Observations on the use of a pain numbing device for repetitive percutaneous sampling in sheep.

AIMS: To evaluate the success of a commercially available analgesic device (CoolSense; Coolsense Ltd, Tel Aviv, Israel) in ameliorating pain while sampling from subcutaneous tissue cages in sheep. METHODS: The CoolSense device was used as part of a major parent study involving repetitive percutaneous sampling of subcutaneous tissue cages in seven sheep. Sampling was performed by passing a hypodermic needle through the skin and withdrawing fluid from the tissue cage. Each sheep had 10 tissue cages that were individually sampled 14 times over 74 h. The device was placed on the skin of the sampling site immediately before sampling cooling and numbing the skin. The reaction of the sheep was observed by the operators, flinching or jumping as the needle was passed through the skin was deemed to be a failure. We recorded the success or failure of the device for each needle stick. This was opportunistic data collection as part of a pharmacokinetic trial, therefore no controls were included. RESULTS: A total of 1655 observations were recorded and then analysed using a generalised linear mixed model. Overall, 1380 of 1655 (83.4%) observations were recorded as successfully providing analgesia. Marked inter-occasion variability was noted with success ranging from 61.42% to 92.86% across sheep:period (approximately 140 observations each). As no controls were available, the effect of treatment could not be evaluated. CONCLUSIONS AND CLINICAL RELEVANCE: The CoolSense device is a viable option for veterinary research and clinical applications.

A randomised controlled masked clinical trial of two treatments for osteoarthritis in dogs.

The product 4CYTE™ Canine (Interpath Pty Ltd., Ballarat, Victoria, Australia) contains four active ingredients: three marine-derived ingredients and Epiitalis®, which is extracted from the seed of the plant Biota orientalis. Carprofen is a non-steroidal anti-inflammatory drug (NSAID) licensed for the treatment of osteoarthritis in dogs and is the active ingredient in several licensed products. This study aimed to compare the efficacy of 4CYTE Canine with carprofen for the treatment of pain from osteoarthritis. The trial was a randomised, masked, parallel group trial in dogs with naturally occurring osteoarthritis. Sixty-nine dogs with body weight of between 10 and 50 kg were enrolled in the study, of which 66 (95.7%) completed the study. The 4CYTE Canine was administered at 60 mg active/kg daily and carprofen at 2-4 mg/kg daily, with a loading dose of up to 4 mg/kg on the first day. The trial duration was 28 days. The primary outcome was defined as improvement in Owner Lameness Score at Day 28 compared with Day 0. Other outcomes measured included Veterinary Lameness Scores and the Owner Mobility Scores. At Day 28, 14 of 29 (48.3%) dogs that received 4CYTE Canine and 13 of 37 (35.1%) dogs that received carprofen had improved. The 4CYTE Canine was found to be non-inferior to carprofen at Day 14 for the Owner Mobility Score and at Day 28 for all three outcomes. This response pattern suggests that improvement in response to 4CYTE Canine continued between Days 14 and 28. These results support the conclusion that 4CYTE Canine is not inferior to carprofen by end-point clinical efficacy.

A pilot study of 4CYTE™ Epiitalis® Forte, a novel nutraceutical, in the management of naturally occurring osteoarthritis in dogs.

The primary goal of this pilot study was to assess, the efficacy of a new nutraceutical, 4CYTE™ Epiitalis® Forte, containing, as a standalone, a proprietary plant oil extract, Epiitalis, in dogs presenting with signs of osteoarthritis (OA). Fifty dogs aged 9.2 (±3.2) years with signs of naturally occurring OA were included in this report. They were free of other comorbidities and were not on any medications except for those utilised for managing their OA. In these dogs, the current treatments were continued to avoid any sudden changes in their disease management. The effects of the 4CYTE Epiitalis Forte were assessed both at the beginning and at the end of a 1 month-long treatment period. The evaluation consisted of an objective lameness assessment (TPI%[total pressure index]) using a gait analysis (GAITRite® Portable Walkway System) and a subjective quality-of-life questionnaire, the Helsinki Chronic Pain Index (HCPI). Additional exploratory objective measurements included the Symmetry Index (SI) and the fore/hind limb ratio (T/P TPI%). Of dogs, 74% (34/46) registered a numerical improvement in TPI% in their worse limb. In addition, of the 93.5% of the dogs that demonstrated improvement in their HCPI scores by at least 5% on the quality-of-life questionnaire, 79% demonstrated improvements in gait based on TPI%. Finally, there were improvements measured in both exploratory objective endpoints SI and T/P TPI%. These encouraging results will be used to develop a protocol for a follow-up placebo-controlled randomised study to confirm the efficacy of this new nutraceutical for dogs suffering from OA.

