Carprofen and buprenorphine prevent hyperalgesia in a model of inflammatory pain in cats

A model of nociceptive threshold determination was developed for evaluation of NSAID analgesia in cats. In a crossover study, eight cats received carprofen (4 mg/kg), buprenorphine (0.01 mg/kg) or saline (0.3 ml) subcutaneously before intradermal kaolin injection on the antebrachium to induce mild inflammation. Pressure thresholds were measured at the injected site using blunt-ended pins advanced by manual inflation of a bladder within a bracelet. Bladder pressure was recorded as threshold (PT) at the behavioural end point. Baseline PT were recorded before kaolin injection (time 0). PT was measured at 2-10 h intervals for 52 h. PT below the lower 95% confidence interval (CI) of baseline values indicated hyperalgesia. After saline, hyperalgesia was detected from 2-6 h, 22-26 h, and at 30 and 36 h. After carprofen, PT remained within the 95% CI. After buprenorphine, PT remained within the 95% CI except at 2h. Carprofen and to some extent buprenorphine, prevented inflammatory hyperalgesia.     

Protective Effect of Wheat Peptides Against Small Intestinal Damage Induced by Non-Steroidal Anti-Inflammatory Drugs in Rats

Non-steroidal anti-inflammatory drugs（NSAIDs） were able to produce tissue damage and oxidative stress in animal models of small intestinal damage. In this study, the putative protective effect of wheat peptides was evaluated in a NSAID-induced small intestinal damage model in rats, different doses of wheat peptides or distilled water were administered daily by intragastric administration for 30 d until small intestinal damage was caused. Before sacrificing, NSAIDs（aspirin and indomethacin） or physiological saline were infused into the digestive tract twice. Wheat peptides administration reduced edema and small intestinal damage, and significantly decreased the level of tumor necrosis factor（TNF）-α in mucous membrane of small intestine. Oxidative stress was significantly increased after NSAID infusion and was reduced by wheat peptides. Wheat peptides increased glutathione peroxidase（GSH-Px） activity in mucous membrane of small intestine. μ-Opioid receptor mRNA expression decreased more significantly in wheat peptides treated rats than in the model control group. Overall, the results suggest that non-steroidal anti-inflammatory drugs induced small intestinal damage in rats and wheat peptides administration may be an effective tool for protecting small intestinal tissue against NSAID-induced small intestinal damage and oxidative stress.     

Pharmacokinetics and bioavailability of oral firocoxib in adult,mixed‐breed goats

Pharmacokinetic (PK) studies of oral firocoxib in large animal species have been limited to horses, preruminating calves, and adult camels. The aim of this study was to describe pharmacokinetics and bioavailability of firocoxib in adult goats. Ten healthy adult goats were administered 0.5 mg/kg firocoxib intravenously (i.v.) and per os (p.o.) in a randomized, crossover study. Plasma firocoxib concentrations were measured over a 96‐hr period for each treatment using HPLC and mass spectrometry, and PK analysis was performed. The p.o. formulation reached mean peak plasma concentration of 139 ng/ml (range: 87–196 ng/ml) in 0.77 hr (0.25–2.00 hr), and half‐life was 21.51 hr (10.21–48.32 hr). Mean bioavailability was 71% (51%–82%), indicative of adequate gastrointestinal absorption of firocoxib. There were no negative effects observed in any animal, and all blood work values remained within or very near reference range at the study's conclusion. Results indicate that oral firocoxib is well‐absorbed and rapidly reaches peak plasma concentrations, although the concentration also decreased quickly prior to the terminal phase. The prolonged half‐life may suggest tissue accumulation and higher plasma concentrations over time, depending on dosing schedule. Further studies to determine tissue residue depletion, pharmacodynamics, and therapeutic concentrations of firocoxib in goats are necessary.     

