Administration In Sheep Research Articles

Pyridoxalated haemoglobin polyoxyethylene conjugate, a nitric oxide scavenger, decreases dose-limiting hypotension associated with interleukin-2 (IL-2) therapy.

Interleukin-2 (IL-2), a cytokine that induces natural killer cells termed lymphokine-activated killer (LAK) cells, is in use as an anticancer agent. During IL-2 therapy, adverse effects, such as vasodilatation and hypotension, are common. Previous studies suggest that these effects are due to nitric oxide (NO). Therefore a model of IL-2-induced hyperdynamic response in sheep was developed to test the effect of pyridoxalated haemoglobin polyoxyethylene conjugate (PHP; a NO scavenger), which is currently in clinical development for the treatment of shock associated with systemic inflammatory response syndrome. Twelve female sheep were divided into four groups (n =3 per group): sham control (Ringer's lactate solution), PHP alone (20 mg x kg(-1) x h(-1) for 96 h), IL-2 alone (recombinant human IL-2; 1,440,000 units/kg intravenously every 8 h) and a combination of PHP and IL-2. All of the sheep received Ringer's lactate solution to maintain haematocrit at baseline levels. The sheep had free access to food and water. A fall in the mean arterial pressure and systemic vascular resistance index by 20% was observed in the IL-2 group, but not in the PHP+IL-2 group. The fluid requirement to maintain the haematocrit was higher in the IL-2 group (5 ml x kg(-1) x h(-1)) than in the PHP+IL-2 group (4 ml x kg(-1) x h(-1)). The sham group showed no changes in any of the parameters. Scavenging NO by PHP prevented the hyperdynamic reaction induced by IL-2 administration in sheep. This activity of PHP may prevent the early discontinuation of IL-2 therapy that results because of these adverse events.

Safety of chronic intrathecal morphine infusion in a sheep model.

The safety of chronically administered intrathecal morphine has been questioned. Therefore, the authors examined the behavioral and neurologic effects and neurotoxicity of continuous intrathecal morphine administration in sheep. Groups of three sheep were implanted with intrathecal infusion systems for the continuous administration of morphine (3, 6, 9, 12, or 18 mg/day) or saline at a fixed infusion rate of 1.92 ml/day beginning approximately 7 days after implantation. Sheep were examined daily for any changes in behavior or neurologic function. After 28-30 days, the animals were humanely killed. Cerebrospinal fluid samples were collected and analyzed for protein, erythrocytes and leukocytes, and morphine content. The spinal cord and meninges with the catheter in situ was removed en bloc and fixed in formalin for histologic analysis. Unilateral hind-leg gait deficits were observed in two of three animals in each of the 12- and 18-mg/day dose groups. Gross and microscopic evaluation of spinal cord tissue from these animals revealed intradural-extramedullary inflammatory masses that compressed the spinal cord at the catheter-tip and mid-catheter areas. This inflammation was ipsilateral to extremities that exhibited gait deficits and had acute and chronic cellular components. The toxicity of intrathecal morphine seems to be dependent on the amount of morphine infused, although the effects of dose versus concentration cannot be clearly distinguished in this study. Intrathecal morphine doses of 12- 18 mg/day produced inflammatory masses extending from the catheter tip down the length of the catheter within the subarachnoid space. Doses of 6-9 mg/day produced mild-to-moderate inflammation 5 cm cranial to the catheter tip. A dose of 3 mg/day produced no neurotoxicity and spinal histopathologic changes that were equivalent to those observed in the saline-treated animals.

Fetal responses to maternal and intra-amniotic lipopolysaccharide administration in sheep.

