Pharmacokinetics of grapiprant,a selective EP4 prostaglandin PGE2 receptor antagonist,after 2 mg/kg oral and i.v. administrations in cats

Drugs that provide effective analgesia in cats are limited. The aim of the study was to assess the pharmacokinetics of grapiprant after 2 mg/kg administration via p.o. and i.v. routes in cats. Six healthy adult cats were used according to an open, single‐dose, two‐treatment, two‐period, randomized cross‐over design. Cats were assigned to two treatment groups and administered with 2 mg/kg of grapiprant (pure powder) through p.o. and i.v. administration. Blood samples were collected at preassigned times and analysed by a validated HPLC method. After both administrations, grapiprant concentrations were detectable in plasma for up to 24 hr in five of six animals. The critical parameters including clearance (173.2 ml hr^?1 kg^?1, range 120–326 ml hr^?1 kg^?1) and volume of distribution (918 ml/kg, range 611–1608 ml/kg) were calculated from the i.v. group. The mean oral F% was low (39.6% range 31.5%–45.2%). If the assumption that the minimal effective concentration in dogs (164 ng/ml) applies in cats too, grapiprant orally administered at 2 mg/kg might be effective for 10 hr. Further studies are necessary to establish the minimal effective concentration in this animal species.     

Pharmacokinetics of cefquinome in red‐eared slider turtles (Trachemys scripta elegans) after single intravenous and intramuscular injections

The purpose of this study was to evaluate the pharmacokinetics of cefquinome (CFQ ) following single intravenous (IV ) or intramuscular (IM ) injections of 2 mg/kg body weight in red‐eared slider turtles. Plasma concentrations of CFQ were determined by high‐performance liquid chromatography and analyzed using noncompartmental methods. The pharmacokinetic parameters following IV injection were as follows: elimination half‐life (t _1/2λz) 21.73 ± 4.95 hr, volume of distribution at steady‐state (V _dss) 0.37 ± 0.11 L/kg, area under the plasma concentration–time curve (AUC _0–∞) 163 ± 32 μg hr^?1 ml^?1, and total body clearance (Cl_T) 12.66 ± 2.51 ml hr^?1 kg^?1. The pharmacokinetic parameters after IM injection were as follows: peak plasma concentration (C _max) 3.94 ± 0.84 μg/ml, time to peak concentration (T _max) 3 hr, t _1/2λz 26.90 ± 4.33 hr, and AUC _0–∞ 145 ± 48 μg hr^?1 ml^?1. The bioavailability after IM injection was 88%. Data suggest that CFQ has a favorable pharmacokinetic profile with a long half‐life and a high bioavailability in red‐eared slider turtles. Further studies are needed to establish a multiple dosage regimen and evaluate clinical efficacy.     

Pharmacokinetics,disposition, and plasma concentrations of dimethyl sulfoxide (DMSO) in the horse following topical,oral, and intravenous administration

Compartmental models were used to investigate the pharmacokinetics of intravenous (i.v. ), oral (p.o. ), and topical (TOP ) administration of dimethyl sulfoxide (DMSO ). The plasma concentration–time curve following a 15‐min i.v. infusion of DMSO was described by a two‐compartment model. Median and range of alpha (t _1/2α) and beta (t _1/2β) half‐lives were 0.029 (0.026–0.093) and 14.1 (6.6–16.4) hr, respectively. Plasma concentration–time curves of DMSO following p.o. and TOP administration were best described by one‐compartment absorption and elimination models. Following the p.o. administration, median absorption (t _1/2ab) and elimination (t _1/2e) half‐lives were 0.15 (0.01–0.77) and 15.5 (8.5–25.2) hr, respectively. The plasma concentrations of DMSO were 47.4–129.9 μg/ml, occurring between 15 min and 4 hr. The fractional absorption (F ) during a 24‐hr period was 47.4 (22.7–98.1)%. Following TOP administrations, the median t _1/2ab and t _1/2e were 1.2 (0.49–2.3) and 4.5 (2.1–11.0) hr, respectively. Plasma concentrations were 1.2–8.2 μg/ml occurring at 2–4 hr. Fractional absorption following TOP administration was 0.48 (0.315–4.4)% of the dose administered. Clearance (Cl) of DMSO following the i.v. administration was 3.2 (2.2–6.7) ml hr^?1 kg^?1. The corrected clearances (Cl_F ) for p.o. and TOP administrations were 2.9 (1.1–5.5) and 4.5 (0.52–18.2) ml hr^?1 kg^?1.     

