Pharmacokinetics, pharmacodynamics and antinociceptive effects of buprenorphine following transdermal administration to horses.

OBJECTIVE: This study describes the pharmacokinetics and pharmacodynamics, including antinociceptive effects, of a transdermal buprenorphine solution in horses. It was hypothesized that transdermal application would lead to sustained blood concentrations and antinociceptive effects with fewer adverse effects compared with intravenous (IV) injection. STUDY DESIGN: Prospective nonrandomized four-part parallel experimental study. ANIMALS: A group of eight horses (three mares and five geldings) aged 6-12 years. METHODS: Horses were administered incremental doses of 15, 30 and 45 µg kg-1 of buprenorphine transdermal solution and a single IV dose of 5 µg kg-1 of buprenorphine with a 2 week washout period between treatments. Concentrations of buprenorphine were determined in plasma using liquid chromatography-tandem mass spectrometry and modeled using a nonlinear mixed effects population pharmacokinetic model to determine pharmacokinetic parameters. Pharmacodynamic effects, including changes in locomotor activity, heart rate, body temperature, gastrointestinal borborygmi, thermal and mechanical nociceptive thresholds were recorded. Mixed effects analysis of variance and post hoc comparisons were performed using a Bonferroni multiple comparison adjustment to assess differences in pharmacodynamic parameters between baseline and each time point within each dose group and between dose groups at the same time point. RESULTS: Transdermal application of buprenorphine resulted in low systemic concentrations relative to IV injection. Bioavailability after transdermal application was 11%. Thermal nociceptive thresholds were significantly (p < 0.05) increased (4.3-10.7% relative to baseline) for up to 72 hours in the IV dose group, but only sporadically in the transdermal dose groups (2.5-9.9% relative to baseline). Changes in locomotor activity, heart rate and borborygmi varied over time and with dose. CONCLUSIONS AND CLINICAL RELEVANCE: Limited thermal antinociceptive effects were observed at the transdermal doses studied likely owing to limited absorption relative to IV dosing. Future studies may be directed toward investigating antinociceptive effects of higher transdermal doses and different application sites.

The impact of surgery resident training on the duration of tibial plateau leveling osteotomy surgery.

OBJECTIVE: To investigate the impact of surgery resident training on surgery duration in tibial plateau leveling osteotomy (TPLO) and evaluate whether surgery duration differs with each year of residency training. STUDY DESIGN: Retrospective medical record review. ANIMALS: A total of 256 client-owned dogs underwent TPLO. METHODS: Records of dogs that underwent TPLO between August 2019 and August 2022 were reviewed. The effects of the surgeon (faculty/resident) and the procedure (arthrotomy/arthroscopy) on TPLO surgery duration were examined with an analysis of variance, and geometric least squares means (GLSM) were compared. A linear mixed effects model (LMM) was fitted to quantify fixed and random effects. RESULTS: Four faculty surgeons performed 74 (29%) TPLOs, while 10 residents performed 182 (71%) TPLOs under the direct supervision of a faculty surgeon. All TPLOs were conducted with arthrotomy (109; 43%) or arthroscopy (147; 57%). Overall, residents (GLSM, 153 min) required 54% more surgery duration than faculty surgeons (GLSM, 99 min). Surgery duration among first-year residents (GLSM, 170 min) was 15% longer than second- (GLSM, 148 min) and third-year (GLSM, 147 min) residents, whereas the duration did not differ statistically between second- and third-year residents. Arthroscopy, meniscal tear treatment, surgery on the right stifle, and increasing patient weight were also associated with longer surgery duration. CONCLUSION: The duration of TPLO surgery significantly decreased after the first year of residency, but did not decrease afterward. CLINICAL SIGNIFICANCE: The results will aid with resource allocation, curricula planning, and cost management associated with resident training.

Ketoprofen in horses: Metabolism, pharmacokinetics, and effects on inflammatory biomarkers.

