Pharmacokinetics of acetaminophen after a single Oral administration of 20 or 40 mg/kg to 7-9 Day-old foals.

Background: Acetaminophen is utilized in human infants for pain management and fever. Neonatal foals might benefit from administration of acetaminophen but effective and safe dosage regimens for neonatal foals remains to be determined. Objective: The objective was to determine the plasma pharmacokinetics of acetaminophen following oral administration of a single dose of 20 mg/kg or 40 mg/kg to neonatal foals. A secondary objective was to evaluate any changes in hematology and biochemistry profiles. Study design: Randomized study. Methods: Eight clinically healthy 7-9-day old Quarter Horse foals (3 colts and 5 fillies) received a single oral dose of acetaminophen either 20 (n = 4) or 40 (n = 4) mg/kg. Hematology and biochemistry profiles were evaluated before and 7 days after drug administration. Blood samples were collected before and 8 times after acetaminophen administration for 48 h to quantify plasma acetaminophen concentrations. Plasma pharmacokinetic parameters were estimated using non- compartmental analysis. Results: The median peak plasma concentrations (and range) occurred at 1.5 (0.5-2) hours, and 1.0 (1-2) hours for the 20 and 40 mg/kg doses. The maximum plasma concentration (and range) was 12 (7.9-17.4) µg/mL for the 20 mg/kg dose and 14 (11-18) µg/mL for 40 mg/kg dose. The median AUC0-∞ ranged from 46 to 100 and 79 to 160 h*-µg/mL for the 20 and 40 mg/kg dose, respectively. Hematology and biochemistry profiles remained within normal limits. Conclusion: Plasma disposition of acetaminophen after oral administration of 20 and 40 mg/kg to neonates is comparable to adult horses. However, safety and the optimal dosage regimen of acetaminophen for treating pain and or pyrexia in neonates in this age group remains to be determined.

Pharmacokinetics of single dose administration of three increasing doses of acetaminophen per os in 1-3-month-old foals.

BACKGROUND: Acetaminophen is a common analgesic and antipyretic drug used in human medicine and might be an alternative to nonsteroidal anti-inflammatory drugs for treating pain and pyrexia in foals. The pharmacokinetics and safety of differing doses of acetaminophen have not been investigated in foals. OBJECTIVES: To determine the plasma pharmacokinetics and any changes in haematology and biochemistry profiles following oral administration of single doses of acetaminophen at 10, 20, and 40 mg/kg to foals. STUDY DESIGN: Randomised cross-over pharmacokinetic study. METHODS: Six Quarter Horse (two colts and four fillies) foals received 10, 20, and 40 mg/kg acetaminophen orally once. Haematology and biochemistry profiles were performed before and 7 days after each drug administration. Blood samples were collected over 64 h after drug administration and were used to quantify plasma acetaminophen concentrations by liquid chromatography. Pharmacokinetic parameters were determined using compartmental analysis. RESULTS: Median (range) acetaminophen plasma concentrations were 4.4 (1.8-5.1), 6.3 (2.6-12.6), and 14 (7.3-18) µg/ml for the 10, 20, and 40 mg/kg doses, respectively. Median acetaminophen area under the concentration versus time curve (AUC)0-∞ ranged from 25 (11-32), 41 (22-74), and 105 (82-142) h × µg/ml for the 10, 20, and 40 mg/kg doses, respectively. Dose-normalised maximal concentrations and AUC0-∞ values were similar across dose concentrations (p > 0.05). Median terminal half-life for all doses was 2.7-2.8 h. Haematology and biochemistry profiles were normal except for blood urea nitrogen and alkaline phosphatase concentrations. MAIN LIMITATIONS: Foals were growing throughout the study, starting at 1 month and ending at 3 months. Deposition of drugs changes with age. The sample size was small and only single doses were evaluated. No liver biopsies were performed. CONCLUSION: Plasma disposition of acetaminophen after a single oral dose of 10, 20, and 40 mg/kg to 1-3-month-old foals varies greatly with the dose. The analgesic and antipyretic effect in foals is unknown.