Pharmacokinetics of intravenous and transdermal fentanyl in alpacas

The purpose of the study was to determine pharmacokinetics of fentanyl after intravenous (i.v.) and transdermal (t.d.) administration to six adult alpacas. Fentanyl was administered i.v. (2 μg/kg) or t.d. (nominal dose: 2 μg kg^?1 hr^?1). Plasma concentrations were determined using liquid chromatography–mass spectrometry. Heart rate and respiratory rate were assessed. Extrapolated, zero‐time plasma fentanyl concentrations were 6.0 ng/ml (1.7–14.6 ng/ml) after i.v. administration, total plasma clearance was 1.10 L hr^?1 kg^?1 (0.75–1.40 L hr^?1 kg^?1), volumes of distribution were 0.30 L/kg (0.10–0.99 L/kg), 1.10 L/kg (0.70–2.96 L/kg) and 1.5 L/kg (0.8–3.5 L/kg) for V₁, V₂, and V_ss, respectively. Elimination half‐life was 1.2 hr (0.5–4.3 hr). Mean residence time (range) after i.v. dosing was 1.30 hr (0.65–4.00 hr). After t.d. fentanyl administration, maximum plasma fentanyl concentration was 1.20 ng/ml (0.72–3.00 ng/ml), which occurred at 25 hr (8–48 hr) after patch placement. The area under the plasma fentanyl concentration‐vs‐time curve (extrapolated to infinity) after t.d. fentanyl was 61 ng*hr/ml (49–93 ng*hr/ml). The dose‐normalized bioavailability of fentanyl from t.d. fentanyl in alpacas was 35.5% (27–64%). Fentanyl absorption from the t.d. fentanyl patch into the central compartment occurred at a rate of approximately 50 μg/hr (29–81 μg/hr) between 8 and 72 hr after patch placement.     

Pharmacokinetics of orbifloxacin in crucian carp (Carassius auratus) after intravenous and intramuscular administration

The pharmacokinetics of orbifloxacin was studied after a single dose (7.5 mg/kg) of intravenous or intramuscular administration to crucian carp (Carassius auratus ) reared in freshwater at 25°C. Plasma samples were collected from six fish per sampling point. Orbifloxacin concentrations were determined by high‐performance liquid chromatography with a 0.02 μg/ml limit of detection, then were subjected to noncompartmental analysis. After intravenous injection, initial concentration of 5.83 μg/ml, apparent elimination rate constant (λ_z) of 0.039 hr^?1, apparent elimination half‐life (T_1/2λz) of 17.90 hr, systemic total body clearance (Cl) of 75.47 ml hr^?1 kg^?1, volume of distribution (Vz) of 1,948.76 ml/kg, and volume of distribution at steady‐state (Vss) of 1,863.97 ml/kg were determined, respectively. While after intramuscular administration, the λ_z, T _1/2λz, mean absorption time (MAT ), absorption half‐life (T _1/2ka), and bioavailability were determined as 0.027 hr^?1, 25.69, 10.26, 7.11 hr, and 96.46%, respectively, while the peak concentration was observed as 3.11 ± 0.06 μg/ml at 2.0 hr. It was shown that orbifloxacin was completely but relatively slowly absorbed, extensively distributed, and slowly eliminated in crucian carp, and an orbifloxacin dosage of 10 mg/kg administered intravenously or intramuscularly would be expected to successfully treat crucian carp infected by strains with MIC values ≤0.5 μg/ml.     