Ketoprofen is an anti-inflammatory drug that is commonly administered to racehorses for the alleviation of musculoskeletal pain and inflammation. This study represents a comprehensive examination of the metabolism (in vivo and in vitro), pharmacokinetics and ex vivo pharmacodynamics, of ketoprofen in horses. The in vitro metabolism as well as specific enzymes responsible for metabolism was determined by incubating liver microsomes and recombinant CYP450 and UGT enzymes with ketoprofen. For the in vivo portion, 15 horses were administered a single intravenous dose of 2.2-mg/kg ketoprofen. Blood and urine samples were collected prior to and up to 120 h post-drug administration. Additional blood samples were collected at select time points and were stimulated with calcium ionophore or lipopolysaccharide, ex vivo, to induce eicosanoid production. Drug, metabolite, and eicosanoid concentrations were determined using LC-MS/MS. Incubation of ketoprofen with equine liver microsomes generated 3-hydroxy ketoprofen, an unidentified hydroxylated metabolite, and ketoprofen glucuronide. Recombinant equine CYP2C23 produced the greatest amount of hydroxylated ketoprofen and recombinant equine UGT1A2 generated ketoprofen glucuronide. Dihydro, 3-hydroxy, and glucuronide metabolites were identified in blood and urine samples. The Vdss was 0.280, 0.385, and 0.319 L/kg for total ketoprofen, S (+) ketoprofen, and R (-) ketoprofen, respectively. The mean half-life was 6.01 h for total ketoprofen, 2.22 h for S (+) ketoprofen, and 1.72 h for R (-) ketoprofen. Stimulation of ketoprofen-treated blood with lipopolysaccharide and calcium ionophore resulted in an inhibition of TXB2 , PGE2 , PGF2alpha , LTB4 , and 15(s)-HETE production for up to 120 h post-drug administration.

Pharmacokinetics and effects of codeine in combination with acetaminophen on thermal nociception in horses.

Codeine and acetaminophen in combination have proven to be an effective analgesic treatment for moderate-to-severe and postoperative pain in humans. Studies have demonstrated that codeine and acetaminophen, when administered as sole agents, are well tolerated by horses. In the current study, we hypothesized that administration of the combination of codeine and acetaminophen would result in a significant thermal antinociceptive effect compared with administration of either alone. Six horses were administered oral doses of codeine (1.2 mg/kg), acetaminophen (20 mg/kg), and codeine plus acetaminophen (1.2 mg/kg codeine and 6-6.4 mg/kg acetaminophen) in a three-way balanced crossover design. Plasma samples were collected, concentrations of drug and metabolites determined via liquid chromatography-mass spectrometry, and pharmacokinetic analyses were performed. Pharmacodynamic outcomes, including effect on thermal thresholds, were assessed. Codeine Cmax and AUC were significantly different between the codeine and combination group. There was considerable inter-individual variation in the pharmacokinetic parameters for codeine, acetaminophen, and their metabolites in horses. All treatments were well tolerated with minimal significant adverse effects. An increase in the thermal threshold was noted at 1.5 and 2 h, from 15 min through 6 h and 0.5, 1, 1.5, and 3 h in the codeine, acetaminophen, and combination groups, respectively.

Concentrations, pharmacokinetics and selected pharmacodynamics of morphine and its active metabolites following oral administration to horses.

The metabolism and pharmacokinetics of intravenous (i.v.) morphine in the horse have been described; however, administration of therapeutic doses has also been associated with neuroexcitation and adverse gastrointestinal effects. In this study, we hypothesized that oral administration would lead to comparable concentrations of morphine and its presumed active metabolite, morphine 6-glucuronide (M6G) without the adverse effects associated with i.v. administration. Eight horses were administered a single i.v. dose of 0.2 mg/kg morphine and oral doses of 0.2, 0.6, and 0.8 mg/kg of morphine in a four-way balanced crossover design, with a 2-week washout period between doses. Concentrations of morphine and metabolites were determined, and pharmacokinetic parameters determined. Physiologic and behavioral outcomes including the number of steps taken, changes in heart rate, and gastrointestinal borborygmi were assessed. Oral administration of morphine resulted in higher concentrations of morphine metabolites, including M6G (Cmax : 11.6-37.8 ng/mL (0.6 mg/kg); 15.8-42.6 ng/mL (0.8 mg/kg)), compared with i.v. Bioavailability was 36.5%, 27.6% and 28.0% for 0.2, 0.6 and 0.8 mg/kg, respectively. Behavioral and physiologic changes were noted in all groups but were less prominent with oral compared with i.v. administration. Results of the current study are encouraging for further study, specifically anti-nociceptive effects of morphine following oral administration.

Dental and temporomandibular joint pathology of the Arctic fox (Vulpeslagopus).

