Influence of centrally administered diltiazem on behavioural responses, clinical symptoms, reticulo-ruminal contractions and plasma catecholamine level after experimentally induced duodenal distension in sheep

A different role of L-type antagonists for voltage-gated calcium channels (VGCC) has been previously identified in different types of experimental and clinical pain in man and animals. Present study examined the role of VGCC blocker - diltiazem administered icv (0.25, 0.5, 1.0 and/or 2.0 mg in toto) on the development of pain related symptoms, clinical signs, plasma catecholamine level and the inhibition of reticulo-rumen motility caused by 5 min lasting mechanical duodenum distension (DD) in the sheep. Experimental DD was conducted by insertion (during surgery) of rubber balloon into the duodenum and the distension by 40 ml of warm water. Duodenal distension resulted in a significant increase of behavioural pain responses, tachycardia, hyperventilation, inhibition of reticulo-rumen contractions rate (from 85% to 45% during 15-20 min), an increase of plasma catecholamine concentration (over sevenfold increase of epinephrine during 2 h following DD, two-times norepinephrine and 84% increase of dopamine). Diltiazem infusion given 10 min before DD decreased intensity of visceral nocifensive responses such as: behavioural changes, tachycardia, hyperventilation, reticulo-rumen motility and efficiently prevented appearance of catecholamine release. These data demonstrated that the development and persistence of acute duodenal pain depends on the activation of Ca²⁺ ion flux leading to neurotransmitters release and modulation of membrane excitability. It seems that diltiazem given icv 10 min prior to DD (as a source of acute visceral pain), inhibited specific receptors α₁ subunits of VGCCs in target tissues, prevent depolarization of cell membranes and release of neurotransmitters responsible for pain sensitivity in sheep. The observed antinociceptive action of VGCCs type-L blockers suggests that these channels play a crucial role in the modulation of acute visceral pain in sheep.     

Centrally administered verapamil prevents the autonomic reaction to visceral pain in sheep

The significant role of voltage gated calcium channels (VGCC) L-type antagonists used concomitantly with opioids in attenuation of clinical pain has been confirmed. The aim of this study was to evaluate the effect of centrally administered verapamil on behavior and biochemical parameters in sheep that have undergone experimental duodenal distension (DD) and to determine whether verapamil exerts any anti-nociceptive effects under these conditions. The study was carried out using 24 mature crossbred ewes, each weighing 38-43 kg. Verapamil, a VGCC blocker, was administered through an intracerebroventricular cannula at the following doses: 0.25, 0.5, 1.0 and 2.0 mg in toto. Ten minutes later experimental DD was conducted by insertion and the distension of rubber balloon (containing 40 ml of warm water) inserted into sheep duodenum. After 5 min of mechanical DD the following reactions were then observed: the significant increase in behavioral pain responses, i.e. tachycardia, hyperventilation, inhibition of reticulo-ruminal contractions (70% approximately, during 15 min), an increase of plasma catecholamine concentration (over 7-fold increase of epinephrine during 2 h following DD, 2-times norepinephrine and ±80% increase of dopamine). Verapamil infusion administered 10 min prior to DD decreased intensity of visceral pain responses, such as: behavioral changes, tachycardia, hyperventilation, inhibition of the reticulo-rumen motility and efficiently prevented the appearance of catecholamine release. These data demonstrated that the development and persistence of duodenal hyperalgesia depends on the activation of Ca²⁺ ion flux leading to neurotransmitters release and modulation of membrane excitability. The observed antinociceptive action of VGCCs type-L blockers suggests that these channels play a crucial role in the modulation of acute visceral hyperalgesia in sheep.     

Anthelmintic activity of Cocos nucifera L. against sheep gastrointestinal nematodes