Pharmacokinetics of fentanyl citrate and norfentanyl in Holstein calves and effect of analytical performances on fentanyl parameter estimation

This study describes the pharmacokinetics of intravenously administered (i.v.) fentanyl citrate, and its primary metabolite norfentanyl in Holstein calves. Eight calves (58.6 ± 2.2 kg), aged 3–4 weeks, were administered fentanyl citrate at a single dose of 5.0 μg/kg i.v. Blood samples were collected from 0 to 24 hr. Plasma (nor)fentanyl concentrations were determined using liquid chromatography with mass spectrometry and a lower limit of quantification (LLOQ ) of 0.03 ng/ml. To explore the effect of analytical performance on fentanyl parameter estimation, the noncompartmental pharmacokinetic analysis was then repeated with a hypothetical LLOQ value of 0.05 ng/ml. Terminal elimination half‐life was estimated at 12.7 and 3.6 hr for fentanyl and norfentanyl, respectively. For fentanyl, systemic clearance was estimated at 2.0 L hr^?1 kg^?1, volume of distribution at steady‐state was 24.8 L/kg and extraction ratio was 0.42. At a hypothetical LLOQ of 0.05 ng/ml fentanyl half‐life, volume of distribution at steady‐state and clearance were, respectively, of 3.0 hr, 8.8 L/kg and 3.4 L kg^?1 hr^?1. Fentanyl citrate administered i.v. at 5.0 μg/kg can reach levels associated with analgesia in other species. Pharmacokinetic parameters should be interpreted with respect to LLOQ , as lower limits can influence estimated parameters, such as elimination half‐life or systemic clearance and have significant impact on dosage regimen selection in clinical practice.     

Pharmacokinetics of firocoxib after intravenous administration of multiple consecutive doses in neonatal foals

The purpose of this study was to determine the pharmacokinetic profile of intravenous firocoxib in neonatal foals. Six healthy foals were administered 0.09 mg/kg firocoxib intravenously once a day for 7 days. Blood was collected for plasma firocoxib analysis using high‐performance liquid chromatography with fluorescence detection at times 0 (day 1 of study only) and 0.08, 0.25, 1, 2, 4, 6, 8, 16 and 24 hr on dose numbers 1, 5 and 7. Blood was also collected immediately prior to doses 3, 4, 5 and 7. Final samples were collected at 36, 48, 72 and 96 hr following the final dose. Noncompartmental analysis using the trapezoidal method with linear interpolation revealed a moderate half‐life (15.9 ± 9.1 hr) with a large volume of distribution at steady state (1.79 ± 0.57 L/kg) and a clearance (96.0 ± 59.2 ml h^?1 kg^?1) that was more rapid than that observed in adult horses.     

Disposition of levetiracetam in healthy adult horses

Nine horses received 20 mg/kg of intravenous (LEV_IV ); 30 mg/kg of intragastric, crushed immediate release (LEV_CIR ); and 30 mg/kg of intragastric, crushed extended release (LEV_CER ) levetiracetam, in a three‐way randomized crossover design. Crushed tablets were dissolved in water and administered by nasogastric tube. Serum samples were collected over 48 hr, and levetiracetam concentrations were determined by immunoassay. Mean ± SD peak concentrations for LEV_CIR and LEV_CER were 50.72 ± 10.60 and 53.58 ± 15.94 μg/ml, respectively. The y ‐intercept for IV administration was 64.54 ± 24.99 μg/ml. The terminal half‐life was 6.38 ± 1.97, 7.07 ± 1.93 and 6.22 ± 1.35 hr for LEV_CIR , LEV_{CER ,} and LEV_IV , respectively. Volume of distribution at steady‐state was 630 ± 73.4 ml/kg. Total body clearance after IV administration was 74.40 ± 19.20 ml kg^?1 hr^?1. Bioavailability was 96 ± 10, and 98 ± 13% for LEV_CIR and LEV_CER , respectively. A single dose of Levetiracetam (LEV ) was well tolerated. Based on this study, a recommended dosing regimen of intravenous or oral LEV of 32 mg/kg every 12 hr is likely to achieve and maintain plasma concentrations within the therapeutic range suggested for humans, with optimal kinetics throughout the dosing interval in healthy adult horses. Repeated dosing and pharmacodynamic studies are warranted.     