INTRODUCTION/CONTEXTE: L'acétaminophène est un médicament analgésique et antipyrétique utilisé communément en médecine humaine. Il pourrait représenter une alternative aux médicaments anti-inflammatoires non-stéroïdiens pour le traitement de la douleur et de la fièvre chez les poulains. La pharmacocinétique et la sécurité de différentes doses d'acétaminophène n'ont pas encore été investigués chez les poulains. OBJECTIFS: Déterminer la pharmacocinétique et les modifications aux profils hématologique et biochimique suivant l'administration orale d'une dose singulière d'acétaminophène à 10, 20 ou 40 mg/kg chez des poulains. TYPE D'ÉTUDE: Étude de pharmacocinétique croisée aléatoire. MÉTHODES: Six chevaux Quarter Horse (2 poulains mâles et 4 femelles) ont reçu 10, 20 et 40 mg/kg d'acétaminophène oralement à une reprise. Les profils hématologique et biochimique ont été analysés avant et 7 jours suivant chaque administration. Les échantillons sanguins ont été récoltés plus de 64 heures après l'administration de la médication et ont été utilisés pour quantifier les concentrations plasmatiques d'acétaminophène par chromatographie liquide. Les paramètres pharmacocinétiques ont été déterminés par analyse compartimentale. RÉSULTATS: Les concentrations plasmatiques médianes d'acétaminophène étaient de 4.4 (1.8-5.1), 6.3 (2.6-12.6), et 14 (7.3-18 ug/mL) pour les doses de 10, 20 et 40 mg/kg respectivement. L'aire sous la courbe médiane pour la concentration versus le temps de l'acétaminophène était de 25 (11-32), 41 (22-74) et 105 (82-142)h*ug/mL pour les doses de 10, 20 et 40 mg/kg respectivement. Les concentrations maximales à doses normalisées et les valeurs AUC0-∞ étaient similaires entre les concentrations des doses (p < 0.05). La demi-vie terminale médiane pour toutes les doses était 2.7-2.8 heures. Les profils hématologique et biochimique étaient normaux, à l'exception des concentrations d'azote uréique sanguine et de phosphatase alcaline. LIMITES PRINCIPALES: Les poulains ont grandi durant l'étude, débutant à 1 mois et se terminant à 3 mois d'âge. La déposition des médicaments varie avec l'âge. La taille de l'échantillon était petit et des doses singulières seulement ont été évaluées. Aucune biopsie de foie n'a été recueillie. CONCLUSIONS: Le sort plasmatique de l'acétaminophène suivant une dose singulière de 10, 20 ou 40 mg/kg chez des poulains de 1-3 mois d'âge varie grandement selon la dose. Les effets analgésique et antipyrétique de l'acétaminophène chez les poulains demeurent inconnus.

Pharmacokinetics and pharmacodynamics of repeat dosing of gabapentin in adult horses.

BACKGROUND: The repeated administration of high doses of gabapentin may provide better analgesia in horses than current clinical protocols. HYPOTHESIS AND OBJECTIVES: Administration of gabapentin at 40 and 120 mg/kg PO q 12 h for 14 days will not alter serum biochemistry findings or cause adverse effects. Our objectives were to evaluate the effect of gabapentin on serum biochemistry, physical examination, and plasma pharmacokinetics of gabapentin. ANIMALS: Six healthy adult mares. METHODS: Horses received 40 and 120 mg/kg of gabapentin orally q 12 h for 14 days. Horses were examined and scored for ataxia and sedation daily. Serum biochemistry variables were analyzed before treatment and days 7 and 14 after gabapentin administration. Plasma disposition of gabapentin was evaluated after the first and last drug administration. Pharmacokinetic parameters were estimated using noncompartmental analysis. RESULTS: No changes occurred in physiologic or biochemical variables. Median (range) maximal plasma gabapentin concentrations (µg/mL) after the last dose (day 15) were 7.6 (6.2-11) and 22 (14-33) for 40 mg/kg and 120 mg/kg doses respectively. Maximal concentration of gabapentin was reached within 1 hour after drug administration. Repeated administration of gabapentin resulted in a median (range) area under the curve (AUC0-12 hours ) last/first dose ratio of 1.5 (1.00-2.63) and 2.92 (1.4-3.8) for the 40 and 120 mg/kg regimens, respectively. CONCLUSION AND CLINICAL IMPORTANCE: Our results suggest that horses tolerate gabapentin up to 120 mg/kg PO q 12 h for 14 days. The analgesic effect of the dosage regimens evaluated in our study warrants further research.

