The pharmacological effects of the anesthetic alfaxalone were evaluated after intramuscular (IM) administration to 6 healthy beagle dogs. The dogs received three IM doses each of alfaxalone at increasing dose rates of 5 mg/kg (IM5), 7.5 mg/kg (IM7.5) and 10 mg/kg (IM10) every other day. Anesthetic effect was subjectively evaluated by using an ordinal scoring system to determine the degree of neuro-depression and the quality of anesthetic induction and recovery from anesthesia. Cardiorespiratory variables were measured using noninvasive methods. Alfaxalone administered IM produced dose-dependent neuro-depression and lateral recumbency (i.e., 36 ± 28 min, 87 ± 26 min and 115 ± 29 min after the IM5, IM7.5 and IM10 treatments, respectively). The endotracheal tube was tolerated in all dogs for 46 ± 20 and 58 ± 21 min after the IM7.5 and IM10 treatments, respectively. It was not possible to place endotracheal tubes in 5 of the 6 dogs after the IM5 treatment. Most cardiorespiratory variables remained within clinically acceptable ranges, but hypoxemia was observed by pulse oximetry for 5 to 10 min in 2 dogs receiving the IM10 treatment. Dose-dependent decreases in rectal temperature, respiratory rate and arterial blood pressure also occurred. The quality of recovery was considered satisfactory in all dogs receiving each treatment; all the dog exhibited transient muscular tremors and staggering gait. In conclusion, IM alfaxalone produced a dose-dependent anesthetic effect with relatively mild cardiorespiratory depression in dogs. However, hypoxemia may occur at higher IM doses of alfaxalone.

The sedative effects of intramuscular (IM) alfaxalone in 2-hydroxypropyl-beta-cyclodextrin (alfaxalone-HPCD) were evaluated in cats. The cats were treated with alfaxalone-HPCD in five occasions with a minimum 14-day interval between treatments: an IM injection of 1.0 mg/kg (IM1), 2.5 mg/kg (IM2.5), 5 mg/kg (IM5) or 10 mg/kg (IM10), or an intravenous injection of 5 mg/kg (IV5). The sedative effects were evaluated subjectively using a composite measurement scoring system (a maximum score of 16). Cardio-respiratory variables were measured non-invasively. The median sedation scores peaked at 10 min (score 9), 15 min (score 14), 10 min (score 16), 10 to 20 min (score 16) and 2 to 5 min (score 16) after the IM1, IM2.5, IM5, IM10 and IV5 treatments, respectively. The IM5 treatment produced longer lasting sedation, compared to the IV5 treatment. Durations of maintenance of lateral recumbency after the IM10 treatment (115 ± 22 min) were longer than those after the IM2.5 (40 ± 15 min), IM5 (76 ± 21 min) and IV5 treatments (50 ± 5 min). Cardio-respiratory variables remained within clinically acceptable ranges, except for each one cat that showed hypotension (<60 mmHg) after the IM10 and IV5 treatments. Tremors, ataxia and opisthotonus-like posture were observed during the early recovery period after the IM2.5, IM5, IM10 and IV5 treatments. In conclusion, IM alfaxalone-HPCD produced dose-dependent and clinically relevant sedative effect at 2.5 to 10 mg/kg in healthy cats. Hypotension may occur at higher IM doses of alfaxalone-HPCD.

To evaluate sedative and physiological effects of low dose intramuscular (IM) alfaxalone, six healthy rabbits were administered single IM doses of alfaxalone at 1mg/kg (IM1), 2.5 mg/kg (IM2.5), or 5 mg/kg (IM5) with a minimum of 7-day washout period. Sedative effects were subjectively evaluated using a composite measure scoring system (maximum sedation score of 16) and pulse rate, respiratory rate, non-invasive blood pressure, and percutaneous oxygen-hemoglobin saturation were measured before and after IM alfaxalone. Loss of righting reflex (LRR) was achieved in all rabbits after IM2.5 and IM5 treatments but in only three rabbits after IM1 treatment. Median (interquartile range) times to LRR were 16 min (15–17), 6 min (6–6), and 4 min (4–4), and median durations of LRR were 0.5 min (0–7), 22.5 min (19–27), and 53 min (48–58) after IM1, IM2.5, and IM5 treatments, respectively. The duration of LRR after IM5 treatment was significantly longer than those after IM1and IM2.5 treatments ( P <0.01). Median value of total sedation scores peaked at 10 min [score 3.5 (3–4)], from 10 min [score 13.5 (12–14)] to 15 min [score 13.5 (12–14)], and from 10 min [score 15 (12–15)] to 15 min [score 15 (14–15)] after IM1, IM2.5, and IM5 treatments, respectively. No rabbit showed circulatory depression and apnea although respiratory rate decreased after IM 2.5 and IM5 treatments. In conclusion, alfaxalone produced a dose-dependent sedative effect and a deep sedation was achieved by alfaxalone at 2.5 mg/kg IM in rabbits.