Pharmacokinetics and antinociceptive effects of the soluble epoxide hydrolase inhibitor t‐TUCB in horses with experimentally induced radiocarpal synovitis

This study determined the pharmacokinetics, antinociceptive, and anti‐inflammatory effects of the soluble epoxide hydrolase (sEH ) inhibitor t ‐TUCB (trans ‐4‐{4‐[3‐(4‐Trifluoromethoxy‐phenyl)‐ureido]‐cyclohexyloxy}‐benzoic acid) in horses with lipopolysaccharide (LPS )‐induced radiocarpal synovitis. A total of seven adult healthy mares (n  = 4–6/treatment) were administered 3 μg LPS into one radiocarpal joint and t ‐TUCB intravenously (i.v.) at 0 (control), 0.03, 0.1, 0.3, and 1 mg/kg in a blinded, randomized, crossover design with at least 3 weeks washout between. Two investigators independently assigned pain scores (at rest, walk and trot) and lameness scores before and up to 48 hr after t ‐TUCB /LPS . Responses to touching the joint skin to assess tactile allodynia, plasma, and synovial fluid (SF ) t ‐TUCB concentrations were determined before and up to 48 hr after t ‐TUCB /LPS . Blood and SF were collected for clinical laboratory evaluations before and up to 48 hr after t ‐TUCB /LPS . Areas under the curves of pain and lameness scores were calculated and compared between control and treatments. Data were analyzed using repeated measures ANOVA with Dunnett or Bonferroni post‐test. p  < .05 was considered significant. Data are mean ± SEM . Compared to control, pain, lameness, and tactile allodynia were significantly lower with 1 mg/kg t ‐TUCB , but not the other doses. For 0.1, 0.3, and 1 mg/kg t ‐TUCB treatments, plasma terminal half‐lives were 13 ± 3, 13 ± 0.5, and 24 ± 5 hr, and clearances were 68 ± 15, 48 ± 5, and 14 ± 1 ml hr^?1 kg^?1. The 1 mg/kg t ‐TUCB reached the SF at high concentrations. There were no important anti‐inflammatory effects. In conclusion, sEH inhibition with t ‐TUCB may provide analgesia in horses with inflammatory joint pain.     

Effects of a constant rate infusion of magnesium sulphate in healthy dogs anaesthetized with isoflurane and undergoing ovariohysterectomy

ObjectiveTo determine the effects of intravenous (IV) magnesium sulphate (MgSO₄) as a bolus followed by a constant rate infusion (CRI) on anaesthetic requirements, neuroendocrine stress response to surgery, haemostasis and postoperative analgesia in healthy dogs undergoing ovariohysterectomy.Study designBlinded randomized clinical trial.AnimalsSixteen female dogs.MethodsAfter intramuscular premedication with acepromazine (0.05 mg kg^?1) and morphine (0.3 mg kg^?1), anaesthesia was induced with diazepam (0.2 mg kg^?1) and propofol (2 mg kg^?1) intravenously and maintained with isoflurane in oxygen in all dogs. Dogs were randomly assigned to two groups, M and C. Group M received MgSO₄ (50 mg kg^?1 over 15 minutes, followed by a 15 mg kg^?1 hour^?1 CRI). Group C received an equivalent bolus and CRI of lactated Ringer's solution. In addition, all dogs received lactated Ringer's solution (10 mL kg^?1 over 15 minutes followed by 10 mL kg^?1 hour^?1). End-tidal isoflurane and carbon dioxide tensions, cardio-respiratory variables, arterial blood gases, electrolytes, ACTH and cortisol concentrations were measured at different time points. Thromboelastography (TEG) was performed pre- and post-anaesthesia. Postoperative pain was evaluated using the short form of the Glasgow Composite Pain Scale. Data were analysed with repeated measures anova and Mann–Whitney U tests (p< 0.05).ResultsNo statistically significant differences between groups were found in any of the measured variables. However, the alpha angle and maximal amplitude recorded by TEG in group M were significantly increased post-anaesthesia, but remained within the reference interval. One dog in Group M and two in Group C received rescue analgesia during recovery.Conclusions and clinical relevanceAs used in this study, MgSO₄ failed to decrease isoflurane requirements, postoperative pain and stress hormone concentrations; however, it did not produce any cardio-respiratory or major haemostatic side effects. Administration of intravenous MgSO₄ together with an opioid during ovariohysterectomy in dogs does not seem to provide any clinical advantage.     

