Pharmacodynamics and pharmacokinetics of phenylbutazone in calves

Phenylbutazone (PBZ) was administered to six calves intravenously (i.v.) and orally at a dose rate of 4.4 mg/kg in a three-period cross-over study incorporating a placebo treatment to establish its pharmacokinetic and pharmacodynamic properties. Extravascular distribution was determined by measuring penetration into tissue chamber fluid in the absence of stimulation (transudate) and after stimulation of chamber tissue with the mild irritant carrageenan (exudate). PBZ pharmacokinetics after i.v. dosage was characterized by slow clearance (1.29 mL/kg/h), long-terminal half-life (53.4 h), low distribution volume (0.09 L/kg) and low concentrations in plasma of the metabolite oxyphenbutazone (OPBZ), confirming previously published data for adult cattle. After oral dosage bioavailability (F) was 66%. Passage into exudate was slow and limited, and penetration into transudate was even slower and more limited; area under curve values for plasma, exudate and transudate after i.v. dosage were 3604, 1117 and 766 microg h/mL and corresponding values after oral dosage were 2435, 647 and 486 microg h/mL. These concentrations were approximately 15-20 (plasma) and nine (exudate) times greater than those previously reported in horses (receiving the same dose rate of PBZ). In the horse, the lower concentrations had produced marked inhibition of eicosanoid synthesis and suppressed the inflammatory response. The higher concentrations in calves were insufficient to inhibit significantly exudate prostaglandin E2 (PGE2), leukotriene B4 (LTB4) and beta-glucuronidase concentrations and exudate leucocyte numbers, serum thromboxane B2 (TxB2), and bradykinin-induced skin swelling. These differences from the horse might be the result of: (a) the presence in equine biological fluids of higher concentrations than in calves of the active PBZ metabolite, OPBZ; (b) a greater degree of binding of PBZ to plasma protein in calves; (c) species differences in the sensitivity to PBZ of the cyclo-oxygenase (COX) isoenzymes, COX-1 and COX-2 or; (d) a combination of these factors. To achieve clinical efficacy with single doses of PBZ in calves, higher dosages than 4.4 mg/kg will be probably required.     

Simultaneous and minimally invasive assessment of muscle tolerance and bioavailability of different volumes of an intramuscular formulation in the same animals

Evaluation of skeletal muscle tolerance during development of new drug formulations for i.m. use is most often based on terminal methods performed in the target species after slaughtering. The objective of this study was to evaluate the effect of muscle damage on the pharmacokinetic parameters of the drug delivered into the muscle using an alternative, noninvasive method. Phenylbutazone (PBZ) was used as the test article. Six ewes received increasing volumes of a 20% PBZ i.m. formulation, according to a cross-over design, and an i.v. bolus of the same formulation. Serial blood samples were taken, and a pharmacokinetic analysis of the plasma activity of creatine kinase and plasma PBZ concentrations was carried out. The amount of muscle damage after i.m. administration of 2, 4, or 8 mL of PBZ, calculated from the area under the curve of plasma creatine kinase across time was 36, 76, and 178 g for a 70-kg ewe. The corresponding absolute bioavailability of PBZ was 100 +/- 32%, 96 +/- 19%, and 100 +/- 17%, and the maximal PBZ concentrations were 42 +/- 3.4, 74 +/- 8.8, and 119 +/- 18.2 microg/mL. The plasma clearance of PBZ (i.v.) was 4.2 +/- 0.94 mL.kg(-1).h(-1). In conclusion, the absolute bioavailability of PBZ after i.m. administration was not altered by the increased volume of formulation administered despite the overall increase in the extent of muscle damage.     