Assessment of Veterinary Students' Responses to Questions Regarding Small Animal Pain Recognition and Analgesic Treatment Options.

Pain recognition and treatment in companion animals are important aspects of veterinary medicine, yet the teaching of these concepts may not be adequate at all academic institutions. This study was designed to evaluate veterinary students' ability to recall signs of pain and specific analgesic drugs in dogs and cats. We hypothesized that students in the fourth, or final, year of their veterinary curriculum would have a better understanding of pain recognition and be able to recall more analgesic options. A brief, voluntary, and anonymous open question survey was made available to all veterinary students, years 1 to 4, at our institution. The questions included, "How does a cat/dog show signs of pain?" and "What pain medications are used in cats/dogs?" Survey responses were collated according to the students' year in the curriculum, and the most common responses for signs of pain and analgesic medications recalled by the students in both the cat and dog were compared for significant differences. Results showed that students in the class of 2017 (seniors) had no superior recall of analgesic medications or recognition of pain in cats or dogs compared to the other classes. Vocalization was the most common sign of pain recalled with at least 50% responses from all classes. Carprofen was the most commonly recalled analgesic for dogs (the difference between classes, p = .04). Meloxicam was the most commonly recalled analgesic for cats (the difference among classes, p < .001). Based on these results, areas of improvement were identified for our analgesic curriculum.

Plasma disposition of gabapentin after the intragastric administration of escalating doses to adult horses.

BACKGROUND: In humans, gabapentin an analgesic, undergoes non-proportional pharmacokinetics which can alter efficacy. No information exists on the pharmacokinetics of dosages >20 mg/kg, escalating dosages or dose proportionality of gabapentin in horses. HYPOTHESIS AND OBJECTIVES: Gabapentin exposure in plasma would not increase proportionally relative to the dose in horses receiving dosages ≥20 mg/kg. To assess the plasma pharmacokinetics of gabapentin after nasogastric administration of gabapentin at dosages of 10 to 160 mg/kg in adult horses. ANIMALS: Nine clinically healthy adult Arabian and Quarter Horses. METHODS: In a randomized blinded trial, gabapentin was administered by nasogastric intubation to horses at 10, 20 mg/kg (n = 3) and 60, 80, 120, 160 mg/kg (n = 6). Plasma was collected before and at regular times over 64 hours after administration of gabapentin. Gabapentin was quantified using a validated chromatographic method. Dose proportionality was estimated using a power model. Pharmacokinetic parameters were estimated using compartmental pharmacokinetic analysis. RESULTS: Plasma pharmacokinetics parameters of gabapentin were estimated after nasogastric administration at dosages of 10 to 160 mg/kg. Gabapentin plasma concentration increased with dose increments. However, the area under the concentration curve from zero to infinity and maximal plasma concentration did not increase proportionally relative to the dose in horses. CONCLUSIONS AND CLINICAL IMPORTANCE: Gabapentin exposure in plasma is not proportional relative to the dose in horses receiving nasogastric dosages of 10 to 160 mg/kg.

2020 AAHA Anesthesia and Monitoring Guidelines for Dogs and Cats.

Risk for complications and even death is inherent to anesthesia. However, the use of guidelines, checklists, and training can decrease the risk of anesthesia-related adverse events. These tools should be used not only during the time the patient is unconscious but also before and after this phase. The framework for safe anesthesia delivered as a continuum of care from home to hospital and back to home is presented in these guidelines. The critical importance of client communication and staff training have been highlighted. The role of perioperative analgesia, anxiolytics, and proper handling of fractious/fearful/aggressive patients as components of anesthetic safety are stressed. Anesthesia equipment selection and care is detailed. The objective of these guidelines is to make the anesthesia period as safe as possible for dogs and cats while providing a practical framework for delivering anesthesia care. To meet this goal, tables, algorithms, figures, and "tip" boxes with critical information are included in the manuscript and an in-depth online resource center is available at aaha.org/anesthesia.

Local and regional anaesthesia in dogs and cats: Overview of concepts and drugs (Part 1).