We aimed to evaluate the induction, anesthesia, and cardiorespiratory effects of intramuscular (IM) anesthetic protocol with alfaxalone following premedication with low-dose medetomidine, butorphanol, or a combination of both (medetomidine–butorphanol) in dogs. Six healthy beagles were administered 1, 2.5, or 5 mg/kg alfaxalone IM following premedication with low-dose medetomidine (5 µg/kg; MA-IM), butorphanol (0.3 mg/kg; BA-IM), or medetomidine-butorphanol (5 µg/kg and 0.3 mg/kg, respectively; MBA-IM). Each dog received 9 treatments with minimum 7-day washout period between treatments. Dogs were allowed to breath room air during anesthetic induction. We attempted endotracheal intubation after alfaxalone administration. Alfaxalone produced a dose-dependent anesthetic effect in each anesthetic protocol. Intubation was achieved in 4 out of 6 dogs that received MA-IM and BA-IM with 2.5 mg/kg alfaxalone and in all dogs that received MBA-IM with 1, 2.5, and 5 mg/kg alfaxalone. The median durations [minimum–maximum] of accepting intubation were 79 [0–89], 97 [84–120], and 117 [84–217] min, respectively. Hypotension (mean arterial blood pressure <60 mmHg) did not develop, but bradycardia (heart rate <60 beats/min) was observed in all dogs that received the MA-IM and MBA-IM protocols. Severe hypoxemia (percutaneous arterial oxygen saturation <90%) developed in 2 dogs that received MBA-IM with 5 mg/kg alfaxalone. We consider that the MA-IM and BA-IM protocols with ≥2.5 mg/kg alfaxalone and the MBA-IM protocol with 1–2.5 mg/kg alfaxalone could provide clinically useful and effective anesthesia without causing severe cardiorespiratory depression in healthy dogs.

25In acidosis, catecholamines are attenuated and higher doses are often required to 26 improve cardiovascular function. Colforsin activates adenylate cyclase in cardiomyocytes 27 without mediating the beta adrenoceptor. In this study, six beagles were administered 28 either colforsin or dobutamine four times during eucapnia (partial pressure of arterial 29 carbon dioxide 35-40 mm Hg; normal) and hypercapnia (ibid 90-110 mm Hg; acidosis) 30 conditions. The latter was induced by carbon dioxide inhalation. Anesthesia was induced 31 with propofol and maintained with isoflurane. Cardiovascular function was measured by 32 thermodilution and a Swan-Ganz catheter. Cardiac output, heart rate, and systemic 33 vascular resistance were determined at baseline and 60 min after 0.3 μg/kg/min (low), 0.6 34 μg/kg/min (middle), and 1.2 μg/kg/min (high) colforsin administration. The median pH 35 was 7.38 [range 7.34-7.42] and 7.04 [range 7.01-7.08] at baseline in the Normal and 36 Acidosis conditions, respectively. Endogenous adrenaline and noradrenaline levels at 37 baseline were significantly (P < 0.05) higher in the Acidosis than in the Normal condition. 38 Colforsin induced cardiovascular effects similar to those caused by dobutamine. 39 Colforsin increased cardiac output in the Normal condition (baseline: 198.8 mL/kg/min 40 [range 119.6-240.9], low: 210.8 mL/kg/min [range 171.9-362.6], middle: 313.8 41 mL/kg/min [range 231.2-473.2], high: 441.4 mL/kg/min [range 373.9-509.3]; P < 0.001) 42 and the Acidosis condition (baseline: 285.0 mL/kg/min [range 195.9-355.0], low: 297.4 43 mL/kg/min [213.3-340.6], middle: 336.3 mL/kg/min [291.3-414.5], high: 366.7 44 mL/kg/min [339.7-455.7] ml/kg/min; P < 0.001). Colforsin significantly increased heart45 rate (P < 0.05 in both conditions) and decreased systemic vascular resistance (P < 0.05 in 46 both conditions) compared to values at baseline. Systemic vascular resistance was lower 51 Catecholamine beta-1 adrenoceptor is present on myocardial cell membranes. 52 The catecholamine dobutamine binds to the beta-1 adrenoceptor and activates the cyclic 53 adenosine monophosphate (cAMP) synthetase adenylate cyclase. The cAMP activates 54 protein kinase A which phosphorylates the L-type calcium ion-and sarcoplasmic 55 reticulum calcium ion-releasing channels and increases intracellular calcium ion 56 concentrations. Dobutamine increases cardiac contractility and heart rate [1]. In contrast, 57 catecholamine beta-2 adrenoceptor is present on the vascular smooth muscle cell 58 membrane. Protein kinase A activated as described above phosphorylates myosin light-59 chain kinase and inhibits actin and myosin gliding. Dobutamine relaxes vascular smooth 60 muscle, has both positive inotropic and vasodilator effects (inodilator), and is cardiotonic 61 and vasodilatory action in dogs [2]. 62Colforsin daropate is a forskolin derivative that directly activates adenylate 63 cyclase in cardiomyocytes and vascular smooth muscle without mediating the 64 catecholamine beta adrenoceptor. As with dobutamine, colfors...