Multicentre,controlled, randomised and blinded field study comparing efficacy of suxibuzone and phenylbutazone in lame horses

Reasons for performing study: In horses, it has been demonstrated that suxibuzone (SBZ) has a lower gastric ulcerogenic effect than phenylbutazone (PBZ). However, no field trials have been reported comparing the efficacy of the drugs in alleviating lameness. Objectives: To compare the therapeutic effect of SBZ to that of PBZ when administered orally in lame horses. Acceptability of both products was also compared. Methods: Lame horses (n = 155) were used in a multicentre, controlled, randomised and double‐blinded clinical trial. Horses were treated orally with either SBZ or PBZ at equivalent therapeutic dosages. PBZ was given to 79 horses at a dose of 4.4 mg/kg bwt/12 h for 2 days, followed by 2.2 mg/kg bwt/12 h for 6 days. SBZ was given to 76 horses at 6.6 mg/kg bwt/12 h for 2 days, followed by 3.3 mg/kg bwt/12 h for 6 days. Efficacy of treatments was evaluated by clinicians in equine practices according to lameness progression throughout the study. Product ingestion was checked daily to evaluate product acceptability. Results: Although SBZ showed a statistically significant tendency to have a better efficacy than PBZ (Odds ratio = 2.7; P = 0.016), significance dissipated once the analysis was adjusted for some imbalanced baseline covariates, confirming that they were actually related to the apparent advantage of SBZ over PBZ. Product acceptability was significantly higher in the SBZ group than in the PBZ group (96.1% vs. 77.2%; P = 0.001). Conclusions: SBZ and PBZ did not show significant differences in alleviating lameness in horses. However, SBZ had better product acceptability when administered orally with some food. Potential relevance: SBZ is a good therapeutic alternative to PBZ in horses since there is no significant difference in alleviating lameness between the 2 therapies.     

Pharmacokinetic studies of flunixin meglumine and phenylbutazone in plasma,exudate and transudate in sheep

Flunixin meglumine (FM, 1.1 mg/kg) and phenylbutazone (PBZ, 4.4 mg/kg) were administered intravenously (i.v.) as a single dose to eight sheep prepared with subcutaneous (s.c.) tissue-cages in which an acute inflammatory reaction was stimulated with carrageenan. Pharmacokinetics of FM, PBZ and its active metabolite oxyphenbutazone (OPBZ) in plasma, exudate and transudate were investigated. Plasma kinetics showed that FM had an elimination half-life (t_½β) of 2.48 ± 0.12 h and an area under the concentration – time curve (AUC) of 30.61 ± 3.41 μg/mL.h. Elimination of PBZ from plasma was slow (t_½β = 17.92 ± 1.74 h, AUC = 968.04 ± μg/mL.h.). Both FM and PBZ distributed well into exudate and transudate although penetration was slow, indicated by maximal drug concentration (C_max) for FM of 1.82 ± 0.22 μg/mL at 5.50 ± 0.73 h (exudate) and 1.58 ± 0.30 μg/mL at 8.00 h (transudate), and C_max for PBZ of 22.32 ± 1.29 μg/mL at 9.50 ± 0.73 h (exudate) and 22.07 ± 1.57 μg/mL at 11.50 ± 1.92 h (transudate), and a high mean tissue-cage fluids:plasma AUC_last ratio obtained in the FM and PBZ groups (80–98%). These values are higher than previous reports in horses and calves using the same or higher dose rates. Elimination of FM and PBZ from exudate and transudate was slower than from plasma. Consequently the drug concentrations in plasma were initially higher and subsequently lower than in exudate and transudate.     

The protective effects of sucralfate and ranitidine in foals experimentally intoxicated with phenylbutazone.

The effects of sucralfate and ranitidine on the gastrointestinal manifestations of phenylbutazone (PBZ) toxicity in horse foals were determined by complete blood count, serum chemistry profile, and gross and histological necropsy examinations. Twenty-eight, three to four month old Belgian-cross foals were randomly assigned to one of four groups. Phenylbutazone was administered at a dosage of 10 mg/kg of bodyweight (BW) per day, intravenously (IV), in equally divided doses to three of the groups. In addition to PBZ, ranitidine was administered at 2 mg/kg BW, IV, twice daily, to one group of seven foals (PBZ/ranitidine group), and sucralfate was administered at 4 g, orally, twice daily to another group of seven foals (PBZ/sucralfate group). A fourth group received normal saline IV and corn syrup orally, twice daily, as placebos (control group). Treatments were administered for ten days. Clinical signs included oral ulceration (in all PBZ-treated foals) and diarrhea (5/7 and 2/7 foals from the PBZ and PBZ/ranitidine groups, respectively). A reduction in total protein and albumin was greatest in the PBZ group and least in the PBZ/ranitidine and PBZ/sucralfate groups when compared to the control group. The PBZ group lost weight during the treatment period. At necropsy, the PBZ group had the greatest area of oral ulceration compared to the other treatment groups. All foals treated with PBZ had gastric ulcers; however, the PBZ group had the most severe gastric epithelial necrosis compared to the other three treatment groups. Duodenal villous atrophy, epithelial necrosis and mucosal inflammation, and a reduction in epithelial mitotic figures were seen in all PBZ-treated foals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics and bioequivalence of two suxibuzone oral dosage forms in horses

