Comparison of Two Different Alfaxalone Concentrations Combined with Midazolam to Anesthetize Cynomolgus Macaques (Macaca fascicularis) for Plethysmography.

Plethysmography is employed in nonhuman primates (NHPs) to calculate respiratory minute volume and determine the exposure time required to deliver an aerosol at the target dose. Anesthetic drugs can impact breathing parameters like steady-state minute volume (SSMV) central to aerosol dosing. Alfaxalone-midazolam mixtures (AM) provide superior parameters for plethysmography in cynomolgus macaques. An obstacle to the use of AM is the volume required to anesthetize via intramuscular injection. A more concentrated formulation of alfaxalone will reduce injection volumes and refine AM protocols. The purpose of this study was to compare AM using the Indexed 10-mg/mL (AM10) formulation compared with an investigational 40-mg/mL (AM40) formulation for IM administration in cynomolgus macaques undergoing plethysmography. We hypothesized that AM10 and AM40 would show no difference in quality of anesthesia (QA), duration of anesthesia, SSMV, accumulated minute volume (AMV), and side effects. We also hypothesized that female macaques would have a longer duration of anesthesia compared with males using both formulations. The study used 15 cynomolgus macaques comprised of 8 females and 7 males. NHPs were compared between 2 separate and randomized anesthetic events no less than one week apart. Each animal served as its own control and animals were randomized by random number generation. Anesthetized NHPs were placed in a sealed plethysmography chamber, and minute volume measurements were calculated every 10 s to determine SSMV. Once SSMV was achieved for 20 min, the trial ended. There were no statistically significant differences between AM10 and AM40 for duration of anesthesia, SSMV, AMV, side effects, or QA. AM40 had a significantly smaller injection volume. Females did not show a significantly longer median duration of anesthesia using either of the alfaxalone formulations. Overall, AM40 offers a more humane anesthetic than AM10 for plethysmography in cynomolgus macaques.

Comparison of the anesthetic efficacy and cardiopulmonary effects of continuous rate infusions of alfaxalone-2-hydroxypropyl-beta-cyclodextrin and propofol in dogs.

OBJECTIVE: To compare the cardiopulmonary effects of continuous rate infusions (CRIs) of alfaxalone-2-hydroxypropyl-beta-cyclodextrin (HPCD) and propofol in healthy dogs. ANIMALS: 6 young adult medium-sized healthy crossbred dogs. PROCEDURES: A crossover design was used with a washout period of 6 days between anesthetic treatments. Each dog was sedated with acepromazine (0.02 mg/kg, IV) and hydromorphone (0.05 mg/kg, IV). Anesthesia was induced with propofol (4 mg/kg) or alfaxalone-HPCD (2 mg/kg). After endotracheal intubation, anesthesia was maintained with the same agent (propofol, 0.25 mg/kg/min; alfaxalone-HPCD, 0.07 mg/kg/min) for 120 minutes. Dogs spontaneously breathed 100% oxygen. Measurements included end-tidal partial pressure of carbon dioxide, heart and respiratory rates, mean arterial blood pressure, thermodilution-derived cardiac output, and body temperature. Paired arterial and mixed venous blood samples were collected for determination of blood pH, PaCO(2), and PaO(2). Data were recorded prior to induction; 5, 15, 30, 60, 90, and 120 minutes after induction of anesthesia; and 20 minutes after stopping the CRI, when feasible. Stroke volume and systemic vascular resistance were calculated. Quality of anesthetic induction and recovery and interval to recovery were recorded. RESULTS: Both propofol and alfaxalone-HPCD produced excellent induction of anesthesia, maintenance, and recovery. Respiratory depression was evident with both anesthetics. Clinically acceptable, mild hemodynamic changes were similar for both anesthetics. CONCLUSIONS AND CLINICAL RELEVANCE: Alfaxalone-HPCD produced clinically acceptable anesthetic quality and hemodynamic values ideal for use as a CRI. Ventilation may need to be supported if hydromorphone is used at these propofol and alfaxalone-HPCD infusion rates.

Comparative bioavailability of fluoxetine after transdermal and oral administration to healthy cats.

OBJECTIVE: To determine bioavailability, pharmacokinetics, and safety for transdermal (TD) and oral administration of fluoxetine hydrochloride to healthy cats. ANIMALS: 12 healthy mixed-breed sexually intact 1- to 4-year-old purpose-bred cats. PROCEDURE: A single-dose pharmacokinetic study involving 3 groups of 4 cats each was conducted in parallel. Fluoxetine in a formulation of pluronic lecithin organogel (PLO gel) was applied to the hairless portion of the pinnae of cats at 2 dosages (5 or 10 mg/kg), or it was administered orally in capsules at a dosage of 1 mg/kg. Plasma samples were obtained and submitted for liquid chromatography-mass spectrometry-mass spectrometry analysis of fluoxetine and its active metabolite, norfluoxetine. RESULTS: Peak fluoxetine concentration (Cmax) was lower and time to Cmax longer for TD administration versus oral administration. Relative bioavailability of each dose administered via the TD route was 10% of the value for oral administration of the drug. Mean plasma elimination half-life after oral administration was 47 and 55 hours for fluoxetine and norfluoxetine, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: This study provides evidence that fluoxetine in a 15% (wt:vol) PLO gel formulation can be absorbed through the skin of cats into the systemic circulation. However, the relative bioavailability for TD administration is approximately only 10% of that for the oral route of administration.