Revisiting the roles of progesterone and allopregnanolone in the nervous system: Resurgence of the progesterone receptors

http://www.uco.es/organiza/departamentos/anatomia-y-anat-patologica/peques/master/juanmorgaz/Muir.pdf

The cardiorespiratory and anesthetic effects of clinical and supraclinical doses of alfaxalone in cats.

Objective—To compare the cardiopulmonary effects of continuous rate infusions (CRIs) of alfaxalone-2-hydroxypropyl-β-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, PaCO2, and PaO2. Data were recorded prior to in...

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

This study aimed to determine the pharmacokinetic parameters and pharmacodynamics of alfaxalone in a 2-hydroxypropyl-beta-cyclodextrin alfaxalone formulation (Alfaxan), Jurox Pty Ltd, Rutherford, NSW, Australia) in cats after single administration at clinical and supraclinical dose rates and as multiple maintenance doses First, a prospective two-period cross-over study was conducted at single clinical and supraclinical doses Second, a single group multiple dose study evaluated the effect of maintenance doses Eight (five female and three male) domestic cats completed the cross-over experiment and six female cats completed the multiple dose study In the first experiment, alfaxalone was administered intravenously (IV) at 5 or 25 mg/kg with a washout period of 14 days In the second experiment, alfaxalone was administered IV at 5 mg/kg followed by four doses each of 2 mg/kg, administered at onset of responsiveness to a noxious stimulus Blood was collected at prescribed intervals and analysed by LCMS for plasma alfaxalone concentration Noncompartmental pharmacokinetics were used to analyse the plasma alfaxalone data The plasma clearance of alfaxalone at 5 and 25 mg/kg differed statistically at 251 and 148 mL/kg/min respectively The elimination half lives were 452 and 766 min respectively Alfaxalone has nonlinear pharmacokinetics in the cat Nevertheless, for cats dosed with sequential maintenance doses, a regression line through their peak plasma concentrations indicated that there was no clinically relevant pharmacokinetic accumulation The duration of nonresponsiveness after each maintenance dose was similar at approximately 6 min, indicating a lack of accumulation of pharmacodynamic effect The cardiovascular and respiratory parameters measured in cats after administration of the labelled doses of Alfaxan were stable In conclusion, the pharmacokinetics of alfaxalone in cats are nonlinear At clinical dose rates, however, neither alfaxalone nor its effects accumulated to a clinically relevant extent Further, in the un-premedicated cat the induction and maintenance of surgical anaesthesia was free of untoward events after a dose of 5 mg alfaxalone/kg body weight followed by four sequential doses of 2 mg/kg as needed (ie, approximately 7 to 8 mg/kg/h)

The pharmacokinetics and pharmacodynamics of alfaxalone in cats after single and multiple intravenous administration of Alfaxan® at clinical and supraclinical doses

Comparison of alfaxalone and propofol administered as total intravenous anaesthesia for ovariohysterectomy in dogs

Plasma pharmacokinetics of alfaxalone in dogs after an intravenous bolus of Alfaxan-CD RTU

The pharmacokinetics and pharmacodynamics of the injectable anaesthetic alfaxalone in the horse.

Alfaxalone (3α-hydroxy-5α-pregnane-11, 20-dione) is a neuroactive steroid with anaesthetic properties and a wide margin of safety. The pharmacokinetic properties of alfaxalone administered intravenously and intraperitoneally in rats (n = 28) were investigated. Mean t(1/2elim) for 2 and 5 mg/kg i.v. was 16.2 and 17.6 min, respectively, but could not be estimated for IP dosing, due to sustained plasma levels for up to 60 min after injection. Clp for i.v. injection was calculated at 57.8 ± 23.6 and 54.3 ± 6.8 mL/min/kg, which were 24.5% and 23% of cardiac output, respectively. The observed C(max) was 3.0 mg/L for IP administration, and 2.2 ± 0.9 and 5.2 ± 1.3 mg/L for 2 and 5 mg/kg i.v. administration, respectively. AUC(0-60) was 96.2 min.mg/L for IP dosing. The relative bioavailability for IP dosing was 26% and 28% compared to i.v. dosing. Differences in t(1/2elim) and Cl(p) from previous pharmacokinetic studies in rats are likely due to variations in alfaxalone formulation rather than sex differences. Alfaxan® given IP caused sustained levels of alfaxalone, no apnoea and longer sleep times than i.v. dosing, although immobilization was not induced in 30% of rats given Alfaxan® IP. A pharmacodynamic study of the effects of combining IP injection of Alfaxan® with other premedication agents is worthwhile, to determine whether improved anaesthesia induction could ultimately provide an alternative anaesthetic regimen for rats.

Kirby Pasloske

Papers

The cardiorespiratory and anesthetic effects of clinical and supraclinical doses of alfaxalone in cats.

Plasma pharmacokinetics of alfaxalone in dogs after an intravenous bolus of Alfaxan-CD RTU

The pharmacokinetics and pharmacodynamics of alfaxalone in cats after single and multiple intravenous administration of Alfaxan® at clinical and supraclinical doses

The pharmacokinetics and pharmacodynamics of the injectable anaesthetic alfaxalone in the horse.

Plasma pharmacokinetics of alfaxalone after a single intraperitoneal or intravenous injection of Alfaxan(®) in rats.