A link between intrauterine infection and premature labor is widely accepted, yet the fetal inflammatory responses to such infections are not well understood. Our aim was to use a sheep model in which an inflammatory state was induced by lipopolysaccharide (LPS) administration during pregnancy to the maternal systemic, intra-amniotic or extra-amniotic compartments. Fetal and maternal blood gases and uterine electromyographic activity along with fetal and maternal circulating concentrations of prostaglandins PGE2 and PGFM, cortisol, and interleukin-6 were determined. Maternal systemic LPS treatment resulted in mild maternal hypoxemia, a rise in temperature, greater fetal hypoxemia, and a marked rise in fetal cortisol and PGE2 concentrations that persisted for 48 h. Intra-amniotic administration of LPS at doses higher than those used systemically caused an increase in fetal cortisol and PGE2 concentrations as well as a rise in uterine activity, but these were lesser in magnitude. Extra-amniotic LPS administration caused no overt fetal or maternal inflammatory responses. We conclude that maternal LPS treatment markedly elevated fetal cortisol and PGE2 concentrations. This may be a potential protective mechanism that aids the fetus in the event of premature delivery. The attenuated fetal response to intra-amniotic LPS treatment, despite the much higher dose used, may support a role for the amniotic fluid in protecting the fetus from endotoxin exposure during pregnancy.

Combined effect of sulpiride and light treatment on the onset of cyclicity in anestrous mares

Levosulpiride (LSP) is the (−)-enantiomer of sulpiride and might represent a valid alternative to the current drugs used for the synchronization in small ruminants. The aim of this study was to provide the pharmacokinetic profile of LSP after intravenous (IV), intramuscular (IM) and oral (PO) administration in sheep. Six healthy female sheep underwent a randomized cross over study design with a wash out period of 1 week. Each animal at the completion of the study received 50 mg of LSP by IV, IM and PO administrations. Plasma samples were collected prior and up to 24 h and, after the extraction procedure, samples were analysed by HPLC with spectrofluorometric detection. LSP concentrations were quantifiable until 10 and 8 h after IV and IM administration, respectively. After PO administration plasma concentrations were low and quantified until 4 h in all the animals. Clearance (121.5 ml/Kg) was fast and volume of distribution (241 ml/Kg h) small; half-life was short and very similar after both IV (1.80 h) and IM (1.66 h) administrations. The bioavailability after IM and PO was high (about 70%) and extremely low (about 6%), respectively. IV and IM groups showed a good correlation between AUC and the LSP dose express in mg/Kg, but very low correlation was found for the PO route. In conclusion, PO administration of LSP is not recommended in sheep while IV and IM administration show comparable PK profiles.

Bupivacaine pharmacokinetics and motor blockade following epidural administration of the bupivacaine-sulphobutylether 7-β-cyclodextrin complex in sheep

Bupivacaine pharmacokinetics and motor blockade following epidural administration of the bupivacaine-sulphobutylether 7-β-cyclodextrin complex in sheep

Spray-dryed bupivacaine-loaded microspheres: in vitro evaluation and biopharmaceutics of bupivacaine following brachial plexus administration in sheep

Microspheres could be used as a drug delivery system to prolong the duration of action of bupivacaine and to reduce its systemic absorption leading to high plasma concentrations related to central nervous and cardiovascular toxicity. Bupivacaine-loaded microspheres were made by spray-drying using polylactide-co-glycolide polymers from different sources and with different bupivacaine–polymer ratio. The characterization of microspheres concerned the shape and size, the bupivacaine drug-content (DC) and the cumulative release profiles. We evaluated in sheep the bupivacaine pharmacokinetics: (i) after short intravenous infusion of 75 mg bupivacaine solution; and (ii) following brachial nerve plexus injections of 75 mg bupivacaine solution alone, with the addition of 75 μg epinephrine, with the addition of 150 μg epinephrine and of bupivacaine (750 mg)-loaded microspheres. Release profiles showed a biphasic pattern whatever the DC. After i.v. infusion the mean clearance value was 1.53±0.53 l/min and the mean elimination half-life was 120.5±73.1 min. Following brachial plexus nerve injection, bupivacaine C max were lower than 100 ng/ml following either solution or microspheres administration. Ninety percent of the 75 mg bupivacaine given as a solution were absorbed in 5.8±1.0 h (bupivacaine alone) compared to 24.6±1.2 h following microsphere administration.

In vivo cerebral pharmacokinetics and pharmacodynamics of diazepam and midazolam after short intravenous infusion administration in sheep.