The development of anthelmintic resistance has made the search for alternatives to control gastrointestinal nematodes of small ruminants imperative. Among these alternatives are several medicinal plants traditionally used as anthelmintics. This work evaluated the efficacy of Cocos nucifera fruit on sheep gastrointestinal parasites. The ethyl acetate extract obtained from the liquid of green coconut husk fiber (LGCHF) was submitted to in vitro and in vivo tests. The in vitro assay was based on egg hatching (EHT) and larval development tests (LDT) with Haemonchus contortus. The concentrations tested in the EHT were 0.31, 0.62, 1.25, 2.5 and 5 mg ml⁻¹, while in the LDT they were 5, 10, 20, 40 and 80 mg ml⁻¹. The in vivo assay was a controlled test. In this experiment, 18 sheep infected with gastrointestinal nematodes were divided into three groups (n = 6), with the following doses administered: G1—400 mg kg⁻¹ LGCHF ethyl acetate extract, G2—0.2 mg kg⁻¹ moxidectin (Cydectin^®) and G3—3% DMSO. The worm burden was analyzed. The results of the in vitro and in vivo tests were submitted to ANOVA and analyzed by the Tukey and Kruskal–Wallis tests, respectively. The extract efficacy in the EHT and LDT, at the highest concentrations tested, was 100% on egg hatching and 99.77% on larval development. The parameters evaluated in the controlled test were not statistically different, showing that despite the significant results of the in vitro tests, the LGCHF ethyl acetate extract showed no activity against sheep gastrointestinal nematodes.     

Pharmacokinetics and bioavailability of moxifloxacin in buffalo calves

The pharmacokinetics of moxifloxacin were investigated in buffalo calves following a single intravenous and intramuscular administration of moxifloxacin (5 mg kg⁻¹ body wt.). Moxifloxacin concentrations in plasma and urine were determined by microbiological assay. Pharmacokinetic analysis of disposition data indicated that intravenous administration data were best described by a two compartment open model, whereas intramuscular administration data were best described by a one compartment open model. Following intravenous administration, the elimination half life (t_1/2β), volume of distribution (Vd_(area)) and total body clearance were 2.69 ± 0.14 h, 1.43 ± 0.08 L kg⁻¹ and 371.2 ± 11.2 ml kg⁻¹ h⁻¹, respectively. Following intramuscular administration, the absorption half life (t_1/2ka) was 0.83 ± 0.20 h. The systemic bioavailability (F) of moxifloxacin in buffalo calves was 80.0 ± 4.08%. Urinary excretion of moxifloxacin was less than 14% after 24 h of administration of drug. In vitro binding of moxifloxacin to plasma proteins of buffalo calves was 28.4 ± 3.77%. From the data of surrogate markers (AUC/MIC, C_max/MIC), it was determined in the buffalo calves that when administered by intravenous or intramuscular route at 5 mg kg⁻¹, moxifloxacin is likely to be effective against bacterial isolates with MIC ? 0.1 μg ml⁻¹.     

Effect of ractopamine hydrochloride and zilpaterol hydrochloride on growth,diet digestibility,intake and carcass characteristics of feedlot lambs

The effects of the β-adrenergic agonists ractopamine hydrochloride (RH; 0.35, 0.70 and 1.05 mg kg^− 1 of BW d^− 1) and zilpaterol hydrochloride (ZH; 0.10, 0.20 and 0.30 mg kg^− 1 of BW d^− 1) on growth performance and carcass characteristics were determined in 84 Dorper × Katahdin lambs (12 lambs per treatment), that were randomly assigned to a complete block design during a 42-day feeding trial. Lambs were fed a corn grain-based diet (18.71% CP and 12.9 MJ/kg ME). Nutrient digestibility of diets and blood serum metabolites were also determined. There were no significant (P > 0.05) differences in growth characteristics by effect of ZH or RH administration. However, lambs final weight, total weight gain and ADG increased linearly (P < 0.05) as levels of both β-adrenergic agonist increased. RH or ZH administration did not affect feed efficiency, diet digestibility or particular blood serum metabolites of lambs. Carcass characteristics of lambs consuming ZH were significantly better (P < 0.01) than RH or control lambs; RH produced significant linear response on carcass weight, dressing percentage, longissimus muscle area, carcass conformation and quality grade, and improved quadratically (P < 0.05) fat thickness and USDA yield grade of lamb carcasses. On the other hand, increasing levels of ZH decreased linearly (P > 0.01) fat thickness and improved (P > 0.05) USDA yield grade and carcass quality grade. Both β-adrenergic agonists improved carcass characteristics; although greater improvements were obtained with ZH than RH for most carcass characteristics.     

