tissues, and to provide a relevant functional annotation of the proteins characterized in these tissues. LC-MS/MS was used to characterize protein expression in coronary band skin (C), claw dermal (D) and lamellar (L) tissues from two heifers. A total of 388 different proteins were identified, with 146 proteins available for identification in C, 279 proteins in D and 269 proteins in L. A functional annotation of the identified proteins was obtained using the on-line Blast2GO tool. Three hundred and sixteen of the identified proteins could be subsequently grouped manually to one or more of five major functional groups related to metabolism, cell structure, immunity, apoptosis and angiogenesis. These were chosen to represent basic cell functions and biological processes potentially involved in the pathogenesis of CHD. The LC-MS/MS-based proteomic analysis presented here is the largest published survey, so far, of the bovine claw tissue proteome.     

SONOGRAPHIC EVALUATION OF THE CRANIAL MEDIASTINUM IN SMALL ANIMALS

Clinical records, radiographs, and sonograms of 17 animals presented for possible cranial mediastinal disease were reviewed. Radiographs were evaluated for accuracy in detection of mediastinal masses. Sonography of the mediastinum was performed using a parasternal approach with the animals in sternal or lateral recumbency. The mediastinum was evaluated for the presence of a mass or other disease. Masses were characterized by echogenicity, size, number, and margination. Mediastinal vessels were studied to determine if there was vascular invasion or compression. A comparison of radiographic and sonographic assessment in cranial mediastinal disease indicates sonography adds valuable information in the diagnosis of mediastinal disease. Results of ultrasound-guided, fine-needle aspirate were documented and found to be advantageous in establishing a diagnosis in mediastinal masses.