The cerebral pharmacokinetics and pharmacodynamics of midazolam and diazepam were examined in chronically instrumented sheep via measurements of their arterio-venous concentration difference across the brain during and after 2-min i.v. infusions. Diazepam (30 mg) or midazolam (10 mg) were administered on 5 separate occasions to 4 sheep. For both drugs, rapid cerebral uptake occurred during the infusion, which quickly turned to elution in the postinfusion period. However, this process was more rapid for midazolam than diazepam. The cerebral pharmacokinetics of both was better described by a kinetic model with slight membrane limitation rather than flow limitation. For diazepam, the estimated brain:plasma partition coefficient was 2.67, and the first and second compartments filled with half-lives of 2.2 and 0.5 min, respectively. For midazolam, these values were 0.27, 0.26 and 1.34 min, respectively. In a subset of sheep, pulmonary arterial-arterial gradients were too small to measure suggesting limited metabolism and small distribution volumes for both drugs in the lungs. Simultaneous dynamic measurements of cerebral blood flow and algesimetry lagged behind both the arterial and sagittal sinus blood concentrations. The changes in cerebral blood flow were best described by a previously published a dynamic model that incorporated long half-lives for drug dissociation from the benzodiazepine receptor (13.3 and 5.5 min for midazolam and diazepam, respectively). Effect compartment modeling of the cerebral blood flow data showed apparent effect compartment half-lives (t1/2,keo) that were longer than the half-lives of cerebral equilibration.

Effect of dexmedetomidine and medetomidine on isoflurane requirements in sheep undergoing orthopaedic surgery

This study compared the anaesthetic sparing and potential hypoxaemic effects of dexmedetomidine and medetomidine, after intravenous administration in sheep.

Bioavailability of levamisole after intramuscular and oral administration in sheep

Aims. To determine the bioavailability of levamisole in sheep. Methods. Levamisole was administered to three groups of six Merino sheep orally and intramuscularly at three dose levels of 5, 7.5 and 10 mg/kg. There was a washout period of 1 week between treatments. Blood samples were collected by jugular venepuncture and plasma was separated immediately by centrifugation and stored at − 20°C until analysed.The levamisole concentration in plasma was determined by high performance liquid chromatography with a u.v. detection method. Individual plasma levamisole concentration-time data were analysed using the compartmental method. Results. The values obtained for ka, Cmax, tmax and F show a moderate rate and extent of absorption after oral administration of levamisole while, after intramuscular administration, these values demonstrate a high rate and extent of absorption of levamisole. The intramuscular bioavailability was higher than the oral bioavailability (rate of absorption three-fold faster, extent of absorption 25 –33% higher and Cmax two-fold higher). The Friedman test involving dose and route of administration showed that the route of administration affects ka, Cmax, tmax and F; significant differences were found in these parameters. Clinical relevance. On the basis of these data, the recommended routes for the administration of levamisole in sheep are oral for gastro-intestinal nematodiasis and intramuscular for extragastric nematodiasis.

Effect of method of blood sample collection on adrenal activity in farmed red deer and sheep following administration of ACTH

AbstractThe effect of method of blood sample collection (automatic blood sampling equipment (ABSE) v. manual) on cortisol and progesterone concentrations was investigated in 20 farmed red deer hinds and 20 domestic sheep ewes following dexamethasone and exogenous ACTH administration. Ten animals were subjected to either automatic sampling or manual sampling via jugular venipuncture in 1 week, with the treatment groups reversed in the 2nd week. The ABSE was programmed to collect a blood sample, then deliver 2 mg dexamethasone, collect a further blood sample 120 min later and then inject 100 fig ACTH. Thereafter, samples were collected at 15-min intervals during a 2·5 h period (12 samples in total). In the manual injection and sampling treatment, four samples were collected: (1) before dexamethasone administration, (2) before ACTH administration, (3) 60 min after ACTH administration, and (4) 150 min after ACTH administration. The success rate of blood sampling with ABSE was 80%. The overall mean packed cell volume (PCV) from samples collected by ABSE from both hinds and ewes was significantly lower than that from samples collected manually (P < 0·01) and PCV declined with time in manually sampled animals (P < 0·01). Plasma cortisol concentrations peaked at 45 min after ACTH administration in sheep and deer. In sheep, there was a marked fluctuation in the plasma cortisol concentrations with time. Both deer and sheep showed a reduced cortisol response to ACTH during week 2 irrespective of sampling method suggesting down-regulation of the response to ACTH. Maximum mean plasma progesterone concentration was reached at 15 to 30 min after ACTH administration. No significant differences in cortisol and progesterone responses due to blood sampling method were found in animals receiving prior dexamethasone treatment. This demonstrates that the ABSE has the ability to be used to effectively conduct ACTH stimulation tests without the need to handle the animals during the test.