A disposition and bioequivalence study with a suxibuzone granulated and a suxibuzone paste oral formulation was performed in horses. Suxibuzone (SBZ) is a nonsteroidal anti-inflammatory drug, which was administered to horses (n = 6) at a dosage of 19 mg/kg bwt by the oral route (p.o.) in a two period cross-over design. Suxibuzone is very rapidly transformed into its main active metabolites, phenylbutazone (PBZ) and oxyphenbutazone (OPBZ). Therefore plasma and synovial fluid concentrations of SBZ, PBZ and OPBZ were simultaneously measured by a sensitive and specific high-performance liquid chromatographic method. The pharmacokinetic parameters were determined by noncompartmental analysis. Suxibuzone could not be detected in any plasma and synovial fluid samples (< 0.04 microgram/mL). Plasma PBZ and OPBZ concentrations were detected between 30 min and 72 h after granulate and paste administration. Mean plasma concentration of PBZ peaked at 5 h (34.5 +/- 6.7 micrograms/mL) and at 7 h (38.8 +/- 8.4 micrograms/mL), and mean area under the concentration-time curve (AUC0-->LOQ) was 608.0 +/- 162.2 micrograms.h/mL and 656.6 +/- 149.7 micrograms.h/mL after granulate and paste administration, respectively. Mean plasma concentration of OPBZ increased to 5-6.7 micrograms/mL, with the maximum concentration (Cmax) appearing between 9 and 12 h after administration of both formulations. The AUCs0-->LOQ for OPBZ were also similar (141.8 +/- 48.3 micrograms.h/mL granulate vs. 171.4 +/- 45.0 micrograms.h/mL paste). It was concluded that the suxibuzone products were bioequivalent with respect to PBZ. For OPBZ, the 95% confidence intervals of the pharmacokinetic parameters were within the acceptable range of 80-125%. The paste formulation provided greater bioavailability of PBZ and OPBZ.     

Plasma progesterone concentration in beef heifers receiving exogenous glucose, insulin, or bovine somatotropin

Three experiments were conducted to evaluate plasma concentrations of glucose, insulin, IGF-I, and progesterone (P4) in pubertal beef heifers receiving exogenous glucose, insulin, or sometribove zinc. All heifers used had no luteal P4 synthesis but received a controlled internal drug-releasing device containing 1.38 g of P4 to estimate treatment effects on hepatic P4 degradation. In Exp. 1, 8 pubertal, nulliparous Angus × Hereford heifers (initial BW = 442 ± 14 kg; initial age = 656 ± 7 d) were randomly assigned to receive, in a crossover design containing 2 periods of 10 h, intravenous (i.v.) infusions (10 mL) of insulin (1 μg/kg of BW; INS) or saline (0.9%; SAL). Treatments were administered via jugular venipuncture in 7 applications (0.15 μg insulin/kg BW per application) 45 min apart (from 0 to 270 min). Blood samples were collected immediately before each infusion as well as at -120, -60, 330, 390, and 450 min relative to the first infusion. Heifers receiving INS had greater (P < 0.01) plasma insulin, reduced (P ≤ 0.04) plasma glucose and IGF-I, and similar (P = 0.62) plasma P4 concentrations compared with SAL heifers. In Exp. 2, the same heifers were assigned to receive, in a similar experimental design as Exp. 1, i.v. infusions (10 mL) of 1) insulin (1 μg/kg BW) and glucose (0.5 g/kg BW; INS+G) or 2) SAL. Heifers receiving INS+G had greater (P ≤ 0.02) plasma insulin, glucose, and P4 but reduced (P = 0.01) plasma IGF-I concentrations compared with SAL heifers. In Exp. 3, the same heifers were assigned to receive, in a crossover design containing 2 periods of 14 d, subcutaneous (s.c.) injections of 1) 250 mg of sometribove zinc (BST) or 2) SAL. Blood samples were collected 3 h apart (0900, 1200, 1500, and 1800 h) from heifers on d 6, 8, and 10 relative to treatment administration (d 1). Heifers receiving BST had greater (P < 0.01) plasma glucose and IGF-I and similar (P ≥ 0.67) plasma insulin and P4 concentrations compared with SAL heifers. Results from this series of experiments suggested that concurrent increases in glucose and insulin are required to reduce hepatic catabolism and increase plasma concentrations of P4 in bovine females.     

