The effect of xylazine on plasma thromboxane B2 concentration in sheep

α₂-adrenoceptor agonist drugs can cause respiratory changes leading to a short period of hypoxaemia in sheep. It has been suggested that this is due to transient platelet aggregation and pulmonary microembolism. If platelet aggregation were to follow platelet activation in response to the administration of α₂ agonists, plasma thromboxane levels would be expected to rise. This study was carried out to measure plasma thromboxane B₂ concentrations before and after the intravenous administration of the α₂-agonist drug xylazine at a dose of 0.1 mg/kg. It was found that the plasma thromboxane concentration rose by 320% and, furthermore, the rise was prevented by the prior administration of atipamezole hydrochloride (0.125 mg/kg), an α₂-adrenoceptor antagonist.     

Correlation between the pharmacokinetics of oxindanac and inhibition of serum thromboxane B2 in calves

The pharmacokinetics and pharmacodynamics of the non-steroidal antiinflammatory drug, oxindanac, were assessed simultaneously in calves after intravenous (i.v.) administration at dose rates of 0.5, 1, 2, 4 and 8 mg/kg. Plasma pharmacokinetic data were fitted to either two or three compartment open models. The elimination t ¹/₂ was constant in the dose range 0.5 to 4 mg/kg (20.2–22.8 h) and shorter at 8 mg/kg (14.7 h). The pharmacodynamics of oxindanac were assessed by its inhibition of serum TxB₂, an index of platelet cyclo-oxygenase activity. Plots of total plasma oxindanac concentration vs. inhibition of serum TxB₂ fitted in all cases a sigmoidal E_max equation. There were no significant differences in the estimates for ED ₅₀ (1.6-1.9 μg/ml), Hill constant (1.3-2.7) or Emax between the doses used in the in vivo studies or when blood was spiked with oxindanac in vitro. Plots of inhibition of serum TxB₂ vs. time were prepared from the pharmacokinetic model equations in each calf in combination with a single sigmoidal E_max plot generated in vitro. These data were not significantly different from the results produced in vivo. It is concluded that oxindanac causes reversible inhibition of platelet cyclo-oxygenase in calves. Its inhibition of serum TxB₂ can be predicted from total plasma drug concentration, as described by a multicompartmental model, and sigmoidal E_max enzyme kinetics. It was not necessary to take into account factors such as drug equilibration between plasma and its target site, free vs. total drug concentration or chirality. This simple model may be useful for predicting the pharmacodynamics of oxindanac in other species.     

Plasma concentrations and therapeutic efficacy of phenylbutazone and flunixin meglumine in the horse: pharmacokinetic/pharmacodynamic modelling

The purpose of the present study was to establish in the horse the relationship between plasma concentration profiles of phenylbutazone (PBZ) and flunixin meglumine (FM) and their pharmacological effects in order to build a predictive pharmacokinetic/pharmacodynamic (PK/PD) model. In five horses, an experimental arthritis was induced by injecting Freund's adjuvant into a carpal joint. PBZ (4 mg/kg) and FM (1 mg/kg) were injected by the intravenous route as a single intravenous dose in two different trials. Five pharmacodynamic end-points were regularly measured after test article injection using standardized procedures: local skin temperature, stride length, the rest angle flexion and the maximal carpal flexion of the injured leg and circumference of the inflamed joint. Plasma drug concentrations and pharmacodynamic data were analysed according to an integrated PK/PD model: for the stride length, the PBZ ECSOr i.e. the plasma concentration for which half the maximum effect could be obtained, was 3.6 ± 2.2 yglml and the maximum potential effect was 10.7 ± 9.4% above the control value. For FM, the corresponding values were 0.93 ± 0.35 μg/ml and 16.3 ± 4.6%. ECSO values for rest angle flexion and local skin temperature were similar to that obtained for stride length. Maximal carpal flexion was an unreliable end-point, and circumference of the joint did not display significant response to the drugs. Using these experimental parameters, a dose-effect relationship was simulated for both drugs: it was shown for PBZ that the model predicts an absence of effect for a 1 mg/kg dose and a maximum effect at about 2 mg/kg: at higher PBZ doses, the maximum effect was not modified, but its duration was increased from 8 h with a 2 mg/kg dose to about 24 h with an 8 mg/kg dose. For FM the model predicts that a dose of 0.5 mg/kg will be without significant effect, whereas a 1 mg/kg dose allows a nearly maximal effect with a return to the control value after a delay of 16 h. A 2 mg/kg dose allows the effect to be maintained for 24 h. It is concluded that PK/PD is a tool of potential value for the preclinical screening of a dosage regimen.     