A comparison of the effects of hydromorphone HCl and a novel extended release hydromorphone on arterial blood gas values in conscious healthy dogs

The purpose of this study was to evaluate arterial blood gases in dogs that were given hydromorphone or extended release liposome-encapsulated hydromorphone (LEH). Dogs were randomly administered LEH, n = 6, (2.0 mg kg⁻¹), hydromorphone, n = 6, (0.2 mg kg⁻¹) or a placebo of blank liposomes, n = 3, subcutaneously on separate occasions. Arterial blood samples were drawn at serial time points over a 6-h time period for blood gas analysis. There was no change from baseline values in P_aCO₂, P_aO₂, (HCO₃-), pH, and SBEc in the dogs that received the placebo. Administration of hydromorphone resulted in significant increases in P_aCO₂ (maximum (mean + SD] 44.4 + 1.1 mm of Hg) and significant decreases in P_aO₂ (minimum (mean + SD) 82.4 + 4.7 mm of Hg) and pH (minimum (mean + SD) 7.31 + 0.01) compared with baseline. Administration of LEH resulted in significant increases in P_aCO₂ (maximum (mean + SD) 44.6 + 0.9 mm of Hg) and significant decreases in P_aO₂ (minimum (mean + SD) 84.8 + 2.6 mm of Hg) and pH (minimum (mean + SD) 7.34 + 0.02) compared with baseline. There was no significant difference between these two groups at any time point. The changes observed in P_aCO₂, P_aO₂, and pH, however, were within clinically acceptable limits for healthy dogs. LEH was determined to cause moderate changes in arterial blood gas values similar to those caused by hydromorphone.     

Pharmacokinetic and pharmacodynamic interactions of tolfenamic acid and marbofloxacin in goats

Pharmacokinetic and pharmacodynamic properties in goats of the non-steroidal anti-inflammatory drug tolfenamic acid (TA), administered both alone and in combination with the fluoroquinolone marbofloxacin (MB), were established in a tissue cage model of acute inflammation. Both drugs were injected intramuscularly at a dose rate of 2 mg kg⁻¹. After administration of TA alone and TA + MB pharmacokinetic parameters of TA (mean values) were C_max = 1.635 and 1.125 μg ml⁻¹, AUC = 6.451 and 3.967 μg h ml⁻¹, t_1/2K₁₀ = 2.618 and 2.291 h, Vdarea/F = 1.390 and 1.725 L kg⁻¹, and ClB/F = 0.386 and 0.552 L kg⁻¹ h⁻¹, respectively. These differences were not statistically significant. Tolfenamic acid inhibited prostaglandin (PG)E₂ synthesis in vivo in inflammatory exudate by 53-86% for up to 48 h after both TA treatments. Inhibition of synthesis of serum thromboxane (Tx)B₂ ex vivo ranged from 16% to 66% up to 12 h after both TA and TA + MB, with no significant differences between the two treatments.From the pharmacokinetic and eicosanoid inhibition data for TA, pharmacodynamic parameters after dosing with TA alone for serum TxB₂ and exudate PGE₂ expressing efficacy (E_max = 69.4 and 89.7%), potency (IC₅₀ = 0.717 and 0.073 μg ml⁻¹), sensitivity (N = 3.413 and 1.180) and equilibration time (t_1/2K_e0 = 0.702 and 16.52 h), respectively, were determined by PK-PD modeling using an effect compartment model. In this model TA was a preferential inhibitor of COX-2 (COX-1:COX-2 IC₅₀ ratio = 12:1). Tolfenamic acid, both alone and co-administered with MB, did not affect leucocyte numbers in exudate, transudate or blood. Compared to placebo significant attenuation of skin temperature rise over inflamed tissue cages was obtained after administration of TA and TA + MB with no significant differences between the two treatments. Marbofloxacin alone did not significantly affect serum TxB₂ and exudate PGE₂ concentrations or rise in skin temperature over exudate tissue cages. These data provide a basis for the rational use of TA in combination with MB in goat medicine.     

CCK1 central receptor antagonist prevented the intestinal stress symptoms in sheep