Museum skull specimens from 224 Arctic foxes (Vulpes lagopus) were examined macroscopically using an established protocol for examination of mammalian skull specimens. Foxes were collected from coastal and island regions of Alaska, USA, except for two individuals. Collection years ranged from 1931 to 2016 with most specimens collected during the 1950s and 1960s. The study population comprised more females (n = 134, 59.8%) than males (n = 83, 37.0%) and individuals of unknown sex (n = 7, 3.1%). There were 108 (48.2%) young adults, 115 (51.3%) adults, and one (0.4%) individual of unknown age. A total of 8,891 teeth (94.5%) were available for examination. The most common types of pathology observed were periodontitis (n = 222, 99.1%), dental fractures (n = 175, 78.1%) and attrition/abrasion (n = 198, 88.4%). Periapical lesions (n = 12, 5.3%), temporomandibular joint (TMJ) osteoarthritis (n = 3, 1.3%) and root number variation (n = 5, 2.2%) were less common. Enamel hypoplasia was noted in eight foxes (3.6%), all of which were discovered on St. Matthew Island, Alaska, in 1963. As in other canid species, periodontitis, attrition/abrasion and tooth fractures are common in the Arctic fox, while TMJ pathology is rare. Loss of tooth crown substance probably reflects the influence of diet, interspecific and conspecific aggression and oral trauma due to trapping and hunting methods. The high prevalence of periodontitis is probably also due to the combined effects of diet, genetics and host immune reaction to oral bacteria.

Dental and temporomandibular joint pathology of the island fox (Urocyon littoralis).

Museum skull specimens from 318 island foxes (Urocyon littoralis) were examined macroscopically according to predefined criteria. The study population included males (n = 129, 40.6%), females (n = 93, 29.3%) and animals of unknown sex (n = 96, 30.2%), and comprised 182 (57.2%) adults, 118 (37.1%) young adults and 18 (5.7%) individuals of unknown age, with juveniles and neonates excluded. The number of teeth present for examination was 11,438 (85.6%) with 1918 (14.4%) absent artefactually, 4 (0.03%) absent congenitally and 243 (1.82%) lost ante mortem through acquired tooth loss. There were seven persistent deciduous teeth (0.05%) in three specimens and 11 supernumerary teeth (0.08%) in 10 specimens. Teeth with extra roots were found in 38 skulls (11.9%) with 0.48% of all teeth affected. Two (0.63%) specimens had one tooth with an abnormal form. Fifty-eight (18.2%) specimens had bone fenestrations. Of the alveoli examined, 5361 (46.9%) displayed bony changes suggestive of periodontitis, with 315 (99.1%) of skulls affected. Of the teeth available for examination in 310 specimens (97.5%), most (n = 6,040, 52.8%) had some degree of attrition or abrasion. Fractures affected 1217 (11.0%) of the teeth present in 266 specimens (83.6%). Twenty-three periapical lesions (0.20%) were present in 16 skulls (5.03%). Evidence of temporomandibular joint osteoarthritis was found in seven specimens (0.02%) on either the mandibular head of the condylar process or on the mandibular fossa of the temporal bone.

Prevalence of and risk factors associated with Salmonella shedding among equids presented to a veterinary teaching hospital for colic (2013-2018).

BACKGROUND: Gastrointestinal disease has been associated with shedding of Salmonella with previous studies demonstrating that horses with colic have a higher risk of acquiring and shedding Salmonella organisms. OBJECTIVES: The purpose of this study was to determine the prevalence of and risk factors associated with Salmonella shedding in a colic population at a referral clinic. STUDY DESIGN: Retrospective case-control study. METHODS: For each colic case that was positive for Salmonella (n = 56), two colic cases (n = 112) that tested negative for Salmonella, were enrolled as controls. Associations between variables and Salmonella shedding were identified using logistic regression. Univariate and multivariable models were developed pertaining to (1) presenting clinicopathological data and (2) clinical variables that developed during hospitalisation. RESULTS: Of the equids presenting with colic, 1585/1917 had a sample submitted for Salmonella testing. Of these, 56 were positive for Salmonella yielding a prevalence of 3.5%. Equids shedding Salmonella were more likely to present in July (odds ratio [OR] = 7.2; 95% confidence interval [CI] = 1.63-32.13; p = 0.009) and present with a history of fever (OR = 53.5; 95% CI = 2.57-1113.03; p = 0.01), increased lactate (OR = 1.6; 95% CI = 1.14-2.29; p = 0.007) and/or neutropenia (OR = 0.79; 95% CI = 0.65-0.97; p = 0.02). Hospitalised equids shedding Salmonella were more likely to be febrile (OR = 4.8; 95% CI = 1.47-15.8; p = 0.01) and 10 times more likely to develop reflux (OR = 10.1; 95% CI = 1.67-61.43; p = 0.01) compared to colic controls. MAIN LIMITATIONS: Retrospective nature of the study and bias inherent to the retrieval of data from medical records cannot be discounted. Classifying Salmonella status based on a single sample may have resulted in misclassification bias. CONCLUSIONS: The prevalence of Salmonella shedding in this colic population was low compared to earlier reports. Certain predictors such as the development of a fever or reflux in hospitalised colic cases were associated with Salmonella shedding and may help the clinician to promptly identify horses likely to shed; thus, helping institute effective use of barrier nursing precautions.