Vitamin B12 responses to cobalt pellets in beef cows

Objective To assess the effectiveness of cobalt pellets in maintaining adequate vitamin B₁₂ in beef cows on pasture of low cobalt content.
Design A field experiment in a herd grazing cobalt deficient pasture.
Animals Mature Murray Grey cows.
Procedure Cows were given a single oral dose of 0, 1, 2 or 4 cobalt pellets (30 g pellets containing 30% by weight cobaltic oxide) with a selenium pellet and a grub screw. Samples of blood, liver, faeces and milk for chemical analyses were collected at intervals over a period of 2 years after treatment.
Results A single cobalt pellet raised liver vitamin B₁₂ concentration of cows above that of untreated cows for at least 28 weeks, and 2 or 4 pellets for 57 weeks. Plasma vitamin B₁₂ concentration was an unreliable indicator of the effectiveness of cobalt pellet therapy. Milk vitamin B₁₂ and faecal cobalt concentrations increased in response to cobalt pellet therapy.
Conclusion These studies show that one cobalt pellet will prevent vitamin B₁₂ inadequacy in beef cows for between 28 and 57 weeks; two or four pellets will prevent inadequacy for 57 to 75 weeks. Milk vitamin B₁₂ concentration may be a useful indicator of the effectiveness of cobalt pellets in increasing the vitamin B₁₂ supply in lactating cows.     

Pharmacokinetics of flunixin and its effect on prostaglandin F2α metabolite concentrations after oral and intravenous administration in heifers

Flunixin meglumine (FM) was administered either orally as granules or intravenously to six heifers in a two period crossover study. Single doses of 2.2 mg/kg body weight were used. Pharmacokinetic variables were calculated using statistical moment methods. The effect exerted by flunixin was measured as changes in the basal plasma concentration of the main metabolite of prostaglandin (PG) F_2α. After oral FM the arithmetic means of pharmacokinetic variables were: MRT = 12.7 h; MAT = 6.3 h; C _max= 0.9 μg/mL; t _max= 3.5 h. The bioavailability was 60% and the mean half-life (harmonic mean) was 6.2 h. Oral administration of FM inhibited as effectively as intravenous administration the prostaglandin biosynthesis. The concentration of the PG metabolite decreased almost as rapidly as after intravenous administration. The duration of the effect was prolonged and the PG metabolite concentration was significantly lower between 10 and 30 h after oral than after intravenous administration. The results indicate that oral dosing of flunixin, in the form of granules, can be an alternative to intravenous administration for therapeutic use in cattle.     

VITAMIN B12 AND COPPER SUPPLEMENTATION IN BEEF CALVES

SUMMARY Bodyweight responses to subcutaneous injections of vitamin B₁₂ and copper were investigated using Hereford calves in the southeast of South Australia, an area known to produce cobalt and copper deficient sheep. Calves were allocated to one of four groups: control; copper; vitamin B₁₂; copper plus vitamin B₁₂. Responses in bodyweight gain to vitamin B₁₂, and to copper were obtained during the trial of one year. The results of biochemical analysis of blood, hair and faeces from calves and of dam's milk are reported. It is concluded that calves raised on cobalt-deficient pastures will require cobalt or vitamin B₁₂ supplementation prior to weaning.     

The role of thromboxane A2 in regulating porcine basilar arterial tone

The aim of the present study was to clarify the participation of endogenous arachidonic acid (AA) metabolites in regulating porcine basilar, coronary, pulmonary and mesenteric arterial tones in vitro . A cyclooxygenase inhibitor, indomethacin, relaxed basilar artery but not other arteries examined. Quinacrine (a phospholipase A₂ inhibitor), OKY-046 (a thromboxane (TX) A₂ synthetase inhibitor) and ONO-3708 (a TXA₂/prostaglandin H₂ receptor antagonist) produced relaxation in basilar arteries with intact endothelium. Nordihydroguaiaretic acid (a lipoxygenase inhibitor) had no effect on the tone. The amount of TXB₂ (a stable metabolite of TXA₂) spontaneously released from porcine basilar arteries was 6–10 fold more than those from other arteries. Indomethacin and OKY-046 mostly inhibited the production of TXB₂. Endothelial denudation decreased indomethacin-induced relaxation and the amount of TXB₂. These results suggest that a vasoconstricting substance(s) is released from endothelial cells and possibly smooth muscle cells in porcine basilar arteries in vitro . The main constricting substance is proposed to be TXA₂. On the other hand, several arteries from peripheral vascular beds did not release this vasoconstricting substance.     