Tachycardia Alone Fails To Change the Myocardial Pharmacokinetics and Dynamics of Lidocaine, Thiopental, and Verapamil after Intravenous Bolus Administration in Sheep

Previous reports have suggested that tachycardia alone can increase the rate of myocardial uptake of some drugs. As part of a systematic study of the determinants of the myocardial uptake and effects of drugs in critical illness, the effect of tachycardia induced by intracardiac pacing on the myocardial disposition and effects of lidocaine, verapamil, and thiopental were studied in chronically instrumented sheep. For each drug, seven sheep received either 100mg of lidocaine, 10mg of verapamil, or 750mg of thiopental over 2min in unpaced and paced (140 beats/min) states on separate occasions and in random order. Arterial and coronary sinus (effluent from the heart) blood samples were taken at regular intervals for 30min, and the maximum rate of change of left ventricular pressure (LV dP/dtmax) was measured as an index of myocardial contractility. There were no differences between unpaced and paced studies in the time courses of arterial and coronary sinus concentrations, or the time-courses of myocardial contractility and blood flow, after bolus iv injections of these drugs. Tachycardia alone does not appear to influence the myocardial kinetics or dynamics of lipophilic drugs that can rapidly diffuse into the heart.

Chloramphenicol pharmacokinetics after intravenous and intramuscular administration in sheep.

The pharmacokinetics of chloramphenicol were studied after intravenous and intramuscular administration of 50 mg/kg body weight in Merino sheep. After intravenous administration, the drug was rapidly distributed extravascularly with a half-life of 10.5 +/- 8.83 min. Extensive distribution was confirmed by an apparent volume of distribution at steady state (1.5 +/- 0.43 1/kg). The elimination half-life was 3.24 +/- 0.60 h. After intramuscular injection, the absorption half-life was 44.33 +/- 19.21 min with a bioavailability of 65%. A maximum serum concentration of 15.57 +/- 3.95 micrograms/ml was determined 2 h after administration. Serum concentrations above 5 micrograms/ml were maintained for approximately 12 h with an elimination half-life of 5.75 +/- 1.25 h, longer than the half-life obtained after intravenous administration. In conclusion, the intramuscular administration of chloramphenical at a dose rate of 50 mg/kg permitted the maintenance of inhibitory concentrations of the antibiotic for the majority of Salmonella and Pasteurella isolates for at least 12 h.

Influence of intravenous L-carnitine administration in sheep preceding an oral urea drench.

Two experiments were conducted to investigate the effect of i.v. administration of L-carnitine on selected metabolites in sheep and to determine the feasibility of using L-carnitine to ameliorate the deleterious effects of hyperammonemia in sheep. In Exp. 1, i.v. L-carnitine solutions were administered at three levels in a replicated Latin square: 0 (CONT), 6.36 (CAR 1), and 12.72 (CAR 2) mmol L-carnitine/kg x (75) BW using Suffolk ewes (n = 6; average BW 75+/-3 kg). Plasma L-carnitine concentration was increased (P<.05) by treatment (51.9 vs 102.3, and 96.4 micromol/L in CONT, CAR 1, and CAR 2, respectively). Plasma glucose concentration was elevated (P<.05) in CAR 2 and CAR 1. Plasma NEFA concentration was highest (P<.05) in CAR 2. Area under the response curve for glucose was greater (P<.02) in CAR 2. In Exp. 2, Suffolk ewes (n = 16; average BW 48+/-2 kg) were used in a randomized complete block design with a 2x2 factorial treatment arrangement to determine the effects of i.v. L-carnitine administration during an oral urea load test (OULT). L-Carnitine (0 and 6.36 mmol/kg x (75) BW) was administered i.v. at 30 min, and an oral urea drench (50% wt/vol; 0 and 300 mg/kg BW) was administered at 60 min. Plasma L-carnitine was increased (P<.0001) by i.v. L-carnitine. Plasma ammonia N was highest (P<.0001) in the UREA treatment compared with the CONT, CARN, and CARN + UREA treatments (148 vs 95, 101, and 108 micromol/L, respectively). Intravenous L-carnitine administration influenced plasma glucose and NEFA concentrations in sheep and, when administered 30 min preceding an OULT, prevented the development of subclinical hyperammonemia in sheep.