Population physiologically based modeling of pirlimycin milk concentrations in dairy cows.

Predictions of drug residues in milk are critical in food protection and are a major consideration in the economics of treatment of mastitis in dairy cows. Nonlinear mixed-effects modeling (NLME) has been advocated as a suitable pharmaco-statistical method for the study of drug residues in milk. Recent developments in physiologically based pharmacokinetic (PBPK) modeling of intramammary drugs allow the combination of a mechanistic description of milk pharmacokinetics with NLME methods. The PBPK model was applied to NLME analysis of a data set consisting of milk drug concentrations from 78 healthy cows and 117 with clinical mastitis. Pirlimycin milk pharmacokinetics were adequately described by the model across the range of observed concentrations. Mastitis was characterized by increased variance in milk production volume. Udder residual volume was larger in cows with 1, or 2 or greater diseased mammary glands than in the healthy cows. Low-producing cows had a greater risk of prolonged milk residues. With the exclusion of the low-production cows, the model predicted that healthy cows required a milk discard time 12 h longer than that indicated by the label, and the diseased cows 36 h longer than indicated by the label. More pirlimycin was systemically absorbed in the gram-positive infected compared with the gram-negative infected or healthy cows, suggesting a greater risk of violative meat residues in gram-positive infected cows. Using NLME and PBPK models, we identified factors associated with changes in pirlimycin milk residues that may affect food safety. This model extends the verification of a simple physiologically based framework for the study of intramammary drugs.

Mathematical modeling and simulation in animal health. Part III: Using nonlinear mixed-effects to characterize and quantify variability in drug pharmacokinetics.

A common feature of human and veterinary pharmacokinetics is the importance of identifying and quantifying the key determinants of between-patient variability in drug disposition and effects. Some of these attributes are already well known to the field of human pharmacology such as bodyweight, age, or sex, while others are more specific to veterinary medicine, such as species, breed, and social behavior. Identification of these attributes has the potential to allow a better and more tailored use of therapeutic drugs both in companion and food-producing animals. Nonlinear mixed effects (NLME) have been purposely designed to characterize the sources of variability in drug disposition and response. The NLME approach can be used to explore the impact of population-associated variables on the relationship between drug administration, systemic exposure, and the levels of drug residues in tissues. The latter, while different from the method used by the US Food and Drug Administration for setting official withdrawal times (WT) can also be beneficial for estimating WT of approved animal drug products when used in an extralabel manner. Finally, NLME can also prove useful to optimize dosing schedules, or to analyze sparse data collected in situations where intensive blood collection is technically challenging, as in small animal species presenting limited blood volume such as poultry and fish.

Survey of systemic antimicrobial prescribing for dogs by Victorian veterinarians.