Pain management in veterinary patients is a crucial component of appropriate patient care. Multimodal analgesia that includes both systemically and locally/regionally administered drugs is generally the most effective approach to providing pain relief. Local anaesthetic drugs used in local and regional blockade are unique in that they can completely block the transmission of pain (in conscious patients) or nociceptive (in anaesthetized patients) signals, thereby providing profound analgesia. In addition, local and regional administration of drugs, when compared with systemic bolus administration, generally results in a lower incidence of dose-related adverse effects. Due to the potential to provide profound analgesia and the high safety margin (when used correctly) of this drug class, local anaesthetics are recommended as part of the analgesic protocol in the majority of patients undergoing surgical procedures or suffering traumatic injuries. This manuscript, Part 1 of a two-part instalment, emphasizes the importance of using local and regional anaesthesia as a component of multimodal analgesia, provides a review of the basic pharmacokinetics/pharmacodynamics of local anaesthetic drugs in general, lists information on commonly used local anaesthetic drugs for local and regional blockade in dogs and cats, and briefly introduces the novel liposome-encapsulated bupivacaine (NOCITA®). Part 2 is a review of local and regional anaesthetic techniques used in dogs and cats (Grubb & Lobprise, 2020).

Local and regional anaesthesia in dogs and cats: Descriptions of specific local and regional techniques (Part 2).

Pain management in veterinary patients is a crucial component of appropriate patient care. Local anaesthetic drugs used in local and regional blockade can completely block the transmission of nociceptive impulses, decreasing both intra-operative nociception and postoperative pain, while decreasing the potential incidence of adverse effects that can be associated with systemic boluses of drugs. For efficacy and safety, this class of drugs is recommended as part of the analgesic protocol in the majority of surgical procedures and traumatic injuries. Numerous local and regional blocks are proven effective in dogs and cats, thus providing the clinician with ample opportunity to include these blocks in practice. This manuscript, Part 2 of a two-part instalment, focuses on brief descriptions of select commonly used local/regional anaesthesia techniques for dogs and cats that cover a multitude of painful surgeries/injuries and that can be implemented in any practice. In Part 1 of this topic, detailed information on local anaesthetic drugs commonly used in small animal practice was reviewed (Grubb & Lobprise, 2020).

Effects of ventilation mode and blood flow on arterial oxygenation during pulse-delivered inhaled nitric oxide in anesthetized horses.

OBJECTIVE To determine the impact of mechanical ventilation (MV) and perfusion conditions on the efficacy of pulse-delivered inhaled nitric oxide (PiNO) in anesthetized horses. ANIMALS 27 healthy adult horses. PROCEDURES Anesthetized horses were allocated into 4 groups: spontaneous breathing (SB) with low (< 70 mm Hg) mean arterial blood pressure (MAP; group SB-L; n = 7), SB with physiologically normal (≥ 70 mm Hg) MAP (group SB-N; 8), MV with low MAP (group MV-L; 6), and MV with physiologically normal MAP (group MV-N; 6). Dobutamine was used to maintain MAP > 70 mm Hg. Data were collected after a 60-minute equilibration period and at 15 and 30 minutes during PiNO administration. Variables included Pao2, arterial oxygen saturation and content, oxygen delivery, and physiologic dead space-to-tidal volume ratio. Data were analyzed with Shapiro-Wilk, Mann-Whitney U, and Friedman ANOVA tests. RESULTS Pao2, arterial oxygen saturation, arterial oxygen content, and oxygen delivery increased significantly with PiNO in the SB-L, SB-N, and MV-N groups; were significantly lower in group MV-L than in group MV-N; and were lower in MV-N than in both SB groups during PiNO. Physiologic dead space-to-tidal volume ratio was highest in the MV-L group. CONCLUSIONS AND CLINICAL RELEVANCE Pulmonary perfusion impacted PiNO efficacy during MV but not during SB. Use of PiNO failed to increase oxygenation in the MV-L group, likely because of profound ventilation-perfusion mismatching. During SB, PiNO improved oxygenation irrespective of the magnitude of blood flow, but hypoventilation and hypercarbia persisted. Use of PiNO was most effective in horses with adequate perfusion.

Pharmacokinetics and physiologic/behavioral effects of buprenorphine administered sublingually and intravenously to neonatal foals.