Pharmacokinetics and tissue concentrations of firocoxib in sows following oral administration

The objectives of this study were to describe the pharmacokinetics of firocoxib following oral (PO) dosing and intravenous (IV) injection in sows. Seven healthy sows were administered 0.5 mg firocoxib/kg IV. Following a 23-d washout period, sows were administered firocoxib at 4.0 mg firocoxib/kg PO. Blood samples were collected at predetermined times for 72 hr after IV and 120 hr after PO administration. Plasma firocoxib concentration was measured using UPLC-MS/MS, and pharmacokinetic analysis was performed using noncompartmental procedures. Tissue firocoxib concentrations were determined at 5, 10 (n = 2/time point), and 21 d (n = 3) after PO administration. The geometric mean half-life following IV and PO administration was 16.6 and 22.5 hr, respectively. A mean peak plasma concentration (Cmax) of 0.06 µg/ml was recorded at 7.41 hr (T_max) after oral administration. Mean oral bioavailability was determined to be 70.3%. No signs of NSAID toxicity were observed on macroscopic and microscopic investigation. Firocoxib was detected in the skin with subcutaneous fat (0.02 µg/g) of one of three sows at 21 days postadministration. Additional work to establish appropriate meat withhold intervals in sows is required. Firocoxib was readily absorbed following PO administration. Further work is needed to better understand the analgesic effects for sows and piglets nursing sows administered firocoxib.     

Pharmacokinetics and Effects of Alkalization after Intravenous Administration of Eltenac in Horses

Eltenac (ELT) [4-(2,6-dichlorophenyl)amino-3-thiophene] is a non-steroidal anti-inflammatory drug (NSAID) that was developed for veterinary use in horses and cattle. The pharmacokinetics of ELT was evaluated in horses at 0.5 mg/kg body weight (BW) after single IV injection after 5 days of repeated IV administration and after a single IV injection in horses previously subjected to 250 mg/kg BW of sodium bicarbonate (NaHCO₃) as an alkalization treatment. The aim was to determine whether blood and subsequent urinary alkalization could modify the pharmacokinetics of ELT. Drug quantification was performed with serum and urine using high performance liquid chromatography with UV-visible detection. The results were also integrated with cyclo-oxygenase-inhibition literature data to review the dosage scheme of ELT in horses. After a single intravenous administration, ELT was characterized by rapid distribution (mean t½_λ1 = 0.18 ± 0.07 hour) and a short elimination half-life (mean t½_λ2 = 2.9 ± 0.68 hour). The volume of distribution was small (V_dss = 253.51 ± 47.55 mL/kg), which is likely because of the high percentage of drug protein binding (approximately 97%). The AUC_0-∞ and Cl_B were 6.92 ± 0.84 h*μg/mL and 73.2 ± 10 mL/h/kg, respectively. Repeated administration did not cause either accumulation or modification of the pharmacokinetic profile. The in vitro effective concentrations were maintained for a 6-hour period. The alkalization procedure appeared to accelerate drug elimination, as ELT was quantifiable only for 6 hours; however, the drug clearance was not significantly modified. Thus, the administration of alkaline compounds to accelerate the elimination of ELT is not completely confirmed.     

In vivo effects of meloxicam on inflammatory mediators,MMP activity and cartilage biomarkers in equine joints with acute synovitis

Reasons for performing study: Meloxicam is a commonly used nonsteroidal anti‐inflammatory drug in equine practice, but little is known about its in vivo effects on joint inflammation and cartilage turnover. Objectives: To study the effects of meloxicam on biomarkers of inflammation, matrix metalloproteinase (MMP) activity, and cartilage biomarkers in joints with experimental synovitis. Methods: In a 2‐period cross‐over study, synovitis was induced at T = 0 h in the L or R intercarpal joint of 6 horses by intraarticular injection of 0.5 ng lipopolysaccharide (LPS). Horses received once daily meloxicam (0.6 mg/kg bwt per os) or placebo starting at post injection hour (PIH) 2, and clinical evaluations as well as blood and synovial fluid (SF) sampling were performed at PIH 0, 8, 24 and 168. Synovial fluid was analysed for prostaglandin E₂, bradykinin, substance P, general MMP activity, glycosaminoglycans (GAG), CS846 epitope, type II collagen cleavage fragments (C2C) and type II collagen carboxypropeptide (CPII). Concentrations in meloxicam‐ vs. placebo‐treated joints over time were compared using a linear mixed model. Results: Lipopolysaccharide injection caused marked transient synovitis without systemic effects. Meloxicam caused a significant reduction in lameness at PIH 8 and 24 and tended to reduce effusion. In addition, meloxicam significantly suppressed SF prostaglandin E₂ and substance P release at PIH 8 and bradykinin at PIH 24 compared to placebo treatment. General MMP activity at PIH 8 and 24 was significantly lower in meloxicam‐ vs. placebo‐treated joints, as were GAG, C2C and CPII concentrations at PIH 24. Conclusions: Acute transient synovitis leads to substantial increases in SF biomarkers of inflammation, MMP activity and cartilage turnover, which can be significantly suppressed by meloxicam. Potential relevance: Early oral treatment with meloxicam ameliorates not only clinical signs and joint inflammation in acute synovitis, but may also limit inflammation‐induced cartilage catabolism.     