OBJECTIVE: Investigate the current antimicrobial prescribing patterns of veterinarians in Victoria for dogs and compare these results to patterns described 20 years ago. METHODS: A questionnaire was sent to 1380 veterinarians in Victoria. The first section collected demographic information of respondents. The second and third sections evaluated respondents' approach to use of antimicrobial drugs for scenarios in dogs in which 'clinical evidence suggests bacterial infection is the likely cause' and where 'it is unknown whether bacterial infection plays a role'. The final section evaluated respondents' approach to use of antimicrobial drugs during dental extraction in a dog. RESULTS: Of the 1380 veterinarians who were contacted, 259 responses were received (response rate 19%). Of these respondents, 95% (246/259) completed their veterinary degree at the University of Melbourne. The ratio of female to male respondents was 2.1 : 1 (171 : 82) and of urban to rural respondents was 1.9 : 1 (159 : 85). Drug selection for some scenarios was open to criticism. For example, to treat chronic prostatitis 16% (42/259) of respondents selected amoxicillin-clavulanate even though it has poor penetration of prostatic tissues. Some prescribing choices have changed since 1997; for example, for acute tracheobronchitis, 36% (73/204) of respondents indicated they would use antimicrobials, compared with 87% of respondents in 1997. For the treatment of idiopathic vestibular disease, only 5% (10/197) of respondents in the current study versus 45% (294/654) in the 1997 survey opted to use antimicrobials. CONCLUSION: Antimicrobial drug selection for treatment of dogs by registered veterinarians in Victoria was generally consistent with recent recommendations, although some details were widely variable.

Chemical stability of morphine and methadone, and of methadone in combination with acepromazine, medetomidine or xylazine, during prolonged storage in syringes.

OBJECTIVE: To assess the chemical and physical stability of morphine and methadone stored in syringes for 12 months and of methadone when mixed with acepromazine, medetomidine or xylazine. METHODS: A high-performance liquid chromatography (HPLC) technique was developed and validated for the analysis of morphine and methadone. Morphine and methadone were dispensed into syringes and stored at 25°C/60% relative humidity (RH) and 40°C/75% RH. Solutions containing mixtures of methadone combined with acepromazine, medetomidine or xylazine were stored in syringes at 25°C/60%RH. At initiation, after 1 week and then 1, 3, 6, 9 and 12 months, samples were analysed by HPLC for the quantification of the morphine or methadone. Measured concentrations were assessed as a function of storage time and temperature using linear regression statistics to calculate stability. RESULTS: When stored at 40°C/75%RH as pre-dispensed syringes, severe physical and chemical changes were observed after the third month for both morphine and methadone. In contrast, at 25°C/60%RH both drugs remained chemically stable for 12 months, with concentration variations not exceeding a 5% change from initiation as stipulated in VICH stability guidelines. When in combination with acepromazine or xylazine, methadone also remained chemically stable, but the combination with medetomidine failed stability criteria prior to 6 months. Precipitation compromised the physical stability of methadone in all unsealed syringes prior to 9 months' storage. CONCLUSION: Pre-dispensing morphine or methadone into unsealed syringes compromises the drugs' physical stability. Mixing of methadone with other drugs can degrade its chemical stability.

The cardiopulmonary effects and quality of anesthesia after induction with alfaxalone in 2-hydroxypropyl-ß-cyclodextrin in dogs and cats: a systematic review.

To systematically review the quality of evidence comparing the cardiopulmonary effects and quality of anesthesia after induction with alfaxalone vs. other anesthetic agents in dogs and cats. Studies published from 2001 until 20th May 2013 were identified with the terms 'alfaxan' OR 'alfaxalone' OR 'alphaxalone' in electronic databases: Discovery, PubMed, ScienceDirect, and Wiley Interscience. The study design and risk of bias of all included studies were assessed. Twenty-two studies from 408 (22 of 408, 5.39%) satisfied the inclusion criteria. Fourteen studies (14 of 22, 64%) focused on dogs and nine (9 of 22, 40%) on cats. One study had both dogs and cats as subjects. (Hunt et al., 2013) Twelve studies were rated an LOE1, and six of these as ROB1. One, seven, and two studies were rated as LOE2, LOE3, and LOE5, respectively. In dogs, strong evidence shows that induction quality with either alfaxalone-HPCD or propofol is smooth. Moderate evidence supports this finding in cats. In dogs, moderate evidence shows that there is no significant change in heart rate after induction with either alfaxalone-HPCD or propofol. In cats, moderate evidence shows no significant difference in postinduction respiratory rate and heart rate between alfaxalone-HPCD and propofol induction. Strong evidence shows dogs and cats have smooth recoveries after induction using either alfaxalone-HPCD or propofol, before reaching sternal recumbency.