Sex-related responses to vitamin B12 and trace element supplementation in prime lambs

Bodyweight, plasma vitamin B12 and blood selenium concentrations were monitored in prime lambs given different forms of supplementation at 2 sites in separate years. At the first site treatment groups comprised control, vitamin B12 injection, selenium given orally and a combination of vitamin B12 and selenium. At the second site cobalt and selenium supplied in a glass bullet was compared with an untreated group. Significant sex-related responses were observed to treatment in terms of bodyweight and at site 2 in plasma vitamin B12 concentrations. A marked bodyweight response to glass bullet supplementation was observed in castrated male lambs but not in ewe lambs. These studies show that sex differences should be considered when investigating trace element deficiencies.     

Assessment of histamine, bradykinin, prostaglandins E1 and E2 and carrageenin as vascular permeability agents in the horse

The vascular leakage induced by histamine, bradykinin, serotonin and prostaglandin E1 and E2 was assessed. The test agents were injected intradermally into the shaved thoracic skin of horses and the vascular leakage estimated either semi-quantitatively by recording the diameter of the lesions or by measuring the actual volume of extravasated plasma in microliters using iodine-125-labelled human serum albumin (125I-HSA) as a marker in the blood plasma. Using the latter method, the vascular leakage induced by carrageenin and the effect of coadministered prostaglandins E1 and E2 upon the vascular leakage of both histamine and bradykinin were also investigated. No obvious lesions resulted when serotonin (10(-2) mol/l) was injected but histamine and bradykinin produced circular lesions which increased in diameter for approximately 30 min. The size of the lesions and volume of extravasated plasma was dose dependent. On a molar basis, bradykinin (10(-6) mol/l, 10(-5) mol/l) was more potent than histamine but they were equipotent at 10(-4) mol/l. The size of the lesions induced by carrageenin were independent of their anatomical location on the thorax. Except for the second hour, the hourly volume of vascular leakage increased until the fifth hour when the experiment was concluded. The maximum vascular leakage resulting from the injection of prostaglandin E1 or E2 (1, 10, 100 or 1000 ng) was 7 microliters but when co-administered with bradykinin (10(-6) mol/l), the volume of leaked plasma increased from 29 to 78 microliters. No synergy was observed when either prostaglandin was co-administered with histamine (10(-5) mol/l).     

Effect of flunixin meglumine on prostaglandin F2α synthesis and metabolism in the pig

The effect of flunixin meglumine on prostaglandin synthesis and metabolism was evaluated in the pig in vivo. It was found that the prostaglandin metabolite, 15-ketodihydro-PGF2 alpha, was decreased in the peripheral circulation within 20 min of injection of the drug. In therapeutic doses in the pig the drug had no effect on the metabolism of PGF2 alpha. Flunixin was compared with some other non-steroidal anti-inflammatory drugs in an in vitro test system utilizing sheep vesicular gland microsomes. It was concluded that this drug is a potent inhibitor of prostaglandin synthesis.     