Interaction between salsolinol (SAL) and thyrotropin-releasing hormone (TRH) or dopamine (DA) on the secretion of prolactin in ruminants

We have recently demonstrated that salsolinol (SAL), a dopamine (DA)-derived compound, is present in the posterior pituitary gland and is able to stimulate the release of prolactin (PRL) in ruminants. The aim of the present study was to clarify the effect that the interaction of SAL with thyrotropin-releasing hormone (TRH) or DA has on the secretion of PRL in ruminants. A single intravenous (i.v.) injection of SAL (5mg/kg body weight (b.w.)), TRH (1microg/kg b.w.), and SAL plus TRH significantly stimulated the release of PRL in goats (P<0.05). The cumulative response curve (area under the curve: AUC) during 120min was 1.53 and 1.47 times greater after the injection of SAL plus TRH than either SAL or TRH alone, respectively (P<0.05). A single i.v. injection of sulpiride (a DA receptor antagonist, 0.1mg/kg b.w.), sulpiride plus SAL (5mg/kg b.w.), and sulpiride plus TRH (1microg/kg b.w.) significantly stimulated the release of PRL in goats (P<0.05). The AUC of PRL during 120min was 2.12 and 1.78 times greater after the injection of sulpiride plus TRH than either sulpiride alone or sulpiride plus SAL, respectively (P<0.05). In cultured bovine anterior pituitary (AP) cells, SAL (10(-6)M), TRH (10(-8)M), and SAL plus TRH significantly increased the release of PRL (P<0.05), but the additive effect of SAL and TRH detected in vivo was not observed in vitro. In contrast, DA (10(-6)M) inhibited the TRH-, as well as SAL-induced PRL release in vitro. All together, these results clearly show that SAL can stimulate the release of PRL in ruminants. Furthermore, they also demonstrate that the additive effect of SAL and TRH on the release of PRL detected in vivo may not be mediated at the level of the AP, but that DA can overcome their releasing activity both in vivo and in vitro, confirming the dominant role of DA in the inhibitory regulation of PRL secretion in ruminants.     

The disposition of suxibuzone in the horse

A high performance liquid chromatographic method is described to determine the anti-inflammatory drug suxibuzone (SXB) and its major metabolites phenylbutazone (PBZ) and oxyphenbutazone (OPBZ) in equine plasma and urine. When suxibuzone (6 mg/kg) was administered intravenously (i.v.) or orally (p.o.) no parent drug was detected in plasma or in urine. The disposition of the metabolite PBZ (i.v.) could be described by a 2 compartment model with a P half-life varying from 7.40 to 8.35 h. Due to severe side effects the use of i.v. suxibuzone should not be encouraged in the horse. PBZ and OPBZ were detected in plasma and urine after p.o. SXB administration. Peak plasma PBZ concentrations (8.8 ± 3.0 μg/ml) occurred 6 h after oral dosing and the terminal exponential constant was 0.11 ± 0.01 h^-1. Phenylbutazone and oxyphenbutazone were detectable in urine (> 1 μg/ml) for at least 36 h, after p.o. administration.
SXB was not hydrolyzed in vitro by horse plasma. Equine liver homogenates however appeared to have a very high capacity for hydrolysing SXB, indicating that first-pass effect could be responsible for the rapid disappearance of this NSAID in the horse.     

Disposition and tolerance of suxibuzone in horses.