Bayesian population pharmacokinetic modeling of florfenicol in pigs after intravenous and intramuscular administration

Bayesian population pharmacokinetic models of florfenicol in healthy pigs were developed based on retrospective data in pigs either via intravenous (i.v.) or intramuscular (i.m.) administration. Following i.v. administration, the disposition of florfenicol was best described by a two‐compartment open model with the typical values of half‐life at α phase (t _1/2α), half‐life at β phase (t _1/2β), total body clearance (Cl), and volume of distribution (V _d) were 0.132 ± 0.0289, 2.78 ± 0.166 hr, 0.215 ± 0.0102, and 0.841 ± 0.0289 L kg^?1, respectively. The disposition of florfenicol after i.m. administration was best described by a one‐compartment open model. The typical values of maximum concentration of drug in serum (C _max), elimination half‐life (t _1/2Kel), Cl, and Volume (V ) were 5.52 ± 0.605 μg/ml, 9.96 ± 1.12 hr, 0.228 ± 0.0154 L hr^?1 kg^?1, and 3.28 ± 0.402 L/kg, respectively. The between‐subject variabilities of all the parameters after i.m. administration were between 25.1%–92.1%. Florfenicol was well absorbed (94.1%) after i.m. administration. According to Monte Carlo simulation, 8.5 and 6 mg/kg were adequate to exert 90% bactericidal effect against Actinobacillus pleuropneumoniae after i.v. and i.m. administration.     

Postoperative pharmacokinetics of meloxicam in horses after surgery for colic syndrome

NSAID s are often used in horses with colic syndrome during the postoperative period, due to their ability to contrast endotoxemia and to promote an analgesic and anti‐inflammatory effect. As the pharmacokinetics of a drug are often modified in unhealthy animals compared to healthy subjects, the aim of this study was to evaluate the pharmacokinetic profile of meloxicam after i.v. administration in horses undergoing laparotomy for colic syndrome. Eight horses received 0.6 mg/kg of meloxicam i.v. towards the end of surgery. Blood samples were taken at scheduled time points during the following 24 hr. The serum concentration of the drug was determined by HPLC . Terminal half‐life (6.88 ± 2.96 hr), volume of distribution at steady‐state (186.53 ± 61.20 ml/Kg) and clearance (27.91 ± 5.72 ml kg^?1 hr^?1) were similar to those reported in literature for healthy horses. This result suggests that no adjustment of the approved dose should be necessary when meloxicam is used to treat horses in the immediate postoperative period after surgery for colic syndrome.     

Comparison of postoperative effects between lidocaine infusion,meloxicam, and their combination in dogs undergoing ovariohysterectomy

ObjectiveTo compare the postoperative analgesic effects of intravenous (IV) lidocaine, meloxicam, and their combination in dogs undergoing ovariohysterectomy.Study designProspective, randomized, double‐blind, controlled clinical trial.AnimalsTwenty‐seven dogs aged (mean ± SD) 16.1 ± 7.5 months and weighing 22.4 ± 17.9 kg scheduled for ovariohysterectomy.MethodsAnaesthesia was induced with propofol and maintained with isoflurane. Dogs (n = 9 in each group) were allocated to receive just prior to and during surgery one of the following regimens: M group, 0.2 mg kg^?1 IV meloxicam then a continuous rate infusion (CRI) of lactated Ringer's at 10 mL kg^?1 hour^?1; L group, a bolus of lidocaine (1 mg kg^?1 IV) then a CRI of lidocaine at 0.025 mg kg^?1 minute^?1; and M + L group, both the above meloxicam and lidocaine treatments. Pain and sedation were scored, and venous samples taken for serum cortisol and glucose measurement before and at intervals for 12 hours after anaesthesia. Pain scores were assessed using a multi‐parameter subjective scoring scale (cumulative scale 0–21) by three observers. The protocol stated that dogs with a total score exceeding 9 or a sub‐score above 3 in any one category would receive rescue analgesia. Sedation was scored on a scale of 0–4.ResultsThere were no significant differences in subjective pain scores, serum cortisol, and glucose concentrations between the three groups. The highest pain score at any time was 5, and no dog required rescue analgesia. None of the three regimens caused any observable side effects during or after anaesthesia. At 1 and 2 hours after extubation dogs in group L were significantly more sedated than in the other two groups.Conclusions and Clinical relevanceThis study suggests that, with the scoring system used, IV lidocaine and meloxicam provide similar and adequate post‐operative analgesia in healthy dogs undergoing ovariohysterectomy.     