The pharmacokinetics of pimobendan enantiomers after oral and intravenous administration of racemate pimobendan formulations in healthy dogs.

Pimobendan is a benzimidazole-pyridazinone derivative, marketed as a racemic mixture for the management of canine heart failure. Pharmacokinetics of the enantiomers of pimobendan and its oral bioavailability have not been described in dogs. The aim of this study was to describe pharmacokinetics of three formulations of pimobendan in healthy dogs: the licensed capsule product, and novel liquid and intravenous formulations. A three-period, nested randomized two-treatment crossover design was used. Pimobendan was administered p.o. at 0.25 and i.v. at 0.125 mg/kg. Blood and plasma samples were analysed by liquid chromatography-mass spectrometry. Noncompartmental modelling was used to describe the pharmacokinetics. Parameters were compared between formulations using a general linear model. Bioequivalence of the oral formulations was tested using CI90 for AUC(0-∞) and Cmax . Bioavailability of pimobendan after oral dosing was 70%. Liquid and capsule formulations were bioequivalent only for AUC. The positive enantiomer of pimobendan (PE) had a larger volume of distribution than the negative enantiomer (NE) (281 ± 48 vs. 215 ± 68 mL/kg; P = 0.003) and a shorter half-life (21.7 vs. 29.9 min; P = 0.004). The NE was distributed more quickly than the PE into blood cells. Enantiomers of pimobendan have differing absorption, distribution and elimination. The pharmacokinetics of pimobendan in healthy dogs was described.

Pharmacokinetics of enrofloxacin following oral and subcutaneous administration in the common ringtail possum (Pseudocheirus peregrinus).

[Correction added on 23 March 2015, after first online publication: Terminal half-life values of enrofloxacin is corrected in the fourth sentence of the abstract] Clinically healthy common ringtail possums (n = 5) received single doses of 10 mg/kg enrofloxacin orally and then 2 weeks later subcutaneously. Serial plasma samples were collected over 24 h for each treatment phase, and enrofloxacin concentrations were determined using a validated HPLC assay. Pharmacokinetic parameters were determined by noncompartmental analysis. Following oral administration, plasma concentrations were of therapeutic relevance (Cmax median 5.45 µg/mL, range 2.98-6.9 µg/mL), with terminal-phase half-life (t½ ) shorter than in other species (median 3.09 h, range 1.79-5.30 h). In contrast, subcutaneous administration of enrofloxacin did not achieve effective plasma concentrations, with plasma concentrations too erratic to fit the noncompartmental model except in one animal. On the basis of the AUC:MIC, enrofloxacin administered at 10 mg/kg orally, but not subcutaneously, is likely to be effective against a range of bacterial species that have been reported in common ringtail possums.

A systematic review and meta-analysis of the efficacy of furosemide for exercise-induced pulmonary haemorrhage in Thoroughbred and Standardbred racehorses.

REASONS FOR PERFORMING STUDY: Furosemide is the most commonly used medication for exercise-induced pulmonary haemorrhage (EIPH); however, critical evaluation of the strength of evidence for efficacy of furosemide is lacking and is warranted so that evidence-based treatment decisions can be made. OBJECTIVES: To evaluate the efficacy of furosemide to reduce the severity or frequency of detection of EIPH in Thoroughbred and Standardbred racehorses. STUDY DESIGN: Systematic review with meta-analyses. METHODS: Primary studies were identified via searches of electronic databases, relevant texts and reference lists of published articles. Studies were not restricted by date or publication status. Only studies published in English were eligible for inclusion. Searches were performed using a predetermined search string. Randomised controlled trials, nonrandomised trials and observational studies were included. Three authors independently assessed each study using the Cochrane collaboration guidelines and Grading of Recommendations Assessment, Development and Evaluation recommendations for rating quality of evidence. Meta-analysis of studies was performed with pooled data to determine whether furosemide reduced the frequency of detection of EIPH (yes or no) as evaluated by tracheobronchoscopy or bronchoalveolar lavage fluid red blood cell number, or if furosemide reduced the severity of EIPH by at least one tracheobronchoscopic grade. RESULTS: Seventeen studies fulfilled the inclusion criteria. The relative risk of detecting any EIPH by tracheobronchoscopy after administration of furosemide was 0.88 (pooled data from 11 studies, n = 5780; 95% confidence interval 0.79-0.97, P = 0.01). When data from only high-quality randomised controlled trials (2 studies, n = 405) were used, the relative risk of detecting endoscopically evident EIPH was 0.68 (95% confidence interval 0.58-0.79, P<0.001). The proportion of horses previously diagnosed with EIPH having a reduction of at least one EIPH grade after furosemide was 68% (2 studies, n = 405; 95% confidence interval 61-78%). CONCLUSIONS: There is high-quality evidence, albeit limited, that administration of furosemide reduces the incidence and severity of EIPH in Thoroughbred or Standardbred racehorses.