Suxibuzone (SBZ), a nonsteroidal anti-inflammatory drug, was administered to 6 horses at a dose rate of 7.5 mg/kg bwt by intravenous (i.v.) route. Plasma and synovial fluid concentrations of suxibuzone and its main active metabolites, phenylbutazone (PBZ) and oxyphenbutazone (OPBZ), were measured simultaneously by a sensitive and specific high-performance liquid chromatographic method. The pharmacokinetic parameters were determined by noncompartmental analysis. Plasma SBZ concentrations rapidly decreased and were not detectable beyond 20 min after treatment. The parent drug was not detected in any synovial fluid samples. Average maximum plasma concentrations of PBZ (16.43 microg/ml) and OPBZ (2.37 microg/ml) were attained at 0.76 and 7.17 h, respectively. The mean residence time (MRT) of PBZ was 6.96 h in plasma. Oxyphenbutazone plasma concentrations were below those reached by phenylbutazone during the first 12 h after suxibuzone administration, even though its values were detectable for at least 24 h (MRT = 10.65 h). Plasma concentrations of PBZ and OPBZ exceeding EC50 and IC50 of TXB2 and PGE2 were reached by at least 12 h. Synovial fluid concentrations of PBZ and OPBZ were 2.87+/-0.37 microg/ml and 0.97+/-0.08 microg/ml at 9 h after suxibuzone administration and exceeded IC50 of PGE2 for at least this time. In the present study, suxibuzone was well tolerated following i.v. injection.     

Salsolinol is present in the bovine posterior pituitary gland and stimulates the release of prolactin both in vivo and in vitro in ruminants

The aims of the present study were to determine whether salsolinol (SAL), a dopamine-related compound, is present in the bovine posterior pituitary (PP) gland, and to clarify the effect of SAL on the secretion of prolactin (PRL) in ruminants. SAL was detected in extract of bovine PP gland using high-pressure liquid chromatography with electrochemical detection (HPLC-EC). A single intravenous (i.v.) injection of SAL (5 and 10mg/kg body weight) significantly and dose-dependently stimulated the release of PRL in goats (P<0.05). Plasma PRL levels reached a peak 10min after the injection, then gradually returned to basal values in 60-80min. The PRL-releasing pattern was similar to that in response to sulpiride (a dopamine receptor antagonist). The intracerebroventricular (i.c.v.) injection of 1mg of SAL had no significant effect on the release of PRL in calves, however, 5mg significantly stimulated the release (P<0.05) with peak values reached 30-40min after the injection. Moreover, SAL significantly stimulated the release of PRL from cultured bovine anterior pituitary cells at doses of 10(-6) and 10(-5)M, compared to control cells (P<0.05). Taken together, our data clearly show that SAL is present in extract of the PP gland of ruminants, and has PRL-releasing activity both in vivo and in vitro. Therefore, this endogenous compound is a strong candidate for the factor having PRL-releasing activity that has been previously detected in extract of the bovine PP gland.     

A non-invasive and quantitative method for the study of tissue injury caused by intramuscular injection of drugs in horses

The present study was undertaken to measure the weight of muscle destroyed by an intramuscular injection of phenylbutazone (PBZ) in horses. In six horses, CK disposition parameters were evaluated after intravenous (i.v.) and intramuscular (i.m.) administration of a CK horse preparation. The same horses received PBZ, a potentially irritating agent, by l.v. and i.m. (neck and hindquarter) routes. Data were analysed using compartmental approaches and instantaneous CK flux was calculated using a discrete deconvolution method. For a 150 U/kg CK dose, the steady-state volume of distribution was 0.050 ± 0.0115 L/kg and the plasma half-life was 112 ± 18 min. After CK i.m. administration, the half-life of the terminal phase was 11.8 ± 5.3 h indicating a flip-flop process and the mean bioavailability of CK was close to 100%. After PBZ i.m. administration, the CK activity was significantly increased with peak values of 508 ± 109 U/L after the neck administration and 873 ± 365 U/L after the gluteal administration. By measuring the total amount of CK released from injured muscle, it was calculated that an equivalent of 0.044 ± 0.029 g/kg of muscle was destroyed after PBZ administration in the neck. The corresponding figure was 0.118 ± 0.048 g/kg after intragluteal PBZ administration. By deconvoluting plasma CK activity, it was shown that the CK entry rate was maximum for the first 30–60 min following PBZ administration, which then decreased slowly to return to the control value after a delay of 24–48 h after PBZ administration. It was concluded that the CK release pattern following a controlled muscular damage was a non-invasive approach useful for quantifying the amount of damaged muscle, and that the calculation of CK input rate by deconvolution was of potential interest in describing events at the muscle cell level.     