Age‐related differences in norfloxacin pharmacokinetic behaviour following intravenous and oral administration in sheep

Summary The pharmacokinetics of norfloxacin after intravenous (IV) and oral (PO) administration in lambs (n=5) and adult sheep (n=5) were studied. After IV administration (10 mg.kg‐1) plasma concentrations were best fitted by a three‐compartment open model in both age groups. Distribution volumes were significantly larger in lambs (approximate 4.0 fold difference between 4 week old and adult sheep). There was no significant difference (p<0.05) between the groups in terms of elimination half‐life but plasma clearance was significantly higher in lambs. Norfloxacin was poorly absorbed after oral administration (60 mg•kg‐1) in sheep (F=4.04%). Mean oral bioavailavility was 73.51% in lambs (30 mg.kg‐1). Norfloxacin elimination was faster in lambs after oral administration. MRTt was significantly prolonged in both age groups when compared with the respective data for IV administration.

Cerebrospinal fluid distribution of opioids after intraventricular & lumbar subarachnoid administration in sheep.

The study of opioid distribution in blood and cerebrospinal fluid (CSF) is required to understand pharmacokinetic-pharmacodynamic relationships following lumbar intrathecal (it) and intracerebroventicular (i.c.v.) administration, and to investigate the contributions of spinal or supraspinal sites of action. The sheep model developed for pharmacokinetic study of analgesics allows atraumatic sampling of plasma and CSF after drug administration by the intravenous (i.v.), i.c.v., and it routes in an unanesthetized animal. Five adult female sheep were prepared with femoral vascular catheters, lumbar it and epidural cannulae, i.c.v. cannulae, and cisterna magna cannulae. Hydromorphone, methadone, naloxone, and [14C] sucrose were injected and collected by two methods: 1) injection into the i.c.v. cannula with lumbar CSF samples collected via the lumbar cannula and 2) injection into the lumbar cannula and cisternal CSF samples collected via ventriculocisternal cannula. Hydromorphone, morphine, and [14C] sucrose were detected at 90-105 min in lumbar CSF after i.c.v. injection. Hydromorphone and [14C] sucrose were detected in i.c.v. cerebrospinal fluid at 50 min after lumbar i.t. injection. Methadone was not detected in i.c.v. cerebrospinal fluid after i.t. injection, nor was methadone significantly detected in lumbar CSF after i.c.v. injection. These data indicate that i.c.v. and i.t. administration of lipophilic opioids produces CSF distributions different from those of hydrophilic opioids. This suggests that lipophilic opioids such as methadone or naloxone exert their effects predominantly on tissues near the site of injection. The study of i.t. and i.c.v. opiate administration and CSF pharmacokinetics may therefore have direct clinical implications.

Cerebral Effects of Propofol following Bolus Administration in Sheep

The effects of bolus administration of propofol (50 mg, 100 mg and 200 mg) on cerebral blood flow and cerebral metabolic rate for oxygen were examined in a chronically catheterized sheep preparation. Depth of anaesthesia was simultaneously measured using a withdrawal response to a noxious electrical stimulus and it was demonstrated that the 100 mg dose induced moderate sedation while the 200 mg dose induced relatively deep anaesthesia. Propofol caused transient dose-dependent decreases in cerebral blood flow, despite minimal changes in blood pressure. These were accompanied by parallel decreases in cerebral metabolic rate but no change in cerebral oxygen extraction. As cerebrovascular responses in the sheep appear similar to those in man, the parallel changes in cerebral blood flow and metabolic rate demonstrated in this study supports the suitability of propofol as a neuroanaesthetic agent.