Clodronate detection and effects on markers of bone resorption are prolonged following a single administration to horses.

BACKGROUND: Clodronate is a potent antiresorptive agent labelled for use in horses over 4 years of age, for the treatment of navicular syndrome. Concerns regarding the extra-label use of clodronate in equine athletes, such as racehorses, have been raised as inhibition of osteoclast activity by clodronate has been postulated to interfere with normal bone healing, which is imperative to the repair of microfractures. The paucity of data describing the long-term pharmacokinetics of clodronate and effects on biomarkers of bone resorption necessitates further study. OBJECTIVES: (1) To determine clodronate concentrations in blood and urine over a 6-month period in horses undergoing treadmill exercise and (2) to assess the effects of clodronate on protein biomarkers of bone remodelling in this same group of horses. STUDY DESIGN: Randomised controlled experimental study. METHODS: Seven exercised Thoroughbred horses received a single im administration of 1.8 mg/kg clodronate and four horses received an equivalent volume of saline. Blood and urine samples were collected prior to, during and for 182 days post drug administration for drug concentration determination using liquid chromatography-tandem mass spectrometry, and determination of protein biomarker (CTX-1 and TRAcP5B) concentrations. RESULTS: Clodronate was detectable in blood for 14-175 days and for up to 175 days in urine. For some horses, concentrations were nondetectable at one time point but detectable at a subsequent time point. The terminal serum half-life ranged from 1.80 to 283.9 days. CTX-1 concentrations were significantly higher, relative to baseline, in both treated and control groups while concentrations of TRAcP5B were significantly lower in the treated group. MAIN LIMITATIONS: Relatively small number of horses studied. CONCLUSIONS: Based on assessment of protein biomarkers, clodronate appears to influence osteoclasts at label doses. Furthermore, results of this study support racing regulations that preclude horses administered bisphosphonates for medical reasons, from racing for a prolonged period of time.

CONTEXTO: Clodronato é um agente antirreabsortivo potente e recomendado para o uso em cavalos com mais de 4 anos de idade, para o tratamento da síndrome do navicular. Há preocupação com o uso indiscriminado de clodronato em equinos atletas, como cavalos de corrida, já que a inibição da atividade dos osteoclastos pelo clodronato tem sido postulada em interferir na cicatrização óssea normal, o que é essencial para a cicatrização de microfraturas. A escassez de informação quanto às ações prolongadas do uso de clodronato e seus efeitos nos biomarcadores de reabsorção óssea requere mais estudos. OBJETIVOS: (1) Determinar a concentração de clodronato no sangue e urina por um período de 6 meses em cavalos submetidos ao exercício em esteira e (2) acessar os efeitos de clodronato nos biomarcadores de remodelação óssea no mesmo grupo de cavalos. DELINEAMENTO DO ESTUDO: Estudo controlado randomizado. METODOLOGIA: Sete cavalos Puro-Sangue Inglês em exercício receberam uma única dose im de 1.8 mg/kg de clodronato e 4 cavalos receberam um volume equivalente de solução fisiológica. Amostras de sangue e urina foram coletadas antes, durante e por 182 dias após a administração de clodronato. Valores de concentração da droga foram determinados utilizando cromatografia líquida-espectrometria de massa (LC-MS/MS), e determinação da concentração de biomarcadores (CTX-1 e TRAcP5B) também foi realizada. RESULTADOS: Clodronato foi detectado no sangue por 14-175 dias e por até 175 dias na urina. Para alguns equinos, a concentração foi não-detectável em um momento, mas detectável no próximo momento. O valor terminal da vida-média em soro foi 1.80-283.9 dias. A concentração de CTX-1 foi significativamente elevada, relativo às amostras iniciais, em ambos os grupos (tratamento e controle), enquanto as concentrações de TRAcP5B foram significativamente menores no grupo de cavalos tratados. PRINCIPAIS LIMITAÇÕES: Número relativamente pequenos de cavalos no estudo. CONCLUSÕES: Baseado nos resultados dos biomarcadores, clodronato parece influencia osteoclastos na dose recomendada. Além disso, os resultados deste estudo suportam o regulamento de cavalos de corrida que impedem que cavalos que receberam bifosfonatos por razão médica de competir por um período de tempo prolongado.

