Concentrations of medetomidine enantiomers and vatinoxan, an α2-adrenoceptor antagonist, in plasma and central nervous tissue after intravenous coadministration in dogs

Objective To quantify the peripheral selectivity of vatinoxan (L-659,066, MK-467) in dogs by comparing the concentrations of vatinoxan, dexmedetomidine and levo-medetomidine in plasma and central nervous system (CNS) tissue after intravenous (IV) coadministration of vatinoxan and medetomidine. Study design Experimental, observational study. Animals A group of six healthy, purpose-bred Beagle dogs (four females and two males) aged 6.5 +/- 0.1 years (mean +/- standard deviation). Methods All dogs were administered a combination of medetomidine (40 mu g kg(-1)) and vatinoxan (800 mu g kg(-1)) as IV bolus. After 20 minutes, the dogs were euthanized with an IV overdose of pentobarbital (140 mg kg(-1)) and both venous plasma and CNS tissues (brain, cervical and lumbar spinal cord) were harvested. Concentrations of dexmedetomidine, levomedetomidine and vatinoxan in all samples were quantified by liquid chromatography-tandem mass spectrometry and data were analyzed with nonparametric tests with post hoc corrections where appropriate. Results All dogs became deeply sedated after the treatment. The CNS-to-plasma ratio of vatinoxan concentration was approximately 1:50, whereas the concentrations of dexmedetomidine and levomedetomidine in the CNS were three- to seven-fold of those in plasma. Conclusions and clinical relevance With the doses studied, these results confirm the peripheral selectivity of vatinoxan in dogs, when coadministered IV with medetomidine. Thus, it is likely that vatinoxan preferentially antagonizes alpha(2)-adrenoceptors outside the CNS.Peer reviewe

Indexing cardiovascular and respiratory variables: allometric scaling principles

To describe the allometric scaling principles underlying appropriate indexing of cardiovascular and respiratory measurements obtained in adult mammals, and to propose guidelines for indexing experimental cardiovascular and respiratory data.PubMed, using the terms 'allometry', 'allometric', 'indexing', 'cardiovascular' and 'respiratory'.Indexing of cardiopulmonary variables is commonly used in attempts to account for the effects of body size on measurements and to standardize them. Some cardiopulmonary variables have been indexed using various functions of body mass in a process that often ignores the underlying relationship between the variable of interest and body size, as described in the allometry literature. This can result in a failure to ideally reduce the effect of body size on measurements in a manner that highlights differences. We review how commonly measured cardiopulmonary variables are related to body mass in mammalian species according to the allometry literature, and offer suggestions on how this information can be used to appropriately index cardiopulmonary variables in a simple and informative manner

Indexing cardiovascular and respiratory variables: allometric scaling principles.

ObjectivesTo describe the allometric scaling principles underlying appropriate indexing of cardiovascular and respiratory measurements obtained in adult mammals, and to propose guidelines for indexing experimental cardiovascular and respiratory data.Database usedPubMed, using the terms 'allometry', 'allometric', 'indexing', 'cardiovascular' and 'respiratory'.ConclusionsIndexing of cardiopulmonary variables is commonly used in attempts to account for the effects of body size on measurements and to standardize them. Some cardiopulmonary variables have been indexed using various functions of body mass in a process that often ignores the underlying relationship between the variable of interest and body size, as described in the allometry literature. This can result in a failure to ideally reduce the effect of body size on measurements in a manner that highlights differences. We review how commonly measured cardiopulmonary variables are related to body mass in mammalian species according to the allometry literature, and offer suggestions on how this information can be used to appropriately index cardiopulmonary variables in a simple and informative manner

Indexing cardiovascular and respiratory variables: allometric scaling principles.

To describe the allometric scaling principles underlying appropriate indexing of cardiovascular and respiratory measurements obtained in adult mammals, and to propose guidelines for indexing experimental cardiovascular and respiratory data.PubMed, using the terms 'allometry', 'allometric', 'indexing', 'cardiovascular' and 'respiratory'.Indexing of cardiopulmonary variables is commonly used in attempts to account for the effects of body size on measurements and to standardize them. Some cardiopulmonary variables have been indexed using various functions of body mass in a process that often ignores the underlying relationship between the variable of interest and body size, as described in the allometry literature. This can result in a failure to ideally reduce the effect of body size on measurements in a manner that highlights differences. We review how commonly measured cardiopulmonary variables are related to body mass in mammalian species according to the allometry literature, and offer suggestions on how this information can be used to appropriately index cardiopulmonary variables in a simple and informative manner

Pharmacokinetics of butorphanol in male neutered cats anesthetized with isoflurane.