Buprenorphine is absorbed following sublingual administration, which would be a low-stress delivery route in foals. However, the pharmacokinetics/pharmacodynamics are not described in foals. Six healthy foals <21 days of age participated in a blinded, randomized, 3-period, 5-sequence, 3-treatment crossover prospective study. Foals received 0.01-0.02 mg/kg buprenorphine administered SL or IV with an equivalent volume of saline administered by the opposite route. Blood was collected from the cephalic vein for pharmacokinetic analysis. Physiologic parameters (HR, RR, body temperature, GI sounds), locomotion (pedometer), and behavioral data (activity level, nursing time, response to humans) were recorded. Plasma concentration of buprenorphine exceeded a presumed analgesic level (0.6 ng/ml) in five foals in the IV group and one in the SL group but only for a very brief time. Pharmacokinetic analysis following IV administration demonstrated a short elimination half-life (t1/2ß 1.95 ± 0.7 hr), large volume of distribution (6.46 ± 1.54 L/kg), and a high total clearance (55.83 ± 23.75 ml/kg/min), which differs from adult horses. Following SL administration, maximum concentrations reached were 0.61 ± 0.11 ng/ml and bioavailability was 25.1% ± 10.9%. In both groups, there were minor statistical differences in HR, RR, body temperature, locomotion, and time spent nursing. However, these differences were clinically insignificant in this single dose study, and excitement, sedation, or colic did not occur.

Oral Coadministration of Fluconazole with Tramadol Markedly Increases Plasma and Urine Concentrations of Tramadol and the O-Desmethyltramadol Metabolite in Healthy Dogs.

Tramadol is used frequently in the management of mild to moderate pain conditions in dogs. This use is controversial because multiple reports in treated dogs demonstrate very low plasma concentrations of O-desmethyltramadol (M1), the active metabolite. The objective of this study was to identify a drug that could be coadministered with tramadol to increase plasma M1 concentrations, thereby enhancing analgesic efficacy. In vitro studies were initially conducted to identify a compound that inhibited tramadol metabolism to N-desmethyltramadol (M2) and M1 metabolism to N,O-didesmethyltramadol (M5) without reducing tramadol metabolism to M1. A randomized crossover drug-drug interaction study was then conducted by administering this inhibitor or placebo with tramadol to 12 dogs. Blood and urine samples were collected to measure tramadol, tramadol metabolites, and inhibitor concentrations. After screening 86 compounds, fluconazole was the only drug found to inhibit M2 and M5 formation potently without reducing M1 formation. Four hours after tramadol administration to fluconazole-treated dogs, there were marked statistically significant (P < 0.001; Wilcoxon signed-rank test) increases in plasma tramadol (31-fold higher) and M1 (39-fold higher) concentrations when compared with placebo-treated dogs. Conversely, plasma M2 and M5 concentrations were significantly lower (11-fold and 3-fold, respectively; P < 0.01) in fluconazole-treated dogs. Metabolite concentrations in urine followed a similar pattern. This is the first study to demonstrate a potentially beneficial drug-drug interaction in dogs through enhancing plasma tramadol and M1 concentrations. Future studies are needed to determine whether adding fluconazole can enhance the analgesic efficacy of tramadol in healthy dogs and clinical patients experiencing pain.

Identification of canine cytochrome P-450s (CYPs) metabolizing the tramadol (+)-M1 and (+)-M2 metabolites to the tramadol (+)-M5 metabolite in dog liver microsomes.

We previously showed that (+)-tramadol is metabolized in dog liver to (+)-M1 exclusively by CYP2D15 and to (+)-M2 by multiple CYPs, but primarily CYP2B11. However, (+)-M1 and (+)-M2 are further metabolized in dogs to (+)-M5, which is the major metabolite found in dog plasma and urine. In this study, we identified canine CYPs involved in metabolizing (+)-M1 and (+)-M2 using recombinant enzymes, untreated dog liver microsomes (DLMs), inhibitor-treated DLMs, and DLMs from CYP inducer-treated dogs. A canine P-glycoprotein expressing cell line was also used to evaluate whether (+)-tramadol, (+)-M1, (+)-M2, or (+)-M5 are substrates of canine P-glycoprotein, thereby limiting their distribution into the central nervous system. (+)-M5 was largely formed from (+)-M1 by recombinant CYP2C21 with minor contributions from CYP2C41 and CYP2B11. (+)-M5 formation in DLMs from (+)-M1 was potently inhibited by sulfaphenazole (CYP2C inhibitor) and chloramphenicol (CYP2B11 inhibitor) and was greatly increased in DLMs from phenobarbital-treated dogs. (+)-M5 was formed from (+)-M2 predominantly by CYP2D15. (+)-M5 formation from (+)-M1 in DLMs was potently inhibited by quinidine (CYP2D inhibitor) but had only a minor impact from all CYP inducers tested. Intrinsic clearance estimates showed over 50 times higher values for (+)-M5 formation from (+)-M2 compared with (+)-M1 in DLMs. This was largely attributed to the higher enzyme affinity (lower Km) for (+)-M2 compared with (+)-M1 as substrate. (+)-tramadol, (+)-M1, (+)-M2, or (+)-M5 were not p-glycoprotein substrates. This study provides a clearer picture of the role of individual CYPs in the complex metabolism of tramadol in dogs.