Concentrations of dexmedetomidine and effect on biomarkers of cartilage toxicity following intra-articular administration in horses.

OBJECTIVE: The goal of this study was to determine plasma, urine, and synovial fluid concentrations and describe the effects on biomarkers of cartilage toxicity following intra-articular dexmedetomidine administration to horses. ANIMALS: 12 research horses. PROCEDURES: Horses received a single intra-articular administration of 1 µg/kg or 5 µg/kg dexmedetomidine or saline. Plasma, urine, and synovial fluid were collected prior to and up to 48 hours postadministration, and concentrations were determined. The effects on CS846 and C2C were determined in synovial fluid at 0, 12, and 24 hours postadministration using immunoassays. RESULTS: Plasma concentrations of dexmedetomidine fell below the limit of quantification (LOQ) (0.005 ng/mL) by 2.5 and 8 hours postadministration of 1 and 5 µg/kg, respectively. Synovial fluid concentrations were above the LOQ (0.1 ng/mL) of the assay at 24 hours in both dose groups. Drug was not detected in urine samples at any time postdrug administration. CS846 concentrations were significantly decreased relative to baseline at 12 hours postadministration in the saline group and significantly increased in the 5-µg/kg-dose group at 24 hours. Concentrations of C2C were significantly decreased at 12 and 24 hours postadministration in the saline treatment group. There were no significant differences in CS846 or C2C concentrations between dose groups at any time. CLINICAL RELEVANCE: Systemic concentrations of dexmedetomidine remained low, compared to synovial fluid concentrations. CS846, a marker of articular cartilage synthesis, increased in a dose-dependent fashion. Based on these findings, further dose titration and investigation of analgesic and adverse effects are warranted.

Hematologic Reference Intervals and Comparison of Natt-Herrick Technique and Smear-Based Leukocyte Estimation in Cockatiels (Nymphicus hollandicus).

Although cockatiels are among the most common avian species maintained as companion animals in the United States, information on standard hematologic reference values for this species is limited. The objectives of this study were to establish hematologic reference intervals (RI) for cockatiels, compare methods using both the Natt-Herrick technique (NHT) and the smear-based estimation technique (SBT), explore age and sex differences in the hematologic findings for this species, and produce the first cockatiel RI for fibrinogen concentration and thrombocyte estimate. Healthy cockatiels (60 males and 60 females, 2-11 years old) from a research colony were included in this study. Blood samples were placed in dipotassium ethylenediaminetetraacetic acid tubes, and erythrocyte counts and thrombocyte estimates were determined via automated analyzer (ADVIA 120) and SBT, respectively. Moreover, leukocyte concentrations were determined using both NHT and SBT to compare these common methods for measuring a complete blood count in cockatiels. Data were analyzed for outliers, distributions, descriptive statistics, and RI via Reference Value Adviser, a set of macroinstructions for Microsoft Excel (Microsoft, Redmond, WA, USA). Lymphocytes were the predominant leukocyte across both methods. According to the NHT, females had significantly higher concentrations of total leukocytes, heterophils, bands, lymphocytes, basophils, and total plasma protein compared with males. Significant inverse polynomial relationships were noted between total leukocyte count and age and lymphocyte counts and age for NHT. Total leukocyte count produced via NHT and SBT were compared using Passing-Bablok and Bland-Altman plots, and no significant constant or proportional biases were found. However, these methods showed wide limits of agreement. While the RI were interchangeable between methods from a clinical standpoint, the same method should be used to assess changes in an individual. The reported RI are uniquely robust given the sample size, balanced sex and age distributions, inclusion criteria, and control over sample collection.