This study characterized the pharmacokinetics of butorphanol in cats anesthetized with isoflurane. Six young healthy male neutered cats were used. Cats were anesthetized with isoflurane in oxygen. Catheters were placed in a jugular vein for blood sampling and in a medial saphenous vein for butorphanol and lactated Ringer's solution administration. Butorphanol tartrate (1 mg/kg over 5 min) was administered intravenously. Blood samples were collected prior to butorphanol administration and at various times up to 365 min following administration. Plasma butorphanol concentration was measured using liquid chromatography/tandem mass spectrometry. Compartment models were fitted to the time-concentration data using nonlinear mixed effect modeling. A three-compartment model best fitted the data. Typical value (% interindividual variability) for the three volumes of distribution, the metabolic clearance, and the two distribution clearances were 230 (72), 1095 (not estimated), and 2596 (not estimated) ml/kg, and 18.4 (72), 169.6 (52), and 55.0 (43), respectively. Pharmacokinetic simulation suggested that a loading dose (µg/kg) calculated as 0.287 × target plasma concentration in ng/ml (CT ) followed by intravenous infusions (µg/kg/min) of 0.098 × CT for 20 min, 0.049 × CT for 40 min, and 0.022 × CT thereafter would rapidly achieve and maintain CT  ± 10% for up to 6.5 h

Effects of Trazodone and Dexmedetomidine on Fentanyl-Mediated Reduction of Isoflurane Minimum Alveolar Concentration in Cats

OBJECTIVE: To screen modulators of biogenic amine (BA) neurotransmission for the ability to cause fentanyl to decrease isoflurane minimum alveolar concentration (MAC) in cats, and to test whether fentanyl plus a combination of modulators decreases isoflurane MAC more than fentanyl alone. STUDY DESIGN: Prospective, experimental study. ANIMALS: A total of six adult male Domestic Short Hair cats. METHODS: Each cat was anesthetized in three phases with a 1 week washout between studies. In phase 1, anesthesia was induced and maintained with isoflurane, and MAC was measured in duplicate using a tail clamp stimulus and standard bracketing technique. A 21 ng mL-1 fentanyl target-controlled infusion was then administered and MAC measured again. In phase 2, a single cat was administered a single BA modulator (buspirone, haloperidol, dexmedetomidine, pregabalin, ramelteon or trazodone) in a pilot drug screen, and isoflurane MAC was measured before and after fentanyl administration. In phase 3, isoflurane MAC was measured before and after fentanyl administration in cats co-administered trazodone and dexmedetomidine, the two BA modulator drugs associated with fentanyl MAC-sparing in the screen. Isoflurane MAC-sparing by fentanyl alone, trazodone-dexmedetomidine and trazodone-dexmedetomidine-fentanyl was evaluated using paired t tests with p < 0.05 denoting significant effects. RESULTS: The MAC of isoflurane was 1.87% ± 0.09 and was not significantly affected by fentanyl administration (p = 0.09). In the BA screen, cats administered trazodone or dexmedetomidine exhibited 26% and 22% fentanyl MAC-sparing, respectively. Trazodone-dexmedetomidine co-administration decreased isoflurane MAC to 1.50% ± 0.14 (p < 0.001), and the addition of fentanyl further decreased MAC to 0.95% ± 0.16 (p < 0.001). CONCLUSIONS AND CLINICAL RELEVANCE: Fentanyl alone does not affect isoflurane MAC in cats, but co-administration of trazodone and dexmedetomidine causes fentanyl to significantly decrease isoflurane requirement

Pharmacokinetics of hydromorphone after intravenous and intramuscular administration in male rhesus macaques (Macaca mulatta).

This study reports the pharmacokinetics of hydromorphone after intravenous and intramuscular administration to rhesus macaques (Macaca mulatta). Hydromorphone (0.075 mg/kg) was administered intravenously as a bolus or intramuscularly on separate occasions to healthy, socially housed, socially reared, adult, intact male rhesus macaques (n = 4). Blood samples were collected prior to and until 10 h after administration. Serum hydromorphone concentrations were analyzed with liquid chromatography-mass spectrometry. Compartment models were fit to time-concentration data. A 3-compartment model with input in and elimination from the central compartment best fit intravenous data, whereas a 1-comparment model best fit intramuscular data. After intravenous administration, the median clearance and terminal half-life were 37.7 (range, 33.7 to 47.1) mL/kg/min and 142 (range, 131 to 218) min, respectively. The median (range) elimination half-life after intramuscular administration was 81.5 (77.2 to 92.5) min. Median intramuscular bioavailability was 92% (range, 75% to 104%). Rhesus macaques maintained concentrations greater than or equal to 4.0 ng/mL for at least 2 h after intravenous and intramuscular administration. The disposition of hydromorphone was characterized by a large volume of distribution and moderate clearance. Intramuscular administration resulted in rapid and almost complete drug absorption. Whole-body pruritus, sedation, and decreased appetite were observed in all macaques after initial drug administration