Comparison of Enterprise Point-of-Care and Nova Biomedical Critical Care Xpress analyzers for determination of arterial pH, blood gas, and electrolyte values in canine and equine blood.

BACKGROUND: Point-of-care analyzers can provide a rapid turnaround time for critical blood test results. Agreement between the Enterprise Point-of-Care (EPOC) and bench-top laboratory analyzers is important to determine the clinical reliability of the EPOC. OBJECTIVES: The aim of the study was (1) to evaluate the precision (repeatability) of blood gas values measured by the EPOC and (2) to determine the level of agreement between the EPOC and Nova Critical Care Express (Nova CCX) for the assessment of arterial pH, blood gases, and electrolyte variables in canine and equine blood. METHODS: Arterial blood samples from dogs were analyzed on the EPOC and Nova CCX analyzers to determine precision and agreement of pH, PaCO2 , PaO2 , and HCT. The same analytes plus Na+ , K- , and Cl- were analyzed for agreement using equine blood. Statistical analyses included assessment of precision using the coefficient of variation (CV%), and agreement using the Deming regression, Pearson correlation, and Bland-Altman plots. RESULTS: Both analyzers provided precise results of pH, PaCO2 , PaO2, and HCT, meeting CV% quality requirement values. In both species, Deming regression results were acceptable and correlation values were above 0.93 for arterial pH and blood gases, but lower for sodium and chloride. Bland-Altman plots demonstrated varying degrees of bias, but good agreement between the 2 analyzers was seen when arterial blood gases and electrolytes were measured, except for PaCO2 and Cl-. CONCLUSION: The EPOC analyzer provides consistent, reliable results for canine arterial blood gas values and for equine arterial blood gas and electrolyte values. Cl- results could be acceptable with the application of a correction factor, but the PaCO2 results were more variable.

Assessment of clinical application of pulse oximetry probes in llamas and alpacas.

The placement and accuracy of pulse oximeter probes can vary markedly among species. For our study, we aimed to assess the accuracy of pulse oximetry and to determine the most clinically useful sites for probe placement in llamas and alpacas. The objectives included an analysis of pulse oximetry probes for accurate assessment of llamas and alpacas and to determine the best placement of the probes to achieve accurate readings. For study 1, saturation of haemoglobin with oxygen was measured in 184 arterial blood gas samples (SaO2) using a co-oximeter and compared to saturation of haemoglobin with oxygen simultaneously measured using a pulse oximeter (SpO2). The bias and precision for the SpO2-SaO2 difference was calculated and plotted on a Bland-Altman plot. For study 2, SpO2 data was collected 624 times from a variety of sites [tongue (T), nasal septum (NS), lip (L), vulva (V), prepuce (P), ear (E), and scrotum (S)] and recorded based upon a percentage of successful readings. Results for study 1 revealed that SpO2 was consistently 0 to -6% points different than SaO2. The bias and precision of the SpO2-SaO2 difference was -2.6 ± 1.7%. Results for study 2 uncovered that 540 recordings were successful readings and were obtained from the tongue and nasal septum with 97% accuracy, the lip 80%, vulva 62%, prepuce 59%, ear and scrotum < 50%. We concluded that pulse oximetry probes provide reliable estimates of arterial haemoglobin oxygen saturation in llamas and alpacas and is most accurately read when placed on the nasal septum or tongue.

Relationship between the melanocortin-1 receptor (MC1R) variant R306ter and physiological responses to mechanical or thermal stimuli in Labrador Retriever dogs.