Attenuation of acute plasma cortisol response in calves following intravenous sodium salicylate administration prior to castration

Pain associated with castration in cattle is an animal welfare concern in beef production. This study examined the effect of oral aspirin and intravenous (i.v.) sodium salicylate on acute plasma cortisol response following surgical castration. Twenty bulls, randomly assigned to the following groups, (i) uncastrated, untreated controls, (ii) castrated, untreated controls, (iii) 50 mg/kg sodium salicylate i.v. precastration and (iv) 50 mg/kg aspirin (acetylsalicylic acid) per os precastration, were blood sampled at 3, 10, 20, 30, 40, 50 min and 1, 1.5, 2, 4, 6, 8, 10 and 12 h postcastration. Samples were analyzed by competitive chemiluminescent immunoassay and fluorescence polarization immunoassay for cortisol and salicylate, respectively. Data were analyzed using noncompartmental analysis, a simple cosine model, anova and t -tests. Intravenous salicylate V _d(ss) was 0.18 L/kg, Cl _B was 3.36 mL/min/kg and t _{1/2 λ} was 0.63 h. Plasma salicylate concentrations above 25  μ g/mL coincided with significant attenuation in peak cortisol concentrations ( P  = 0.029). Peak salicylate concentrations following oral aspirin administration was <10  μ g/mL and failed to attenuate cortisol response. Once salicylate concentrations decreased below 5  μ g/mL, cortisol response in the castrated groups was significantly higher than uncastrated controls ( P  = 0.018). These findings have implications for designing drug regimens to provide analgesia during routine animal husbandry procedures.     

Predictive factors and the effect of phenoxybenzamine on outcome in dogs undergoing adrenalectomy for pheochromocytoma

BACKGROUND: Some studies in dogs undergoing adrenalectomy for pheochromocytoma suggest that anesthetic complications and perioperative mortality are common. In humans, surgical outcome has improved with the use of phenoxybenzamine (PBZ) before adrenalectomy. HYPOTHESIS: Dogs treated with PBZ before adrenalectomy have increased survival compared with untreated dogs. ANIMALS: Forty-eight dogs that underwent adrenalectomy for pheochromocytoma. METHODS: A retrospective medical record review for dogs that underwent adrenalectomy for pheochromocytoma at a veterinary medical teaching hospital over the period from January 1986 through December 2005. RESULTS: Twenty-three of 48 dogs were pretreated with PBZ (median dosage: 0.6 mg/kg PO q12h) for a median duration of 20 days before adrenalectomy. Duration of anesthesia and surgery, percentage of dogs with pheochromocytoma involving the right versus left adrenal gland, size of tumor, and presence of vascular invasion were similar for PBZ-treated and untreated dogs. Thirty-three (69%) of 48 dogs survived adrenalectomy in the perioperative period. PBZ-treated dogs had a significantly (P = .014) decreased mortality rate compared with untreated dogs (13 versus 48%, respectively). Additional significant prognostic factors for improved survival included younger age (P = .028), lack of intraoperative arrhythmias (P = .0075), and decreased surgical time (P = .0089). CONCLUSIONS AND CLINICAL IMPORTANCE: Results from this retrospective study support treatment with PBZ before surgical removal of pheochromocytoma in dogs.     

Pharmacokinetics of intravenous and intramuscular buprenorphine in the horse

The purpose of this study was to determine the pharmacokinetics of buprenorphine following intravenous (i.v.) and intramuscular (i.m.) administration in horses. Six horses received i.v. or i.m. buprenorphine (0.005 mg/kg) in a randomized, crossover design. Plasma samples were collected at predetermined times and horses were monitored for adverse reactions. Buprenorphine concentrations were measured using ultra-performance liquid chromatography with electrospray ionization mass spectrometry. Following i.v. administration, clearance was 7.97±5.16 mL/kg/min, and half-life (T(1/2)) was 3.58 h (harmonic mean). Volume of distribution was 3.01±1.69 L/kg. Following i.m. administration, maximum concentration (C(max)) was 1.74±0.09 ng/mL, which was significantly lower than the highest measured concentration (4.34±1.22 ng/mL) after i.v. administration (P<0.001). Time to C(max) was 0.9±0.69 h and T(1/2) was 4.24 h. Bioavailability was variable (51-88%). Several horses showed signs of excitement. Gut sounds were decreased 10±2.19 and 8.67±1.63 h in the i.v. and i.m. group, respectively. Buprenorphine has a moderate T(1/2) in the horse and was detected at concentrations expected to be therapeutic in other species after i.v. and i.m. administration of 0.005 mg/kg. Signs of excitement and gastrointestinal stasis may be noted.     