The aim of this study was to determine the influence of mechanically induced duodenal distension (DD) and lorglumide (CCK1 receptor antagonist) premedication on electrical activity of various parts of gastrointestinal (GI) tract and the blood plasma cortisol level in sheep. The influence of lorglumide on the unfavourable effects of duodenal distension (performed with a balloon filled with water--40 and 80 ml; DD40 and DD80) was investigated in this study. These effects in sheep were as follows: the atony of forestomachs and abomasum and the transitory stimulation of myoelectrical activity of small intestine and distal parts of large intestine. The animals, under general anaesthesia, had electrodes inserted into the muscular layers of the organ, the duodenal fistula and (in another group of animals) also the ruminal fistula. Five minute duodenal distension (DD40 and DD80) caused an immediate and complete inhibition of the frequency of spike bursts as well as reticulo-ruminal and abomasal contractions, but also a transitory significant increase of spike bursts of the intestinal wall. The duodenal distension (DD40 and DD80) caused a significant increase of plasma cortisol concentration. Lorglumide did not significantly change the motility of gastrointestinal tract and cortisol concentration, but 10 min after the intracerebroventricular (i.c.v.) infusion in the doses of 1 and 2 mg in toto (i.e. 25 and 50 micrograms/kg B.W.) it decreased the cortisol concentration by 59.7%, as compared with the control values. Lorglumide administered in the above mentioned doses 10 min before the DD40 prevented all signs of intestinal stress and decreased the release of cortisol, but only for 10 min since the beginning of the duodenal distension. It is concluded, that lorglumide--an antagonist of the central CCK1 receptors can be an effective antistressoric agent in the stomach atony caused by the duodenal distension (mechanical-algetic-emotional stress) in sheep.     

Pharmacokinetics of propofol infusions, either alone or with ketamine, in sheep premedicated with acepromazine and papaveretum

The pharmacokinetics of propofol were investigated in two groups of five Scottish blackface sheep undergoing surgery for the implantation of subcutaneous tissue pouches. After premedication with acepromazine and papaveretum, anaesthesia was induced with either propofol at 4 mg kg⁻¹ intravenously (group 1) or with a mixture of propofol at 3 mg kg⁻¹ and ketamine at 1 mg kg ⁻¹ intravenously (group 2). Anaesthesia was maintained with a variable infusion rate of either propofol alone (group 1) or propofol and ketamine (group 2). Both regimens produced satisfactory conditions for superficial surgery of the body surface. The mean (SD) duration of anaesthesia was 64·8 (3·1) minutes for group 1 and 60 (0) minutes for group 2; the mean total dose of propofol given to the sheep in group 1 was 801 (84) mg, and the sheep in group 2 received 470 (46) mg of propofol and 267 (30) mg of ketamine. The mean elimination half-life of propofol was 56·6 (13·1) minutes in group 1 and 50·3 (21·4) minutes in group 2; the mean volume of distribution at steady state was 1037 (0480) litre kg⁻¹ in group 1 and 1·515 (0939) litre kg⁻¹ in group 2; the mean body clearance was 85·4 (28·0) ml kg⁻¹ min⁻¹ in group 1 and 1280 (35·0) ml kg⁻¹ min⁻¹ in group 2; the mean residence time corrected for a bolus injection was 12·1 (4·2) minutes in group 1 and 11·9 (6·6) minutes in group 2; for the infusion, the mean residence time was 72·1 (4·2) minutes in group 1 and 69·9 (7·9) minutes in group 2. There were wide variations in the blood propofol concentrations reached in individual sheep by using this standard dosing regimen. All the sheep recovered quickly from anaesthesia; the mean times to extubation, sternal recumbency and standing for the animals in group 1 were 2·8 (0·4) 6·3 (1·2) and 10·9 (1·6) minutes from the end of the infusion, and the times for group 2 were 5·3 (0·9), 11·2 (1·7) and 15·1 (2·2) minutes.     