Experimental combined aflatoxin B1 and ochratoxin A intoxication in pigs

Twenty-one pigs weighing approximately 18 kg were placed in 7 groups of 3 and given diets containing respectively aflatoxin B1 alone at 0.375 and 0.0750 mg/kg, ochratoxin A alone at 1 and 2 mg/kg, 0.375 mg/kg of aflatoxin B1 plus 1 mg/kg of ochratoxin A and 0.750 mg/kg aflatoxin B1 and 2 mg/kg of ochratoxin A. The remaining group served as untreated control. At the respective dose levels, pigs receiving similar doses of ochratoxin A alone or in combination with aflatoxin B1, were similarly affected, the clinical effects of aflatoxin having been mostly obscured by those due to ochratoxin A. Mild degenerative hepatic changes typical of aflatoxicosis were observed in pigs fed this toxin alone or in combination with ochratoxin A. In kidneys of pigs fed diet containing 1 and 2 mg of ochratoxin A alone changes included interstitial fibrosis of the vortex and dystrophy and degeneration of the tubular epithelium. Similar lesions but less pronounced fibrosis were found in kidneys of pigs receiving both toxins. The respective lower dose levels of mycotoxins selected were judged to be about the no-effect levels for each dosed separately under the conditions of the trial. Such levels have been found not infrequently on mould affected grain and stock foods. The result highlights the difficulties that may be experienced in the recognition of such multimycotoxicoses as they are likely to occur in the field and indicate the need for toxicological analysis as well as pathological investigation in establishing a diagnosis.     

Agreement of SpO2, SaO2 and ScO2 in anesthetized cynomolgus monkeys (Macaca fascicularis)

Objective To assess the agreement between three measurements of arterial oxygen saturation (SpO₂, SaO₂ and ScO₂) in anesthetized cynomolgus monkeys. Study Design Prospective study. Animals Eleven mature, male cynomolgus monkeys (Macaca fasicularis). Methods Monkeys were anesthetized with intramuscular ketamine followed by intravenous propofol. The trachea of each was intubated and the lungs ventilated. Arterial oxygen saturation was measured with a Nonin 8500 V pulse oximeter, using a lingual clip on the cheek. Arterial blood samples were taken from an indwelling catheter. Inspired oxygen concentration was varied from 12 to 20%, and 88 paired arterial blood samples and saturation measurements were taken. Arterial oxygen saturation in the blood samples was measured using a cooximeter. The saturation was also calculated from the arterial oxygen tension using the Adair equation. The results were compared using Bland and Altman's method. Results The pulse oximeter readings were 2.7% higher than that of the cooximeter, with a limit of agreement of ?3.9 to 9.3%. The pulse oximeter readings were 1.8% higher than the calculated saturation, with a limit of agreement of ?6.5% to 10.1%. The cooximeter readings were 0.9% lower than the calculated saturation, with a limit of agreement of ?5.6% to 3.8%. Conclusions The agreement between SpO₂ and other measurements of arterial oxygen saturation in this study is typical for this technique. The bias and limits of agreement are consistent with reports in other species. Clinical relevance The Nonin 8500 V is a useful pulse oximeter for clinical use in primates.     

Serum and red cell folate and serum vitamin B12 levels in horses

SUMMARY Vitamin B12 and folate concentrations were determined by radioimmunoassay in groups of horses in Queensland. Highest serum vitamin B¹² levels were found in supplemented performance horses. These, together with pastured horses that included pregnant and lactating mares, had significantly greater serum folate activity than permanently stabled animals. The range of red cell folate concentrations was much narrower in horses in training than from any other group. Red cell folate may be a better indicator of a horse's folate status than the serum folate value. Vitamin B¹² and folate concentrations were highest in spring and summer. Small intestinal dysfunction in 2 horses was not associated with vitamin B¹² or folate malabsorption. Serum folate levels returned to normal 24 h after intramuscular injections of 75 to 150 mg folic acid, whereas serum vitamin B¹² values remained elevated for at least one week following injections of 8 to 10 mg to non-supplemented horses.     

Comparative study of the action of flunixin meglumine and tolfenamic acid on prostaglandin E2 synthesis in bovine inflammatory exudate

An acute non-immune inflammation model was used to compare the action of two non-steroidal anti-inflammatory drugs, flunixin meglumine and tolfenamic acid, on prostaglandin E₂, (PGE₂) synthesis in bovine inflammatory exudate. The tissue cage model used involves subcutaneous implantation of polypropylene cages and subsequent stimulation by carrageenan injection of the granulation tissue which develops within the cage. Twelve calves were randomly assigned to three groups receiving placebo, flunixin meglumine and tolfenamic acid, respectively. Inflammatory exudate was sampled 30 min after carrageenan injection and at seven subsequent time points. PGE², levels were determined by radioimmunoassay. At each time point post-carrageenan injection, flunixin meglumine inhibited PGE₂, synthesis to a greater extent than tolfenamic acid. At 4, 8,12 and 24 h these differences were statistically significant.