Multicentre, randomised clinical trial evaluating the efficacy and safety of alfaxalone administered to bitches for induction of anaesthesia prior to caesarean section.

OBJECTIVE: To determine the clinical safety and efficacy of alfaxalone in bitches undergoing caesarean section (CS) and their puppies when it is administered for induction of anaesthesia followed by maintenance with isoflurane and oxygen and in conjunction with perioperative pharmaceuticals. DESIGN: A multicentre, randomised, positive-controlled clinical study. METHODS: A total of 74 bitches were enrolled in the study with 48/74 (65%) and 26/74 (35%) receiving alfaxalone and propofol, respectively, for induction of anaesthesia. Bitches were examined prior to induction and monitored during induction, surgery and recovery. Assessments were made for quality of induction, maintenance and recovery from anaesthesia. Assessments were made on pup viability for suction, dorsal flexion, withdrawal and anogenital reflexes. RESULTS: Of the 48 bitches receiving alfaxalone, 47 (98%) and 39 (81%) scored a top score of excellent for induction and anaesthesia effectiveness, respectively. For the same parameters with propofol in 26 bitches, 23 (88%) and 17 (65%) scored excellent. Average scores for recovery were not different between the two treatment groups with alfaxalone 46/48 (96%) and 25/26 (96%) of propofol induced bitches scoring a good or excellent rating. Bitches tolerated a number of concurrent medications throughout the peri-operative period. No bitch fatalities were observed in this study. There were no statistically significant differences between treatment groups for the puppy variables. Live puppies born by CS to bitches having been administered alfaxalone or propofol had similar survival rates 24 h after birth (i.e. 205/213 (96%) and 124/131 (95%), respectively). CONCLUSION: This study confirms the safety and efficacy of alfaxalone for the purpose of anaesthetic induction for CS in the bitch. In addition, alfaxalone had a negligible effect on the neonate with >95% of puppies alive 24 h after the bitch had recovered from anaesthesia with alfaxalone induction.

In vivo histologically equivalent evaluation of gastric mucosal topologic morphology in dogs by using confocal endomicroscopy.

BACKGROUND: Confocal endomicroscopy (CEM) is an endoscopic technology permitting in vivo cellular and subcellular imaging. CEM aids real-time clinical assessment and diagnosis of various gastrointestinal diseases in people. CEM allows in vivo characterization of small intestinal mucosal morphology in dogs. OBJECTIVE: To determine the feasibility of CEM to evaluate gastric mucosal morphology in dogs and to characterize the appearance in healthy dogs. ANIMALS: Fourteen clinically healthy research colony dogs. METHODS: Experimental study. Under general anesthesia, dogs underwent standard endoscopic evaluation and CEM of the gastric mucosa. In the initial 6 dogs, fluorescent contrast was provided with the fluorophore acriflavine (0.05% solution), applied topically. Subsequently, 8 dogs were assessed using a combination of fluorescein (10% solution, 15 mg/kg IV), followed by acriflavine administered topically. For each fluorophore, a minimum of 5 sites were assessed. RESULTS: Confocal endomicroscopy provided high quality in vivo histologically equivalent images of the gastric mucosa, but reduced flexibility of the endoscope tip limited imaging of the cranial stomach in some dogs. Intravenous administration of fluorescein allowed assessment of cellular cytoplasmic and microvasculature features. Topical application of acriflavine preferentially stained cellular nucleic acids, allowing additional evaluation of nuclear morphology. Identification of Helicobacter-like organisms was possible in 13 dogs. CONCLUSION AND CLINICAL IMPORTANCE: Confocal endomicroscopy provides in vivo images allowing assessment of gastric mucosal morphology during endoscopy, potentially permitting real-time diagnosis of gastrointestinal disease.