PK-PD integration and modeling of marbofloxacin in sheep

The fluoroquinolone antimicrobial drug, marbofloxacin, was administered intravenously (IV) and intramuscularly (IM) to sheep at a dose rate of 2 mg kg⁻¹ in a 2-period cross-over study. Using a tissue cage model of inflammation, the pharmacokinetic properties of marbofloxacin were established for serum, inflamed tissue cage fluid (exudate) and non-inflamed tissue cage fluid (transudate). For serum, after IV dosing, mean values for pharmacokinetic parameters were: clearance 0.48 L kg⁻¹ h⁻¹; elimination half-life 3.96 h and volumes of distribution 2.77 and 1.96 L kg⁻¹, respectively, for V_darea and V_ss. After IM dosing mean values for pharmacokinetic variables were: absorption half-time 0.112 h, time of maximum concentration 0.57 h, terminal half-life (T½el) 3.65 h and bioavailability 106%. For exudate, mean T½el values were 12.38 and 13.25 h, respectively, after IV and IM dosing and for transudate means were 13.39 h (IV) and 12.55 h (IM).The in vitro minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) and ex vivo time-kill curves for marbofloxacin in serum, exudate and transudate were established against a pathogenic strain of Mannheimia haemolytica. Integration of in vivo pharmacokinetic data with MIC determined in vitro provided mean values of area under curve (AUC)/MIC ratio for serum, exudate and transudate of 120.2, 156.0 and 156.6 h after IV dosing and 135.5, 165.3 and 146.2 h after IM dosing, respectively. After IM administration maximum concentration (C_max)/MIC ratios were 21.1, 6.76 and 5.91, respectively, for serum, exudate and transudate. The ex vivo growth inhibition data after IM administration were fitted to the sigmoid E_max (Hill) equation to provide values for serum of AUC_24 h/MIC producing, bactericidal activity (22.51 h) and virtual eradication of bacteria (35.31 h). It is proposed that these findings might be used with MIC₅₀ or MIC₉₀ data to provide a rational approach to the design of dosage schedules which optimise efficacy in respect of bacteriological as well as clinical cures.     

Efficiency of entomopathogenic fungi in the control of eggs and larvae of the horn fly Haematobia irritans (Diptera: Muscidae)

The present study assessed the pathogenic effect of isolates E9, IBCB425 and IBCB159 of the Metarhizium anisopliae fungus, JAB06, JAB07 and AM09 of Beauveria bassiana, IBCB133 and CB75 of Isaria fumosorosea (=Paecilomyces fumosoroseus) and CG189 and CG195 of Isaria farinosa (=Paecilomyces farinosus) against eggs and larvae of the horn fly Haematobia irritans. Eggs were inoculated with suspensions containing 10⁶, 10⁷ and 10⁸ conidia ml⁻¹ of the fungal isolates and observed after 48 h to determine viability. In the larvae study, eggs were allowed to hatch into fresh bovine feces that had been treated with 10⁸, 10⁷ or 10⁶ conidia mg feces⁻¹. In both studies, 5 days after initial procedures, all formed pupae were transferred to an incubator at 27 ± 0.5 °C until the emergence of the adult flies was complete. The M. anisopliae isolates did not cause the death of H. irritans eggs, but they did promote the death of larvae that hatched from treated eggs, and therefore increased the total mortality. Isolate E9 promoted 100% mortality of treated larvae at a concentration of 10⁸ conidia ml⁻¹. For the B. bassiana isolates, no activity was observed against insect eggs or larvae. Both I. fumosorosea isolates promoted significant mortality (p < 0.05) of eggs at every concentration of conidia. Isolate CG195 of I. farinosa increased the mortality of larvae and pupae that hatched from treated eggs and promoted significant total mortality (p < 0.05) of the insect at every concentration of conidia.     

Assessment of orocaecal transit time in cats by the breath hydrogen method: the effects of sedation and a comparison of definitions

Oro-caecal transit times (OCTTs) were assessed in 10 healthy adult cats by the lactulose breath hydrogen method with either no sedation (group A), or after the intramuscular administration of three sedative regimens: a combination of acetylpromazine at 0·1 mg kg⁻¹ with buprenorphine at 10 μg kg⁻¹ (group B), ketamine at 5 mg kg⁻¹ with midazolam at 0·1 mg kg⁻¹ (group C), or medetomidine at 50 μg kg⁻¹ (group D). For each test, the OCTT was defined by four methods: a visual assessment, the first maintained 4 ppm increase in hydrogen production, and the first maintained 0·5 ml hr⁻¹ increase in hydrogen production assessed by two cumulative sum methods. Depending on the definition, the median OCTTs of the cats were between 113 and 131·5 minutes in group A, 86·5 and 97·5 minutes in group B, 218 and 235·5 minutes in group C and 86·5 and 97·5 minutes in group D. By two of the definitions, the median OCTTs in group C were significantly longer than in group A (P≤0·037) and approached significance by the other two definitions. The use of sedatives significantly increased the inter-individual variability of the OCTTs, particularly in groups C and D. There were significant differences between the median OCTTs defined by the four different methods, but all the methods were very highly and significantly correlated (r_s≤0·9503, P<0·0001).     