Pharmacokinetics of posaconazole in koalas (Phascolarctos cinereus) after intravenous and oral administration

The pharmacokinetic profile of posaconazole in clinically normal koalas (n = 8) was investigated. Single doses of posaconazole were administered intravenously (i.v.; 3 mg/kg; n = 2) or orally (p.o.; 6 mg/kg; n = 6) with serial plasma samples collected over 24 and 36 hr, respectively. Plasma concentrations of posaconazole were quantified by validated high‐performance liquid chromatography. A noncompartmental pharmacokinetic analysis of data was performed. Following i.v. administration, estimates of the median (range) of plasma clearance (CL) and steady‐state volume of distribution (V_ss) were 0.15 (0.13–0.18) L hr^?1 kg^?1 and 1.23 (0.93–1.53) L/kg, respectively. The median (range) elimination half‐life (t_1/2) after i.v. and p.o. administration was 7.90 (7.62–8.18) and 12.79 (11.22–16.24) hr, respectively. Oral bioavailability varied from 0.43 to 0.99 (median: 0.66). Following oral administration, maximum plasma concentration (C_max; median: 0.72, range: 0.55–0.93 μg/ml) was achieved in 8 (range 6–12) hr. The in vitro plasma protein binding of posaconazole incubated at 37°C was 99.25 ± 0.29%. Consideration of posaconazole pharmacokinetic/pharmacodynamic (PK/PD) targets for some yeasts such as disseminated candidiasis suggests that posaconazole could be an efficacious treatment for cryptococcosis in koalas.     

Branchial Ionic Flux Responses in Rainbow Trout to Chloramine-T after Acclimation to Different Levels of Water Hardness

Abstract

Whole-body unidirectional and net Na⁺ and Cl^– fluxes were determined in rainbow trout Oncorhynchus mykiss exposed to chloramine-T (9 mg/L) alone or in combination with 17 mmol NaCl/L (0.1 % weight per volume, w/v) after acclimation to either city of Ottawa tap water (TW: Na⁺ 0.121 ± 0.004 mmol/L; K⁺ 0.015 ± <0.001 mmol/L; Ca²⁺ 0.351 ± 0.004 mmol/L; Cl^– 0.141 ± 0.002 mmol/L) or artificial soft water (ASW: Na⁺ 0.043 ± 0.003 mmol/L; K⁺ 0.005 ± <0.001 mmol/L; Ca²⁺ 0.063 ± 0.002 mmol/L; Cl^– 0.026 ± 0.002 mmol/L). Preexposure fluxes revealed that ASW-acclimated fish had reduced rates of Na⁺ uptake and efflux compared with TW-acclimated fish. However, rates of Cl^– uptake among ASW-acclimated fish were comparable with those of TW-acclimated fish. Exposure to chloramine-T in TW resulted in significant increases in the Cl^– efflux, giving rise to a significant and negative net flux. Exposure of ASW-acclimated fish to chloramine-T caused a significant negative increase in the Na⁺ efflux and net flux but only a negative increase in the Cl^– net flux. The addition of 17 mmol NaCl/L (0.1% w/v) eliminated the negative net ionic fluxes, resulting in significant increases in influx. The combined use of chloramine-T with NaCl is a potential method of remediating ionic disturbances that may be caused by treating trout with chloramine-T.     

Comparative pharmacokinetics and pharmacokinetic/pharmacodynamic analysis by nonlinear mixed‐effects modeling of cefquinome in nonpregnant,pregnant, and lactating goats after intravenous and intramuscular administration

Cefquinome is a fourth‐generation cephalosporin that is used empirically in goats. Different physiologic factors like pregnancy or lactation could determine the pharmacokinetic behavior of drugs in the organism. The objectives of this study are to (a) compare the pharmacokinetics of cefquinome after intravenous and intramuscular administration in adult nonpregnant (n = 6), pregnant (n = 6), and lactating goats (n = 6), at a dose of 2 mg/kg, with rich sampling by nonlinear mixed‐effects modeling, (b) conduct a pharmacokinetic/pharmacodynamic analysis to evaluate the efficacy of the recommended posology in goats with different physiological states, and (c) determine the optimal posology that achieve a PTA value ≥ 90%, taking into account a T > MIC ≥ 60% of a MIC value ≤ 0.25 µg/ml, in the different subpopulations of goats for both routes. Gestation significantly increased Ka and V1, while reduced F0, Cl, and Q. On the other hand, lactation significantly increased V1 and reduced Tk0. Cefquinome concentrations achieved in placental cotyledon, amniotic fluid, and fetal serum indicate a minimal penetration across the placental barrier. Moreover, milk penetration of cefquinome was minimal. The total body clearance of cefquinome for goats was 0.29 L kg^?1 hr^?1, that is apparently higher than the reported for cows (0.13 L kg^?1 hr^?1) and pigs (0.16 L kg^?1 hr^?1). So, the optimal dose regimen for cefquinome after intravenous and intramuscular administration required higher dose and frequency of administration compared with recommendations for cows or pigs. Therefore, 2 mg kg^?1 8 hr^?1 and 5 mg kg^?1 12 hr^?1 could be used for IV and IM routes, respectively, for the treatment of respiratory infections caused by P. multocida and M. haemolytica, but only 5 mg kg^?1 12 hr^?1 by both routes should be recommended for Escherichia coli infections.     