Treatment of dairy cows with PGF2α or NSAID,in combination with antibiotics,in cases of postpartum uterine inflammation

Background

The aim of the study was to test the effect of two treatments in cases of acute puerperal metritis (APM) and clinical metritis (CM).

Methods

Cows with APM and CM (n = 40)) were matched according to plasma fibrinogen levels (Fb) into three groups. Two negative control groups D (n = 11) and E (n = 17) were composed of healthy cows. The proportion of animals with APM and CM was similar within the groups. Treatment was started on the 3rd day postpartum (PP). In group A (n = 15), intramuscular (i.m.) administration of ceftiofur was used for five days in combination with flunixin for three days. Group B (n = 15) received i.m. administration of ceftiofur for five days followed by two injections of prostaglandin F2_α, with an interval of 8 h, on the 8th day PP. Group C (n = 10) served as a control group with no treatment. The general health status, body temperature (BT) and vaginal discharge were evaluated daily. Endometrial biopsies for bacteriology were taken once a week for seven weeks PP. Blood samples for the analysis of acute phase proteins were collected once a week for six weeks PP. Samples for progesterone analysis were taken twice a week for seven weeks PP. Fertility performance data were recorded.

Results

The area under the curve of BT was higher in group B than in group D cows (P < 0.05). No differences were found for vaginal discharge. There were no differences in bacterial growth, start of ovarian activity or serum amyloid-A or fibrinogen levels among the groups. The haptoglobin concentration was higher in the first and second weeks PP in group B compared with the other groups (P < 0.05). The number of days open was higher in group A than in both groups B and D (P < 0.05). The pregnancy rate after the first two services was higher (P < 0.05) in groups B and D than in groups A and C. The number of services per pregnancy was lower in group B than in group C (P < 0.05).

Conclusions

Regardless of more severe uterine inflammation found in animals from group B, these cows showed the same fertility parameters as healthy animals.     

The Effect of Diclofenac Na (Voltarol) on the Haematopoietic Cells of Bone Marrow in Sheep

Veterinary Research Communications -     

Wintertime pharmacokinetics of intravenously and orally administered meloxicam in semi-domesticated reindeer (Rangifer tarandus tarandus)

ObjectiveTo investigate the pharmacokinetics of orally and intravenously (IV) administered meloxicam in semi-domesticated reindeer (Rangifer tarandus tarandus).Study designA crossover design with an 11 day washout period.AnimalsA total of eight young male reindeer, aged 1.5–2.5 years and weighing 74.3 ± 6.3 kg, mean ± standard deviation.MethodsThe reindeer were administered meloxicam (0.5 mg kg^–1 IV or orally). Blood samples were repeatedly collected from the jugular vein for up to 72 hours post administration. Plasma samples were analysed for meloxicam concentrations with ultraperformance liquid chromatography combined with triple quadrupole mass spectrometry. Noncompartmental analysis for determination of pharmacokinetic variables was performed.ResultsThe pharmacokinetic values, median (range), were determined. Elimination half-life (t_½) with the IV route (n = 4) was 15.2 (13.2–16.8) hours, the volume of distribution at steady state was 133 (113–151) mL kg^?1 and clearance was 3.98 (2.63–5.29) mL hour^–1 kg^–1. After oral administration (n = 7), the peak plasma concentration (C_max) was detected at 6 hours, t_½ was 19.3 (16.7–20.5) hours, C_max 1.82 (1.17–2.78) μg mL^–1 and bioavailability (n = 3) 49 (46–73)%. No evident adverse effects were detected after either administration route.Conclusions and clinical relevanceA single dose of meloxicam (0.5 mg kg^–1 IV or orally) has the potential to maintain the therapeutic concentration determined in other species for up to 3 days in reindeer plasma.