Dental and Temporomandibular Joint Pathology of the Steller Sea Lion (Eumetopias jubatus).

Skulls from 112 Steller sea lions (Eumetopias jubatus) were examined according to predefined criteria. Of the specimens, 73 (65.2%) were from males, 29 (25.9%) from females and 10 (8.9%) were of unknown sex, with 50 adults (44.6%), 61 young adults (54.5%) and one of unknown age (0.9%). The number of teeth evaluated was 3,521. Adults had more acquired tooth loss than young adults (P <0.0001). A total of 1,660 teeth (47.1%) from 111 specimens (99.1%) had evidence of attrition or abrasion. Adults displayed more attrition or abrasion than young adults (P <0.0001). A total of 241 teeth (6.8%) from 47 specimens (42%) had tooth fractures. Adults had more fractured teeth than young adults (P <0.0001). Bony changes consistent with periodontitis affected 36.7% of teeth. Adults had more teeth affected by periodontitis than young adults (P <0.0001). Temporomandibular joint osteoarthritis lesions were found in 54 specimens (48.2%) with more in adults than in young adults (P <0.0001). Although the significance of our findings is unknown, the occurrence and severity of these lesions may play an important role in the morbidity and mortality of Steller sea lions.

Good clinical outcomes achieved in young dogs with tibial tuberosity avulsion fracture repairs when implants were left in situ past skeletal maturity.

OBJECTIVE: To evaluate outcomes of tibial tuberosity avulsion fractures (TTAF) in dogs with implants left in situ past skeletal maturity and to compare clinical outcomes with published outcomes in dogs whose implants were removed 4 to 6 weeks postoperatively. ANIMALS: 47 client-owned dogs. PROCEDURES: In this retrospective study, 47 dogs had surgery to correct a TTAF before 10 months of age and had the implants left in situ past skeletal maturity. Of these, 42 were followed for a median of 36 months postoperatively. Short- and long-term complications were recorded and compared with historically published data in which the implants were removed within 6 weeks of surgery. RESULTS: 14% (6/42) of our population experienced minor long-term complications (stiffness and lameness), 6% (3/47) experienced major short-term complications (repair failure), and 14% (6/24) experienced major long-term complications (implant removal). There was no difference in long-term outcomes when compared with results of historical reports in which implants were removed 4 to 6 weeks postoperatively. Client satisfaction was high, with 93% (38/41) grading outcomes as excellent and 95% (39/41) stating they would have surgery performed again in retrospect. CLINICAL RELEVANCE: Immature dogs with surgically repaired TTAFs have favorable long-term outcomes when the implants were left in situ past skeletal maturity. Dogs with TTAF repairs may not need implant removal unless it becomes clinically necessary. Avoiding a second procedure will decrease patient morbidity, recovery time, and cost.

Craniomaxillofacial trauma in immature dogs-etiology, treatments, and outcomes.

Treatment of craniomaxillofacial (CMF) trauma in dogs often requires a multidisciplinary approach and a thorough understanding of the CMF anatomical structures involved. This retrospective study aimed to utilize computed tomography (CT) studies of immature dogs evaluated for CMF trauma and to describe common fracture locations, treatment modalities, and complications, as well as the fracture healing outcomes. The medical records and CT studies of 94 dogs under 1 year of age over a 13-year period were evaluated. The skeletal location of CMF fractures, as well as the severity of displacement and fragmentation of each fracture, was recorded. Case demographic data and trauma etiology were also recorded. Animal bites accounted for the majority of trauma (71.0%). The most likely bone or region to be fractured was the maxillary bones, followed by the molar region of the mandibles. Up to 37 bones or specific regions were fractured in any given patient, with an average of 8.8 ± 3.1 fractured bones or regions per dog. Rostral mandibular trauma was associated with intra-articular fractures of the temporomandibular joint (p = 0.016). Patients sustained concomitant injuries in 32% of the cases. Muzzle therapy was the main treatment performed for most dogs (53.2%), followed by soft tissue closure (47.9%) and selective dental extractions (27.6%). Healing complications were recorded in 71.6% of the dogs, with malocclusion being the most reported complication (55.2%), and associated with dentate mandibular jaw fractures (p = 0.05). The average number of complications per dog was 2.4. No statistically significant association was found between treatment modality and healing outcome. There was a positive correlation between the severity of fracture fragmentation and displacement and a negative healing outcome (all rho >0.7). Further treatment was required in 55.6% of the dogs. Additional dental extractions were performed in 77.7% of patients. Healing complications were common in the immature CMF trauma case. Thus, the need for a comprehensive assessment of the entire CMF region during the initial visit, as well as follow-up, preferably using CT or cone beam CT, is underscored.