Naringin and vitamin E influence the oxidative stability and lipid profile of plasma in lambs fed fish oil

Thirty two Merino lambs (15 weeks old) fed barley straw and fish oil enriched concentrate were used to assess the effect of vitamin E (6 g kg⁻¹ DM) and naringin (1.5-3 g kg⁻¹ DM) on plasma lipid peroxidation (TBARS), total antioxidant status (TAS), immune response, plasma cholesterol, and triglycerides. After 21 days feeding the experimental diets, lambs were subjected to a 4 h transportation stress period and then held 4 more hours without feed. TBARS values before stress were lower for animals consuming vitamine E and naringin when compared to control lambs (P < 0.05). However, after stress all groups presented similar levels of TBARS. TAS decreased (P < 0.05) in all groups in response to stress with values recovering (P < 0.05) to pre-stress values following 4 h of rest. A rise (P < 0.05) in serum concentrations of triacylglycerol following 21 d of fish oil supplementation was dampened in lambs consuming vitamin E or naringin. Both pre-stress TBARS and triacylglycerol-reducing effects of naringin added to fish oil enriched concentrate for fattening lambs are reported.     

Intracerebroventricular administration of PD 140.548 N-methyl-D-glucamine attenuates the release of cortisol and catecholamines induced by duodenal distension in the sheep

The aim of this study was to determine the influence of mechanically induced duodenal distension (DD) and PD 140.548 N-methyl-D-glucamine (a specific peptide antagonist of a CCK1 receptor) premedication on mechanographical reticulo-ruminal activity, animal general behaviour, catecholamines (CA) and the blood plasma cortisol levels, as well as the clinical symptoms of visceral pain induced by DD in sheep. After 24 h fasting, 6 animals, Polish merino sheep were praeanaesthetised by i.m. injection of ketamine (20 mg x kg(-1) b.w.) and anaesthetised with i.v. infusion of pentobarbital (20 mg x kg(-1) b.w.) and a permanent stainless steel cannula (gate cannula) was inserted inside the lateral cerebral ventricle (controlled by cerebrospinal fluid efflux) 10 mm above the bregma and 5 mm laterally from the midline suture using stereotaxic method. Under the same general anaesthesia and analgesia a T-shaped silicon cannula, was inserted into the duodenum (12 cm from pylorus) and a second one was inserted into the dorsal sac of the rumen. During 7 consecutive days after surgery each animal was treated i.m. with procaine penicillin (300000 I.U..kg(-1) b.w.), dihydrostreptomycine (DHS, 10 microg x kg(-1) b.w.), prednisolone acetate 1.2 mg x kg(-1) b.w.) together and i.m. injection of ketamine (20 mg x kg(-1) b.w.), separetely. The influence of PD 140.548 N-methyl-D-glucamine on the unfavourable effects of duodenal distension using a 10 cm long balloon filled with 40 and 80 ml (DD40 and DD80) water at animal body temperature was investigated in this study. Five minutes DD40 and DD80 caused an immediate and compete inhibition of the reticulo-ruminal frequency, a significant increase in plasma CA and cortisol levels, an increase in the heart rate, hyperventilation and other symptoms of pain, proportionally to the degree of intestinal distension. Intracerebroventricular (i.c.v.) administration of PD 140.548 alone at a dose of 0.25, 0.5, 1 or 2 mg in toto did not significantly change the reticulo-ruminal motility, CA and cortisol concentrations, but 10 min after the i.c.v. infusion (or 10 min before DD) at a dose 1 and 2 mg in toto , it completely blocked the increase of blood plasma cortisol, epinephrine (E), norepinephrine (NE) and dopamine (DA) concentrations for 20 min. In the some time it prevented the reticulo-ruminal atony provocked by DD. It is concluded that PD 140.548 N-methyl-D-glucamine--an antagonist of the central CCK1 receptor can be an effective analgesic agent in duodenal pain. This action is due to the inhibition of peripheral CCK1 type receptor in the central descending nerve pathway, facilitating pain transmission in sheep perhaps in the hypothalamic-pituitary-adrenal axis.     