In vivo confocal endomicroscopy of small intestinal mucosal morphology in dogs.

BACKGROUND: Confocal endomicroscopy (CEM) is an endoscopic technology that permits in vivo cellular and subcellular imaging of the gastrointestinal mucosa. OBJECTIVE: To determine the feasibility of CEM to evaluate small intestinal mucosal topologic morphology in dogs and to characterize the appearance in healthy dogs. ANIMALS: Fourteen clinically healthy research colony dogs. METHODS: Experimental study. Dogs were anesthetized for standard endoscopic evaluation of the small intestine followed by CEM. Two fluorophores were used to provide contrast: fluorescein (10% solution, 15 mg/kg IV) before administration of topical acriflavine (0.05% solution) via an endoscopy spray catheter. A minimum of 5 sites within the small intestine were assessed and at each location, sequential adjustment of imaging depth allowed collection of a three-dimensional volume equivalent to an 'optical biopsy'. CEM-guided pinch biopsies were obtained for histologic examination. RESULTS: CEM provided high-quality in vivo cellular and subcellular images. Intravenous administration of fluorescein provided sufficient contrast to allow assessment of the vasculature, cellular cytoplasmic features and goblet cell numbers, and distribution. Topical application of acriflavine preferentially stained cellular nucleic acids, allowing evaluation of nuclear morphology. Quality of captured images was occasionally affected by motion artifact, but improved with operator experience. CONCLUSION AND CLINICAL IMPORTANCE: CEM provides in vivo images that allow for cellular and subcellular assessment of intestinal mucosal morphology during endoscopy. This has implications for aiding in vivo diagnosis of gastrointestinal disease.

Bioequivalence of a new liquid formulation of benazepril compared with the reference tablet product.

OBJECTIVE: To compare the bioequivalence and 'switchability' of two formulations of benazepril (tablet and liquid) after oral administration. DESIGN: Randomised cross-over design, followed by parallel comparison. METHODS: Twelve mixed-breed dogs were administered either a tablet (Group A) or liquid formulation (Group B) of benazepril orally at 0.45 mg/kg daily for 4 days. With no washout period, the dogs then received the alternative treatment at the same dose for a further 4 days. Blood samples taken prior to treatment and serially after treatment were analysed for plasma concentrations of benazepril and benazeprilat and the activity and concentration of angiotensin-converting enzyme (ACE). The calculated percentage inhibition of ACE was defined as the primary outcome variable. RESULTS: No statistically significant differences were found between groups A and B for any variable evaluated. The mean (± SD) percentage of ACE inhibition was 85.5 ± 7.04% for the liquid formulation and 85.9 ± 6.66% for the tablet formulation. The mean of the ratios was 1.00 (80% confidence interval 0.96-1.04). No evaluated effect term (sequence, formulation or period) had any statistical effect on any outcome variable. CONCLUSION: This study supports a conclusion that, based on pharmacodynamic response, the liquid formulation of benazepril is bioequivalent to the reference tablet formulation. Further, the lack of a sequence effect supports the switchability of these two formulations.

Animal Health Modeling & Simulation Society: a new society promoting model-based approaches in veterinary pharmacology.

The Animal Health Modeling & Simulation Society (AHM&S) is a newly founded association (2012) that aims to promote the development, application, and dissemination of modeling and simulation techniques in the field of Veterinary Pharmacology and Toxicology. The association is co-chaired by Pr. Johan Gabrielsson (Europe), Pr. Jim Riviere (USA), and secretary Dr. Jonathan Mochel (Switzerland). This short communication aims at presenting the membership, rationale and objectives of this group.