OBJECTIVE: Variants in the MC1R gene have been associated with red hair color and sensitivity to pain in humans. The study objective was to determine if a relationship exists between MC1R genotype and physiological thermal or mechanical nociceptive thresholds in Labrador Retriever dogs. STUDY DESIGN: Prospective experimental study. ANIMALS: Thirty-four Labrador Retriever dogs were included in the study following public requests for volunteers. Owner consent was obtained and owners verified that their dog was apparently not experiencing pain and had not been treated for pain during the previous 14 days. The study was approved by the Institutional Animal Care and Use Committee. METHODS: Nociceptive thresholds were determined from a mean of three thermal and five mechanical replications using commercially available algometers. Each dog was genotyped for the previously described MC1R variant (R306ter). Data were analyzed using one-way anova with post hoc comparisons using Tukey's test (p < 0.05). RESULTS: Thirteen dogs were homozygous wild-type (WT/WT), nine were heterozygous (WT/R306ter), and eight were homozygous variant (R306ter/R306ter) genotype. Four dogs could not be genotyped. A significant difference (p = 0.04) in mechanical nociceptive thresholds was identified between dogs with the WT/WT genotype (12.1±2.1 N) and those with the WT/R306ter genotype (9.2±2.4 N). CONCLUSION: A difference in mechanical, but not thermal, nociceptive threshold was observed between wild-type and heterozygous MC1R variants. Differences in nociceptive thresholds between homozygous R306ter variants and other genotypes for MC1R were not observed. CLINICAL RELEVANCE: Compared with the wild-type MC1R genotype, nociceptive sensitivity to mechanical force in dogs with a single variant R306ter allele may be greater. However, in contrast to the reported association between homozygous MC1R variants (associated with red hair color) and nociception in humans, we found no evidence of a similar relationship in dogs with the homozygous variant genotype.

Tramadol metabolism to O-desmethyl tramadol (M1) and N-desmethyl tramadol (M2) by dog liver microsomes: Species comparison and identification of responsible canine cytochrome P-450s (CYPs).

Tramadol is widely used to manage mild to moderately painful conditions in dogs. However, this use is controversial since clinical efficacy studies in dogs showed conflicting results, while pharmacokinetic studies demonstrated relatively low circulating concentrations of O-desmethyltramadol (M1). Analgesia has been attributed to the opioid effects of M1, while tramadol and the other major metabolite (N-desmethyltramadol, M2) are considered inactive at opioid receptors. The aims of this study were to determine whether cytochrome P450 (CYP) dependent M1 formation by dog liver microsomes is slower compared with cat and human liver microsomes; and identify the CYPs responsible for M1 and M2 formation in canine liver. Since tramadol is used as a racemic mixture of (+)- and (-)-stereoisomers, both (+)-tramadol and (-)- tramadol were evaluated as substrates. M1 formation from tramadol by liver microsomes from dogs was slower than from cats (3.9-fold), but faster than humans (7-fold). However, M2 formation by liver microsomes from dogs was faster than from cats (4.8-fold) and humans (19-fold). Recombinant canine CYP activities indicated that M1 was formed by CYP2D15, while M2 was largely formed by CYP2B11 and CYP3A12. This was confirmed by dog liver microsomes studies that showed selective inhibition of M1 formation by quinidine and M2 formation by chloramphenicol and CYP2B11 antiserum, and induction of M2 formation by phenobarbital. Findings were similar for both (+)-tramadol and (-)-tramadol. In conclusion, low circulating M1 concentrations in dogs is explained in part by low M1 formation and high M2 formation, which are mediated by CYP2D15 and CYP2B11/CYP3A12, respectively.

Cardiorespiratory Changes and Pain Response of Lift Laparoscopy Compared to Capnoperitoneum Laparoscopy in Dogs.

OBJECTIVE: To compare intraoperative physiologic variables and post-operative pain associated with lift laparoscopy and conventional capnoperitoneum laparoscopy. STUDY DESIGN: Prospective randomized case controlled study. ANIMALS: Healthy dogs (n = 30). METHODS: Dogs having laparoscopic ovariohysterectomy were randomly assigned to lift laparoscopy (n = 14) or capnoperitoneum (16) laparoscopy. Physiologic variables measured intraoperatively were documented. Postoperatively, pain response was assessed in a blinded fashion using the short Glasgow pain scale and von Frey filament aesthesiometry. RESULTS: Lift laparoscopy was associated with less frequency of hypercapnia, required less anesthetic gas, and was not more time-consuming or painful than capnoperitoneum laparoscopy. CONCLUSIONS: Lift laparoscopy is a feasible alternative to capnoperitoneum laparoscopy, especially in dogs where pressurized capnoperitoneum is not desired.