Simultaneous infusions of propofol and ketamine in ponies premedicated with detomidine: a pharmacokinetic study

The pharmacokinetics of propofol and ketamine administered together by infusion were investigated in four ponies. Blood propofol and plasma ketamine and norketamine concentrations were measured by high performance liquid chromatography. After premedication with detomidine (20 μg kg⁻¹) anaesthesia was induced with ketamine (2·2 mg kg ⁻¹ intravenously). The trachea was intubated and the ponies were allowed to breathe 100 per cent oxygen. A bolus dose of propofol (0·5 mg kg⁻¹) was then administered intravenously and propofol and ketamine were infused for 60 and 45 minutes, respectively. The average mean infusion rate of propofol was 0·136 mg kg⁻¹ min⁻¹, and the ketamine infusion rate was maintained at 50 μg kg⁻¹ min⁻¹. The mean (SD) elimination half-lives of propofol and ketamine were 69·0 (8·0) and 89·8 (26·7) minutes, the mean volumes of distribution at steady state were 0·894 (0·161) litre kg⁻¹ and 1·432 (0·324) litre kg⁻¹ the mean body clearances were 33·1 (4·5) and 23·9 (3·8) ml kg⁻¹ min⁻¹ and the mean residence times for the infusion were 87·1 (4·1) and 110·7 (8·2) minutes, respectively. Norketamine, the main metabolite of ketamine, was detected throughout the sampling period. The mean residence time for norketamine was 144 (16) minutes. All the ponies recovered quickly from the anaesthesia; the mean times to sternal recumbency and standing were 11·1 (5·3) and 30·0 (20·8) minutes, respectively, from the end of the infusion.     

Characteristics of prolactin-releasing response to salsolinol (SAL) and thyrotropin-releasing hormone (TRH) in ruminants

The secretion of prolactin (PRL) is stimulated by thyrotropin-releasing hormone (TRH), and inhibited by dopamine (DA). However, we have recently demonstrated that salsolinol (SAL), a DA-derived endogenous compound, is able to stimulate the release of PRL in ruminants. The aims of the present study were to compare the characteristics of the PRL-releasing response to SAL and TRH, and examine the relation between the effects that SAL and DA exert on the secretion of PRL in ruminants in vivo and in vitro. Three consecutive intravenous (i.v.) injections of SAL (5 mg/kg body weight (b.w.): 19.2 μmol/kg b.w.) or TRH (1 μg/kg b.w.: 2.8 nmol/kg b.w.) at 2-h intervals increased plasma PRL levels after each injection in goats (P < 0.05); however, the responses to SAL were different from those to TRH. There were no significant differences in each peak value between the groups. The rate of decrease in PRL levels following the peak was attenuated in SAL-treated compare to TRH-treated animals (P < 0.05). PRL-releasing responses to SAL were similar to those to sulpiride (a DA receptor antagonist, 0.1 mg/kg b.w.: 293.3 nmol/kg b.w.). In cultured bovine anterior pituitary (AP) cells, TRH (10⁻⁸ M) significantly increased the release of PRL following both 15- and 30-min incubation periods (P < 0.05), but SAL (10⁻⁶ M) did not increase the release during the same periods. DA (10⁻⁶ M) completely blocked the TRH-induced release of PRL for a 2-h incubation period in the AP cells (P < 0.05). Sulpiride (10⁻⁶ M) reversed this inhibitory effect but SAL (10⁻⁶ M) did not have any influence on the action of DA. These results show that the mechanism(s) by which SAL releases PRL is different from the mechanism of action of TRH. Furthermore, they also show that the secretion of PRL is under the inhibitory control of DA, and SAL does not antagonize the DA receptor's action.     

Nitrogen and phosphorus surpluses on Danish dairy and pig farms in relation to farm characteristics

N and P surpluses per hectare at farm level were determined on 63 private pilot farms with data from 2 to 7 years between 1997 and 2003 (a total of 245 observations). Farms were classified in the following four farm types: Conventional mixed dairy, organic mixed dairy, conventional pig farms (indoor) and conventional pig farms with outdoor sows. Import of nutrients with concentrate and fertilizer was the major input to all conventional farm types. On the organic dairy farms major input was N fixation, but also import of nutrients with concentrate and manure were important inputs. Output from the dairy farms was dominated by nutrients in milk. On pig farms nutrients in meat dominated the output, but also export of nutrients with cash crops and manure were important outputs. Farm type, year and farm within farm type significantly affected both N and P surpluses per hectare. Farm type was the major source of variation in both N and P surpluses. In the period investigated N surplus decreased by 6.5 kg N ha^− 1 yr^− 1 and P surplus decreased by 0.7 kg P ha^− 1 yr^− 1. The N and P surpluses observed on the conventional dairy farms significantly exceeded surpluses observed on the organic dairy farms. At equal number of livestock units (LU) per hectare (1.28 LU ha^− 1) the difference was 43 kg N ha^− 1 and 6 kg P ha^− 1. At equal rates of N or P in manure to fields (147 kg N ha^− 1, 29 kg P ha^− 1, respectively) the difference was 45 kg N ha^− 1 and 4 kg P ha^− 1. Conventional dairy farms and pig farms with sows indoors had equal N and P surpluses at equal rates of N or P in manure to fields. Corrected to the average year (1999.5) the estimated average N and P surpluses showed highest levels on pig farms with outdoor sows (251 kg N ha^− 1, 42 kg P ha^− 1) and lowest levels on organic dairy farms (113 kg N ha^− 1, 7 kg P ha^− 1). Surpluses on the conventional dairy farms were 175 kg N ha^− 1 and 16 kg P ha^− 1 and on the indoor pig farms they were 123 kg N ha^− 1 and 13 kg P ha^− 1. The N and P surpluses observed on Danish conventional mixed dairy farms were comparable with intensive dairy farming systems in other European countries.     