Effects of oral clenbuterol on the clinical and inflammatory response to endotoxaemia in the horse.

Pro-inflammatory cytokines, such as IL-1ß and TNFα, play a major role in activating leukocytes and endothelial cells during the systemic inflammatory response to endotoxin in the horse. ß2 agonist drugs, such as clenbuterol, inhibit leukocyte activation. This study aimed to determine the effects of oral clenbuterol on clinical and leukocyte responses, including production of TNFα, in an in vivo endotoxin challenge model. In a randomised crossover design, horses received either clenbuterol or a placebo product prior to the administration of low dose endotoxin (30 ng/kg over 30 min). Clinical signs were measured and leukocyte counts and serial blood samples were obtained over 6 h. Pre-treatment with oral clenbuterol (0.8 µg/kg) significantly reduced (P=0.046) the peak rectal temperature and the peak plasma TNFα concentration (P=0.026) following endotoxin challenge. These data suggest that oral clenbuterol at the therapeutic dose has anti-inflammatory effects in horses challenged with a low dose of endotoxin.

Bioavailability of two L-thyroxine formulations after oral administration to healthy dogs.

OBJECTIVE: To describe the pharmacokinetics of two veterinary formulations of L-thyroxine available in Australia. METHODS: A two-phase randomised, crossover, open-label trial followed by a third-phase parallel-dosing trial was conducted in 11 healthy dogs with an investigative oral L-thyroxine liquid formulation and a reference tablet formulation. Blood sampling was done at defined intervals and serum total L-thyroxine concentrations were measured by radioimmunoassay. The post-dose concentrations were plotted as a function of time for each period and the relative bioavailability of the two formulations were compared using a general linear model with factors for dog, phase, sequence and formulation. RESULTS: Following oral administration of the reference tablet at the dose of 100 µg/kg, a maximum plasma concentration of approximately 96.2 nmol/L (baseline endogenous corrected) was reached within 3.77 h. For the investigative liquid preparation at a dose of 50 µg/kg, the maximum plasma concentration was 60.1 nmol/L (baseline endogenous corrected), which was reached within 3.59 h. CONCLUSION: The geometric mean of the relative bioavailability for the liquid/tablet product was 1.1, which suggests that the relative bioavailability of thyroxine following administration of tablet or liquid formulation is similar.

The exogenous fluorophore, fluorescein, enables in vivo assessment of the gastrointestinal mucosa via confocal endomicroscopy: optimization of intravenous dosing in the dog model.

This study described the pharmacokinetics of the intravenous fluorophore, fluorescein, and aimed to evaluate its utility for use in upper gastrointestinal confocal endomicroscopy (CEM). Six healthy, mature, mixed-breed dogs were anesthetized and then dosed intravenously with fluorescein at 15 mg/kg. Blood samples were collected at predetermined time-points. Dogs were examined by upper gastrointestinal confocal endomicroscopy and monitored for adverse effects. Plasma fluorescein concentrations were measured using high-performance liquid chromatography (HPLC) with UV/Vis detection. Mean plasma concentration at 5 min was 57.6 ± 18.2 mg/L, and plasma concentrations decreased bi-exponentially thereafter with a mean concentration of 2.5 mg/L ± 1.26 at 120 min. Mean terminal plasma elimination half-life (t½ß ) was 34.8 ± 8.94 min, and clearance was 9.1 ± 3.0 mL/kg/min. Apparent volume of distribution at steady-state was 0.3 ± 0.06 L/kg. Fluorescein provided optimal fluorescent contrast to enable in vivo histologically equivalent evaluation of topologic mucosal morphology within the first 30 min following intravenous administration. Adverse effects were not observed. Based upon the calculated clearance, a constant rate infusion at a rate of 0.18 mg/kg/min is predicted to be adequate, following an initial loading dose (2 mg/kg), to maintain plasma concentration at 20 mg/L for optimal CEM imaging during the study period.