Pharmacokinetics and metabolism of ketoprofen after intravenous and intramuscular administration in camels

The pharmacokinetics of ketoprofen were determined after an intravenous (i.v.) and intramuscular (i.m.) dose of 2.0 mg/kg body weight in five camels (Camelus dromedarius) using gas chromatography/mass spectrometry (GC/MS). The data obtained (median and range) following i.v. administration was as follows: the elimination half-life (t(1/2beta)) was 4.16 (2.65-4.29) h, the steady state volume of distribution (Vss) was 130.2 (103.4-165.3) mL/kg, volume of distribution (area method) (Vd(area)) was 321.5 (211.4-371.0) mL/kg, total body clearance (Cl) was 1.00 (0.88-1.08) mL/min x kg and renal clearance was 0.01 (0.003-0.033) mL/min x kg. Following i.m. administration, the drug was rapidly absorbed with peak serum concentration of 12.2 (4.80-14.4) microg/mL at 1.50 (1.00-2.00) h. The systemic availability of ketoprofen was complete. The apparent half-life was 3.28 (2.56-4.14) h. A hydroxylated metabolite of ketoprofen was identified by (GC/MS) under electron impact (EI) and chemical ionization (CI) scan modes. The detection times for ketoprofen and hydroxy ketoprofen in urine after an intravenous (i.v.) dose of 3.0 mg/kg body weight was 24.00 and 70.00 h, respectively. Serum protein binding of ketoprofen at 20 microg/mL was extensive; (99.1+/-0.15%).     

Long-term feed intake regulation in sheep is mediated by opioid receptors

These experiments were conducted to determine if 1) syndyphalin-33 (SD33), a mu-opioid receptor ligand, affects feed intake; 2) SD33 effects on feed intake are mediated by actions on opioid receptors; and 3) its activity can counteract the reduction in feed intake associated with administration of bacterial endotoxin. In Exp. 1, 5 mixed-breed, castrate male sheep were housed indoors in individual pens. Animals had ad libitum access to water and concentrate feed. Saline (SAL; 0.9% NaCl) or SD33 (0.05 or 0.1 micromol/kg of BW) was injected i.v., and feed intake was determined at 2, 4, 6, 8, 24, and 48 h after the i.v. injections. Both doses of SD33 increased (at least P < 0.01) feed intake at 48 h relative to saline. In Exp. 2, SAL + SAL, SAL + SD33 (0.1 micromol/kg of BW), naloxone (NAL; 1 mg/kg of BW) + SAL, and NAL + SD33 were injected i.v. Food intake was determined as in Exp. 1. The SAL + SD33 treatment increased (P = 0.022) feed intake at 48 h relative to SAL + SAL. The NAL + SAL treatment reduced (at least P < 0.01) feed intake at 4, 6, 8, 24, and 48 h, whereas the combination of NAL and SD33 did not reduce feed intake at 24 (P = 0.969) or 48 h (P = 0.076) relative to the saline-treated sheep. In Exp. 3, sheep received 1 of 4 treatments: SAL + SAL, SAL + 0.1 micromol of SD33/kg of BW, 0.1 microg of lipopolysaccharide (LPS)/kg of BW + SAL, or LPS + SD33, and feed intake was monitored as in Exp. 1. Lipopolysaccharide suppressed cumulative feed intake for 48 h (P < 0.01) relative to saline control, but SD33 failed to reverse the reduction in feed intake during this period. These data indicate that SD33 increases feed intake in sheep after i.v. injection, and its effects are mediated via opioid receptors. However, the LPS-induced suppression in feed intake cannot be overcome by the opioid receptor ligand, SD33.     