Effects of pulse-delivered inhaled nitric oxide administration on pulmonary perfusion and arterial oxygenation in dorsally recumbent isoflurane-anesthetized horses.

OBJECTIVE: To image the spatial distribution of pulmonary blood flow by means of scintigraphy, evaluate ventilation-perfusion (VA/Q) matching and pulmonary blood shunting (Qs/Qt) by means of the multiple inert gas elimination technique (MIGET), and measure arterial oxygenation and plasma endothelin-1 concentrations before, during, and after pulse-delivered inhaled nitric oxide (PiNO) administration to isoflurane-anesthetized horses in dorsal recumbency. ANIMALS: 3 healthy adult Standardbreds. PROCEDURES: Nitric oxide was pulsed into the inspired gases in dorsally recumbent isoflurane-anesthetized horses. Assessment of VA/Q matching, Qs/Qt, and Pao2 content was performed by use of the MIGET, and spatial distribution of pulmonary blood flow was measured by perfusion scintigraphy following IV injection of technetium Tc 99m-labeled macroaggregated human albumin before, during, and 30 minutes after cessation of PiNO administration. RESULTS: During PiNO administration, significant redistribution of blood flow from the dependent regions to the nondependent regions of the lungs was found and was reflected by improvements in VA/Q matching, decreases in Qs/Qt, and increases in Pao2 content, all of which reverted to baseline values at 30 minutes after PiNO administration. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of PiNO in anesthetized dorsally recumbent horses resulted in redistribution of pulmonary blood flow from dependent atelectatic lung regions to nondependent aerated lung regions. Because hypoxemia is commonly the result of atelectasis in anesthetized dorsally recumbent horses, the addition of nitric oxide to inhaled gases could be used clinically to alleviate hypoxemia in horses during anesthesia.

The effects of pulse-delivered inhaled nitric oxide on arterial oxygenation, ventilation-perfusion distribution and plasma endothelin-1 concentration in laterally recumbent isoflurane-anaesthetized horses.

OBJECTIVES: Anaesthetized horses commonly become hypoxaemic due to ventilation/perfusion (V·A/Q·) mismatch and increased pulmonary shunt fraction (Qs·/Qt·). Pulse-delivered inhaled nitric oxide may improve oxygenation but may increase plasma concentration of the potent vasoconstrictor, endothelin-1 (ET-1). Objectives: Study 1) compare arterial oxygen concentration (PaO2) and saturation (SaO2), calculated Qs·/Qt· and ET-1 concentration; and Study 2) assess V·A/Q· matching and measured Qs·/Qt· in isoflurane-anaesthetized horses in left lateral recumbency receiving pulse-delivered inhaled nitric oxide (PiNO group) or inhalant gas only (C group). STUDY DESIGN: Prospective research trial. ANIMALS: Ten Healthy adult Standardbred horses. Two horses were anaesthestized in both groups in a random cross-over design with >4 weeks between studies. METHODS: Study 1) Cardiopulmonary data including PaO2, SaO2, Qs·/Qt· and ET-1 concentration were measured or calculated prior to and at various points during PiNO administration in 6PiNO and 6C horses. Two-way repeated measures anova with Bonferroni significant difference test was used for data analysis with p < 0.05 considered significant. Study 2) V·A/Q· matching and Qs·/Qt· were determined using the multiple inert gas elimination technique in 3 horses. Data were collected after 60 minutes of anaesthesia without PiNO (baseline) and 15 minutes after PiNO was pulsed during the first 30%, and then the first 60%, of inspiration. Data were descriptive only. RESULTS: Study 1) PaO2 and SaO2 were higher and calculated Qs·/Qt· was lower in the PiNO group than the C group at most time points. ET-1 was not different over time or between groups. Study 2) V·A/Q· matching and measured Qs·/Qt· were improved from baseline in all horses but PiNO60% provided no improvement when compared to PiNO30%. CONCLUSIONS AND CLINICAL RELEVANCE: PiNO delivered in the initial portion of the inspiration effectively relieves hypoxaemia in anaesthetized horses by improving V·A/Q· matching and decreasing Qs·/Qt· without affecting ET-1.