Pharmacokinetics of oxytetracycline after intramuscular administration with lidocaine in sheep, comparison with a conventional formulation

The pharmacokinetic behaviour of oxytetracycline (OTC) was studied in 11 sheep after intravenous and intramuscular administration at a single dosage of 20 mg kg⁻¹ bodyweight. A conventional formulation was injected by the intravenous route and two different preparations were administered by the intramuscular route: a conventional formulation (T-100) and an aqueous solution of OTC with lidocaine (1 per cent) (OTC-Q. The objective was to determine whether there are differences between both formulations in the disposition kinetics of OTC after intramuscular administration to sheep. After intravenous administration of the conventional formulation, plasma oxytetracycline concentrations were best fitted to an open two-compartment model. Mean apparent volume of distribution was 0·77±0·02 litre kg⁻¹ and the harmonic mean half-life was three hours. The OTC transfer process between central and peripheral compartments was fast and that did not influence the elimination process. After intramuscular administrations of both formulations, half-lives were longer than after intravenous administration (mean values of 14·1 and 58·2 hours for T-100 and OTC-L respectively). In both cases, a biphasic absorption, a ‘flip-flop’ model and a complete bioavailability were found. OTC-L provided therapeutic plasma concentrations over 0·5 μg ml⁻¹ (the minimum inhibitory concentration for most susceptible pathogens) for a longer period of time than T-100 (72 hours compared with 36 or 48 hours).     

Effects of 5-azacytidine on lymphocyte-metaphases of Creole cows carrying the rob(1;29)

The Robertsonian translocation rob(1;29) is the most important chromosomal abnormality in cattle. It has been demonstrated that carriers of this chromosomal alteration exhibit reduced fertility due to an early embryonic loss. In the present study we analyzed the effects of DNA methylation inhibitor 5-azacytidine (5-aza-C) on metaphase lymphocytes from Uruguayan Creole cows carrying the rob(1;29). The analysis was focused on the chromatin structure of rob(1;29) comparing it to active and inactive BTAX chromosomes. Lymphocyte cultures were treated with 5-aza-C (1 × 10⁻³ M) for 2 h to analyze regions of chromatin decondensation. A comparative analysis of chromatin decondensation among rob(1;29), active BTAX and inactive BTAX showed significant differences (p = 1.07 × 10⁻⁷). Post-hoc pair-wise comparisons using the Mann-Whitney U-test showed significant differences between rob(1;29) and active BTAX (p = 1.97 × 10⁻⁵) and between the active BTAX and inactive BTAX (p = 2.55 × 10⁻⁷). Nevertheless, rob(1;29) did not show significant differences when compared to inactive BTAX (p = 0.078). Robertsonian translocation rob(1;29) showed a despiralization pattern similar to the inactive X chromosome. Pericentromeric despiralization in rob(1;29) and the inactive X chromosome was similar, with an average value and standard error of 0.75 ± 0.11 and 0.75 ± 0.083, respectively. A single condensed region was observed in the inactive X chromosome, whereas in rob(1;29) two regions of condensation, one proximal to the centromere and another proximal to the telomere were detected. Our results show that rob(1;29) and the inactive X chromosome present instability regions susceptible to 5-aza-C. Further studies will be needed to understand the nature and expression pattern of genes located in chromatin condensed regions of rob(1;29).