Seasonal variation of endogenous adrenocorticotropic hormone concentrations in healthy non-geriatric donkeys in Northern California.

Elevated plasma adrenocorticotropic hormone (ACTH) is often used to diagnose pituitary pars intermedia dysfunction (PPID) in horses. The hormone naturally increases in the fall in horses, and donkeys have been found to have higher ACTH concentrations than horses. However, circannual variation of ACTH has not been assessed in donkeys. The objective of the study was to establish seasonal variation of basal plasma ACTH concentrations over the course of a year in clinically healthy, non-geriatric donkeys. It was hypothesized that donkey ACTH concentrations would be higher than those reported in horses without PPID in all seasons, and that, similarly to horses, ACTH concentrations would further increase in the fall months. Twenty-six healthy adult donkeys (10 standards, 16 miniatures), a median (range) of 6 (2-13) years of age, were included. Donkeys were housed at a single location. Serial plasma samples were obtained monthly for 12 months. Plasma ACTH concentrations were determined by immunoassay. Data are presented as median (range), with a P-value < 0.05 considered significant. ACTH concentrations were lowest in the winter and spring [12.8 (5.0-73.6) pg/ml and 12.5 (2.8-62.6) pg/ml, respectively], with an increase in the summer [53.2 (29.7-305.0) pg/ml], and peak in the fall [77.1 (12.4-319.0) pg/ml]. ACTH concentrations were highest in the month of September [122.0 (41.7-319.0) pg/ml]. Donkey ACTH concentrations were higher than equine reference ranges from May through November but showed similar circannual variation with dramatic increases in the fall months. Species-specific reference ranges are necessary for accurate interpretation of endocrinopathy screenings in donkeys.

Characterization of the pharmacokinetics, behavioral effects and effects on thermal nociception of morphine 6-glucuronide and morphine 3-glucuronide in horses.

OBJECTIVE: To describe the pharmacokinetics, behavioral and physiologic effects and effects on thermal thresholds of morphine, morphine 6-glucuronide (M6G) and morphine 3-glucuronide (M3G) following administration to horses. STUDY DESIGN: Randomized balanced crossover study. ANIMALS: A total of seven University-owned horses, five mares and two geldings, aged 3-6 years. METHODS: Horses were treated with a single intravenous dosage of saline, morphine (0.2 mg kg-1), M6G (0.01 mg kg-1) and M3G (0.03 mg kg-1). Blood was collected prior to (baseline) and at several times post administration. Drug and metabolite concentrations were determined by liquid chromatography-mass spectrometry, and plasma pharmacokinetics were calculated. Behavioral observations and physiologic variables (heart rate, step counts, packed cell volume, total plasma protein and gastrointestinal sounds) were determined at baseline and for up to 6 hours. The effects on thermal nociception were determined and thermal excursion was calculated. RESULTS: The volumes of distribution were 4.75-10.5, 0.244-0.295 and 0.215-0.356 L kg-1 for morphine, M6G and M3G, respectively. Systemic clearances were 26.8-39.6, 3.16-3.88 and 1.46-2.13 mL minute-1 kg-1 for morphine, M6G and M3G, respectively. Morphine administration resulted in signs of excitation as evidenced by an increase in step counts and subjective behavioral observations, whereas M6G and M3G, based on the same criteria, appeared to cause sedative-like effects. Significant effects on thermal nociception were observed until 4 hours post morphine administration, 1 hour post M6G administration and at various times post M3G administration. CONCLUSIONS AND CLINICAL RELEVANCE: Results of this study provide additional information regarding the use of morphine in horses. Less locomotor excitation and gastrointestinal adverse effects, compared with morphine, coupled with favorable effects on thermal nociception are encouraging for further study of the pharmacodynamics of both M6G and M3G in horses.

Pharmacokinetics of grapiprant and effects on TNF-alpha concentrations following oral administration to horses.