Fetal responses to maternal and fetal methamphetamine administration in sheep

OBJECTIVES: The current study was designed to test the hypothesis that maternally administered methamphetamine decreasesfetal Pao 2 by reducing uterine blood flow and to determine the cardiovascular and blood gas responses to varying doses of methamphetamine given both to the fetus and the mother. STUDY DESIGN: Nine near-term pregnant sheep were surgically instrumented to measure maternal and fetal blood pressure and heart rate and uterine and umbilical blood flow. Fetal blood gases and pH were determined before and after each dose of methamphetamine. Methamphetamine was administered as intravenous bolus injections (30 to 35 minutes separating administration of each dose) into the maternal femoral vein in increasing doses of 0.03, 0.1, 0.3, and 1.0 mg/kg and on a separate days to the fetus into the hind limb vein as doses of 0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg estimated fetal weight. RESULTS: Maternal methamphetamine administration produced a dose-related increase in maternal and fetal blood pressure and uterine vascular resistance, whereas uterine blood flow decreased in a dose-related fashion. Umbilical blood flow tended to increase slightly, but this did not reach significance. Fetal Pao 2 decreased significantly, whereas fetal pH decreased only modestly. Direct fetal administration of methamphetamine produced dose-related increases in fetal blood pressure and umbilical blood flow and a significant decrease in fetal pH but no change in fetal Pao 2. CONCLUSIONS: The fetal Pao 2 decrease observed after maternal administration of methamphethamine appears to be a result of decreased uteroplacental perfusion, whereas the observed changes in fetal blood pressure and fetal pH appear to be a result of the direct action of methamphetamine on the fetus.

Pharmacokinetics and Tissue Uptake of D-α-Tocopherol in Sheep Following a Single Intraperitoneal Injection

D-α-Tocopherol in an emulsible base was administered i.p. to four groups of five sheep each at doses of 0, 1250, 2500, and 5000 IU. Blood was sampled regularly until slaughter at 7 d after administration. Plasma and tissue concentrations of D-α-tocopherol were measured by HPLC. Pharmacokinetic analysis of plasma concentrations, for the three tested doses, showed an absence of significant difference for lag time to absorption (.9 to 2.5h), half-time of absorption (15 to 30h), plasma half-life (31 to 42h), and time of maximal concentration (18 to 31h). In contrast, dose had a significant effect on area under the tocopherol plasma curve and on the maximal concentration. For both parameters, statistical evidence indicated nonlinearity for disposition of D-α-tocopherol, but without biological significance; by 7 d after dosing, amounts of residue of tocopherol were highest in the pancreas and adrenal glands (approximately 65 and 47μg/g, respectively, for the 5000 IU dose) and lowest in neck muscle (approximately 4μg/g for the 5000 IU dose). Kidney had an intermediate level of tocopherol. The intraperitoneal route is an efficient route for tocopherol administration in sheep.

Comparative Spinal Neuropathy of Hydromorphone and Morphine after 9-and 30-Day Epidural Administration in Sheep

Comparative Spinal Neuropathy of Hydromorphone and Morphine after 9-and 30-Day Epidural Administration in Sheep

The effect of suppressing bone resorption on Mg metabolism in sheep ( Ovis aries)

The administration of a pyrophosphate analogue, hydroxyethylidene biphosphonate (HEBP), strikingly decreased plasma free hydroxyproline concentration, which suggests that HEBP suppresses bone resorption in sheep. Plasma Mg concentration was not affected by HEBP administration in sheep fed an adequate amount of Mg. HEBP administration stimulated hypomagnesemic and hypomagnesuric effects of Mg restriction. Bone Mg plays an important role in maintaining plasma Mg concentration in sheep fed an inadequate amount of Mg.