Characteristics of prolactin-releasing response to salsolinol in vivo in cattle

The aims of the present study were to clarify the effect of salsolinol (SAL), a dopamine (DA)-derived endogenous compound, on the secretion of prolactin (PRL) in cattle. The experiments were performed from April to June using calves and cows. A single intravenous (i.v.) injection of SAL (5 mg/kg body weight [BW]) or sulpiride (a DA receptor antagonist, 0.1 mg/kg BW) significantly stimulated the release of PRL in male and female calves (P < 0.05), though the response to SAL was smaller than that to sulpiride. The secretory pattern of PRL in response to SAL or sulpiride in female calves resembled that in male calves. A single i.v. injection of SAL or sulpiride significantly stimulated the release of PRL in cows (P < 0.05). There was no significant difference in the PRL-releasing response between the SAL- and sulpiride-injected groups in cows. A single intracerebroventricular injection of SAL (10 mg/head) also significantly stimulated the release of PRL in castrated calves (P < 0.05). These results show that SAL is involved in the regulatory process for the secretion of PRL, not only in male and female calves, but also in cows. The results also suggest that the potency of the PRL-releasing response to SAL differs with the physiological status of cattle.     

Ketorolac Is Not More Effective Than Flunixin Meglumine or Phenylbutazone in Reducing Foot Pain in Horses

The objective was to compare the analgesic efficacy of ketorolac tromethamine (KT) and two other nonsteroidal anti-inflammatory drugs (NSAIDs), including flunixin meglumine (FM) and phenylbutazone (PB), using a heart bar shoe (HBS) model of reversible foot lameness in horses. Nine adult horses were used in a blinded, randomized, placebo-controlled crossover study. After induction of left front limb lameness using a modified HBS model, one of three NSAIDs (KT, 2.0 mg/kg IV; FM, 1.1 mg/kg IV; PB, 4.4 mg/kg IV) or saline (placebo) was administered IV as a single dose. Lameness was assessed every 30 minutes for 2 hours, then every hour up to 12 hours using both a lameness grading scale (lameness score; LS) and a body-mounted inertial sensor system (lameness locator; LL). High-performance liquid chromatography and mass spectrometry were used to measure plasma drug concentration at various time points. There was no difference in percent reduction of LS or LL value between KT and any other group, or between FM and placebo. The PB group showed a significantly higher percentage in LS reduction than the placebo and FM groups. The mean percent reduction in LL value was greater for the PB group than that for the placebo and FM groups. Plasma drug concentration was similar among horses for each drug at each time point, with drug concentrations decreasing over time. Thus, variation in plasma drug concentration did not influence lameness reduction for any drug. Ketorolac tromethamine was not superior to FM or PB in reducing lameness using a HBS model.     

Adrenocortical response to ACTH in Angora and Spanish goat wethers.

Angora goats do not cope well with stress compared with goats of other breeds. Our hypothesis that this involves subclinical primary hypoadrenocorticism associated with low cortisol release in response to ACTH stimulation was tested by measuring adrenocortical response (plasma cortisol) in six Spanish (37 +/- 2 kg BW) and six Angora wethers (39 +/- 3 kg BW) under simulated acute and chronic ACTH challenges. In Exp. 1 (acute ACTH challenge), wethers were dosed i.v. with high (2.5 IU/kg BW) or low (.4 IU/kg BW) quantities of ACTH. In Exp. 2 (chronic ACTH challenge), ACTH at the rate of .015 IU/(kg BW x min) or saline (.15 M NaCl) was infused i.v. at 15 mL/h for 6 h. The mean baseline plasma cortisol concentration before ACTH stimulation was similar (P > .05) between Angora and Spanish goats in Exp. 1 (averaged over days) and in Exp. 2. The cortisol concentration response area (ng/ (mL x min) x 10(-3)) above the baseline was similar (P > .05) between Angora and Spanish goats during low (7.6 +/- .5 and 9.0 +/- 1.7, respectively) and high (12.8 +/- 1.0 and 16.0 +/- 1.8, respectively) levels of acute ACTH challenge (Exp. 1) and during chronic ACTH challenge (45.1 +/- 5.9 and 41.8 +/- 7.3, respectively; Exp. 2). In conclusion, these data indicate that, under the conditions of this study, adrenocortical responsiveness to ACTH stimulation is not different between Angora and Spanish goat wethers and, thus, may not contribute to stress susceptibility in Angora goats.