Pharmacokinetics and pharmacodynamics of intravenous and transdermal flunixin meglumine in alpacas

The aim of this study was to determine the pharmacokinetics and prostaglandin E₂ (PGE₂) synthesis inhibiting effects of intravenous (IV) and transdermal (TD) flunixin meglumine in eight, adult, female, Huacaya alpacas. A dose of 2.2 mg/kg administered IV and 3.3 mg/kg administered TD using a cross‐over design. Plasma flunixin concentrations were measured by LC‐MS/MS. Prostaglandin E₂ concentrations were determined using a commercially available ELISA. Pharmacokinetic (PK) analysis was performed using noncompartmental methods. Plasma PGE₂ concentrations decreased after IV flunixin meglumine administration but there was minimal change after TD application. Mean t_1/2λz after IV administration was 4.531 hr (range 3.355 to 5.571 hr) resulting from a mean Vz of 570.6 ml/kg (range, 387.3 to 1,142 ml/kg) and plasma clearance of 87.26 ml kg^?1 hr^?1 (range, 55.45–179.3 ml kg^?1 hr^?1). The mean C_max, T_max and t_1/2λz for flunixin following TD administration were 106.4 ng/ml (range, 56.98 to 168.6 ng/ml), 13.57 hr (range, 6.000–34.00 hr) and 24.06 hr (18.63 to 39.5 hr), respectively. The mean bioavailability for TD flunixin was calculated as 25.05%. The mean 80% inhibitory concentration (IC₈₀) of PGE₂ by flunixin meglumine was 0.23 µg/ml (range, 0.01 to 1.38 µg/ml). Poor bioavailability and poor suppression of PGE₂ identified in this study indicate that TD flunixin meglumine administered at 3.3 mg/kg is not recommended for use in alpacas.     

Propofol anaesthesia for surgery in late gestation pony mares

Objective To characterize propofol anaesthesia in pregnant ponies. Animals Fourteen pony mares, at 256 ± 49 days gestation, undergoing abdominal surgery to implant fetal and maternal vascular catheters. Materials and methods Pre‐anaesthetic medication with intravenous (IV) acepromazine (20 µg kg^?1), butorphanol (20 µg kg^?1) and detomidine (10 µg kg^?1) was given 30 minutes before induction of anaesthesia with detomidine (10 µg kg^?1) and ketamine (2 mg kg^?1) IV Maternal arterial blood pressure was recorded (facial artery) throughout anaesthesia. Arterial blood gas values and plasma concentrations of glucose, lactate, cortisol and propofol were measured at 20‐minute intervals. Anaesthesia was maintained with propofol infused initially at 200 µg kg^?1 minute^?1, and at 130–180 µg kg^?1 minute^?1 after 60 minutes, ventilation was controlled with oxygen and nitrous oxide to maintain PaCO₂ between 5.0 and 6.0 kPa (37.6 and 45.1 mm Hg) and PaO₂ between 13.3 and 20.0 kPa (100 and 150.4 mm Hg). During anaesthesia flunixin (1 mg kg^?1), procaine penicillin (6 IU) and butorphanol 80 µg kg^?1 were given. Lactated Ringer's solution was infused at 10 mL kg^?1 hour^?1. Simultaneous fetal and maternal blood samples were withdrawn at 85–95 minutes. Recovery from anaesthesia was assisted. Results Arterial blood gas values remained within intended limits. Plasma propofol levels stabilized after 20 minutes (range 3.5–9.1 µg kg^?1); disposition estimates were clearance 6.13 ± 1.51 L minute^?1 (mean ± SD) and volume of distribution 117.1 ± 38.9 L (mean ± SD). Plasma cortisol increased from 193 ± 43 nmol L^?1 before anaesthesia to 421 ± 96 nmol L^?1 60 minutes after anaesthesia. Surgical conditions were excellent. Fetal umbilical venous pH, PO₂ and PCO₂ were 7.35 ± 0.04, 6.5 ± 0.5 kPa (49 ± 4 mm Hg) and 6.9 ± 0.5 kPa (52 ± 4 mm Hg); fetal arterial pH, PO₂ and PCO₂ were 7.29 ± 0.06, 3.3 ± 0.8 kPa (25 ± 6 mm Hg) and 8.7 ± 0.9 kPa (65 ± 7 mm Hg), respectively. Recovery to standing occurred at 46 ± 17 minutes, and was generally smooth. Ponies regained normal behaviour patterns immediately. Conclusions and clinical relevance Propofol anaesthesia was smooth with satisfactory cardiovascular function in both mare and fetus; we believe this to be a suitable anaesthetic technique for pregnant ponies.     