Grapiprant is a prostaglandin E2 receptor antagonist that has been found to be an effective anti-inflammatory in dogs and that is devoid of some of the adverse effects associated with traditional NSAIDs that elicit their effects through inhibition of PGE2 production. Previously published reports have described the pharmacokinetics of this drug in horses when administered at 2 mg/kg; however, pharmacodynamic effects in this species have yet to be described. The objective of the current study was to describe the pharmacokinetics and pharmacodynamics of grapiprant at a higher dose. Eight horses received a single oral administration of 15 mg/kg. Plasma concentrations were determined for 96 h using liquid chromatography-tandem mass spectrometry. Non-compartmental analysis was used to determine pharmacokinetic parameters. Pharmacodynamic effects were assessed ex vivo by stimulating blood samples with PGE2 and determining TNF-ɑ concentrations. Maximum concentration, time to maximum concentration and area under the curve were 327.5 (188.4-663.0) ng/ml, 1 (0.75-2.0) hour and 831.8 (512.6-1421.6) h*ng/ml, respectively. The terminal half-life was 11.1 (8.27-21.2) hr. Significant stimulation of TNF alpha was noted for 2-4 h post-drug administration. Results of this study suggest a short duration of EP4 receptor engagement when administered at a dose of 15 mg/kg.

Pharmacokinetics, adverse effects and effects on thermal nociception following administration of three doses of codeine to horses.

BACKGROUND: In humans, codeine is a commonly prescribed analgesic that produces its therapeutic effect largely through metabolism to morphine. In some species, analgesic effects of morphine have also been attributed to the morphine-6-glucuronide (M6G) metabolite. Although an effective analgesic, administration of morphine to horses produces dose-dependent neuroexcitation at therapeutic doses. Oral administration of codeine at a dose of 0.6 mg/kg has been shown to generate morphine and M6G concentrations comparable to that observed following administration of clinically effective doses of morphine, without the concomitant adverse effects observed with morphine administration. Based on these results, it was hypothesized that codeine administration would provide effective analgesia with decreased adverse excitatory effects compared to morphine. Seven horses received a single oral dose of saline or 0.3, 0.6 or 1.2 mg/kg codeine or 0.2 mg/kg morphine IV (positive control) in a randomized balanced 5-way cross-over design. Blood samples were collected up to 72 hours post administration, codeine, codeine 6-glucuronide, norcodeine morphine, morphine 3-glucuronide and M6G concentrations determined by liquid chromatography- mass spectrometry and pharmacokinetic analysis performed. Pre- and post-drug related behavior, locomotor activity, heart rate and gastrointestinal borborygmi were recorded. Response to noxious stimuli was evaluated by determining thermal threshold latency. RESULTS: Morphine concentrations were highest in the morphine dose group at all times post administration, however, M6G concentrations were significantly higher in all the codeine dose groups compared to the morphine group starting at 1 hour post drug administration and up to 72-hours in the 1.2 mg/kg group. With the exception of one horse that exhibited signs of colic following administration of 0.3 and 0.6 mg/kg, codeine administration was well tolerated. Morphine administration, led to signs of agitation, tremors and excitation. There was not a significant effect on thermal nociception in any of the dose groups studied. CONCLUSIONS: The current study describes the metabolic profile and pharmacokinetics of codeine in horses and provides information that can be utilized in the design of future studies to understand the anti-nociceptive and analgesic effects of opioids in this species with the goal of promoting judicious and safe use of this important class of drugs.

Corrigendum: Craniomaxillofacial Trauma in Dogs-Part I: Fracture Location, Morphology and Etiology.

[This corrects the article DOI: 10.3389/fvets.2020.00241.].

Prediction of gestational age based on foetal ultrasonographic biometric measurements in light breed horses.

A table was generated, based on foetal ultrasonographic measurements in light breed mares, for each day of gestation beginning with day 100, to provide the predicted value of four biometric parameters: biparietal diameter (BPD), eye approximated volume (EyV), foetal aortic diameter (AortD) and femur length (FL). Using this table, day of gestation was successfully predicted in 23 Quarter Horses (QH) with known mating or ovulation dates. BPD, EyV and FL were the best foetal age predictors between 100- and 200-days gestation predicting within 2 weeks of the actual day of gestation, while BPD and EyV were best between 200 and 300 days (within 3 weeks), and EyV was best after 300 days (within 3 weeks).