Pharmacokinetics of intravenous gentamicin in healthy young‐adult compared to aged alpacas

The study objective was to evaluate the effects of age on aminoglycoside pharmacokinetics in eight young‐adult (<4 years) and eight aged (≥14 years) healthy alpacas, receiving a single 6.6 mg/kg intravenous gentamicin injection. Heparinized plasma samples were obtained at designated time points following drug administration and frozen at ?80°C until assayed by a validated immunoassay (QMS ^®). Compartmental and noncompartmental analyses of gentamicin plasma concentrations versus time were performed using WinNonlin (v6.4) software. Baseline physical and hematological parameters were not significantly different between young and old animals with the exception of sex. Data were best fitted to a two‐compartment pharmacokinetic model. The peak drug concentration at 30 min after dosing (23.8 ± 2.1 vs. 26.1 ± 2 μg/ml, p = .043 ) and area under the curve (70.4 ± 10.5 vs. 90.4 ± 17.6 μg hr/ml, p = .015 ) were significantly lower in young‐adult compared to aged alpacas. Accordingly, young alpacas had a significantly greater systemic clearance than older animals (95.5 ± 14.4 and 75.6 ± 16.1 ml hr^?1 kg^?1; p = .018 ), respectively). In conclusion, a single 6.6 mg/kg intravenous gentamicin injection achieves target blood concentrations of >10 times the MIC of gentamicin‐susceptible pathogens with MIC levels ≤2 μg/ml, in both young‐adult and geriatric alpacas. However, the observed reduction in gentamicin clearance in aged alpacas may increase their risk for gentamicin‐related adverse drug reactions.     

Effect of dietary chloride content on the elimination of bromide by dogs

The effect of dietary chloride content (0·2, 0·4 and 1·3 per cent chloride on a dry matter basis) on the disposition of a single oral dose of bromide (14 mg kg⁻¹ was evaluated in normal beagles. Increasing the dietary chloride content from 0·2 to 1·3 per cent resulted in a significant decrease in the mean apparent elimination half-life from 69 ± 22 days to 24 ± 7 days. The mean area under the concentration curve ( ) for dogs fed 1·3 per cent chloride was significantly smaller than the for dogs fed 0·2 per cent chloride. Dietary chloride had no effect on the maximum serum concentrations (C_max) or on the time (T_max) to reach the maximum concentrations. The steady-state serum bromide concentrations predicted from the single dose data for daily doses of 14 mg kg⁻¹ of bromide were significantly lower in dogs fed 1·3 per cent chloride (310 ± 150 mg litre⁻¹) than in dogs fed 0·2 per cent chloride (1950 ± 1140 mg litre⁻¹). The predicted mean daily doses of bromide necessary to maintain serum levels within the therapeutic range for dogs fed 1·3 per cent chloride (43 ± 13 mg kg⁻¹) were almost twice as high as the dose estimated for dogs fed 0·4 per cent chloride (22 ± 3 mg kg⁻¹) and nearly three times as high as the dose estimated for dogs fed 0·2 per cent chloride (15 ± 4 mg kg^−l). These differences were statistically significant (P=0·002).