alphadolone and alphaxalone

Modern views of anesthetic neurosteroid interaction with the GABA(A) receptor conceptualize steroid ligands interacting with a protein binding site on the receptor. It has generally been assumed that the steroid interaction/binding site is contained in an extracellular domain of the receptor, and that steroid interactions are of high potency, evidenced by the low aqueous ligand concentrations required to achieve potentiation of channel function. We have been considering implications of the observations that steroids are quite lipophilic and that recently identified putative steroid binding sites are in transmembrane domains of the receptor. Accordingly, we expect that both the effective plasma membrane steroid concentration and steroid pharmacophore properties will contribute to steady-state potency and to the lifetime of steroid actions following removal of free aqueous steroid. Here we review our recent studies that address the evidence that membrane partitioning and intracellular accumulation are non-specific contributors to the effects of anesthetic steroids at GABA(A) receptors. We compare and contrast the profile of anesthetic steroids with that of sulfated steroids that negatively regulate GABA(A) receptor function. These studies give rise to the view that the inherent affinity of anesthetic steroid for GABA(A) receptors is very low; low effective aqueous concentrations are accounted for by lipid partitioning. This yields a very different picture of the interaction of neurosteroids with the GABA(A) receptor than that of steroid interactions with classical intracellular steroid receptors, which exhibit inherently high affinity. These considerations have practical implications for actions of endogenous neurosteroids. Lipophilicity will tend to promote autocrine actions of neurosteroids at GABA(A) receptors within cells that synthesize neurosteroids, and lipophilic retention will limit intercellular diffusion from the source of steroid synthesis. Lipophilicity and steroid access to the receptor binding sites also must be considerations in drug design if drugs are to effectively reach the target GABA(A) receptor site.

Topics: Animals; Binding Sites; Fluorescent Dyes; GABA Antagonists; Membrane Potentials; Neurons; Neurotransmitter Agents; Pregnanediones; Receptors, GABA-A; Synaptic Membranes; Synaptic Transmission

The disposition kinetics of the two steroid components of the anaesthetic agent Althesin have been determined in seven male patients undergoing peripheral vascular reconstructive surgery. The blood decay profiles for both alphaxalone and alphadolone can be described by an open two-compartment model, with a mean alpha phase half life of 1.9 min, and a mean beta phase half life of 34 min. The systemic clearances of alphaxalone and alphadolone were 1.52 l min-1 and 1.09 l min-1 respectively (p less than 0.01). The remaining derived kinetic parameters showed no difference for the two steroids except for a greater fraction of the alphadolone administered being present in the peripheral compartment at steady-state conditions (p less than 0.05). The relative contributions of metabolic loss to total loss of drug from the body were 0.56 and 0.85 at 10 min and 60 min respectively for alphaxalone, and 0.42 and 0.80 respectively for alphadolone (p less than 0.01 and p less than 0.05). Although alphadolone exists as the acetate in the proprietary formulation, rapid hydrolysis to the native steroid seems to occur in man. The exact site of this hydrolysis remains uncertain at present.

Topics: Aged; Anesthetics; Half-Life; Humans; Kinetics; Male; Middle Aged; Pregnanediones

The safety and efficacy of prolonged infusion of alphaxalone/alphadolone (Alfathesin: Glaxo) was assessed in 20 critically ill patients needing sedation during intermittent positive pressure ventilation in a general intensive care unit. The mean dose of Alfathesin infused was 1542 ml (range: 225 to 4820 ml) over 6.9 days (3 to 16 days) at rates between 5 and 15 ml/hour. Significant increases in plasma urea, creatinine, bilirubin, alkaline phosphatase and white cell count occurred during the infusion, but these were expected from each patient's clinical course. Lipoprotein electrophoresis invariably showed loss of the alpha band and appearance of a densely staining pre-beta band. Four patients had involuntary movements during the infusion and two patients fitted when the infusion stopped. Both had cerebral injuries. Subjective assessment of the quality of sedation was "very good" or "good" in 15 patients and "fair" in five.

Topics: Adult; Aged; Anesthetics; Cholesterol; Clinical Trials as Topic; Drug Combinations; Electroencephalography; Female; Humans; Infusions, Parenteral; Intensive Care Units; Lipoproteins; Male; Middle Aged; Pregnanediones; Triglycerides

In the literature there appears to be variability in reported levels of certain hormones during haemorrhage, specifically adrenocorticotrophic hormone (ACTH) and β-endorphin. It is possible that this variability may be due to the choice of anaesthetic. Therefore, the effect of 3 common research-only anaesthetic agents (alphaxalone-alphadolone, propofol, and pentobarbitone) on ACTH and β-endorphin levels during haemorrhage was assessed in pigs. Animals were divided into 3 groups: group I received alphaxalone-alphadolone (n = 5), group II received propofol (n = 6), and group III received pentobarbitone (n = 6). Pigs were subjected to a continuous fixed-volume haemorrhage under one of the above anaesthetics while being mechanically ventilated. ACTH and β-endorphin levels increased significantly during haemorrhage under propofol and pentobarbitone anaesthesia but not with alphaxalone-alphadolone. For ACTH there was no significant difference between the groups, whereas for β-endorphin there was a significant difference between the propofol- and pentobarbitone-anaesthetized pigs. The increase in heart rate during haemorrhage was significantly different between the alphaxalone-alphadolone and propofol as well as between the propofol and pentobarbitone groups. The drop in blood pressure was only significantly different between the alphaxalone-alphadolone- and propofol-anaesthetized pigs. These results indicate that the choice of anaesthetic agent can affect the hormone response to haemorrhage and may account for the variable hormone levels reported in the published literature to date.

Topics: Adrenocorticotropic Hormone; Anesthesia; Anesthetics; Animals; beta-Endorphin; Blood Pressure; Heart Rate; Hemorrhage; Hypovolemia; Pentobarbital; Pregnanediones; Propofol; Swine

In this study, we investigated the antinociceptive and sedative effects of the opioids fentanyl, morphine, and oxycodone given alone and in combination with two neurosteroids: alphadolone and alphaxalone. An open-field activity monitor and rotarod apparatus were used to define the sedative effects caused by opioid and neurosteroid compounds given alone intraperitoneally to male Wistar rats. Dose-response curves for antinociception were constructed using only nonsedative doses of these drugs. At nonsedating doses, fentanyl, morphine, and oxycodone all caused dose-dependent tail flick latency (TFL) antinociceptive effects. Because neither neurosteroid altered TFL, electrical current was used as the test to determine doses of neurosteroid that caused antinociceptive effects at nonsedative doses. Alphadolone 10 mg/kg intraperitoneally caused significant antinociceptive effects in the electrical test but alphaxalone did not. All three opioid dose-response curves for TFL antinociception were shifted to the left by coadministration of alphadolone even though alphadolone alone had no effect on TFL. Alphaxalone given alone had no antinociceptive effects at nonsedative doses and it had no effect on opioid antinociception. Neither neurosteroid caused sedative effects when combined with opioids. We conclude that coadministration of alphadolone, but not alphaxalone, with morphine, fentanyl, or oxycodone potentiates antinociception and that this effect is not caused by an increase in sedation.

Topics: Analgesics, Opioid; Anesthetics; Animals; Consciousness; Dose-Response Relationship, Drug; Drug Synergism; Injections, Intraperitoneal; Male; Motor Activity; Pain Measurement; Pain Threshold; Postural Balance; Pregnanediones; Rats

Studies have shown that the steroid anaesthetic alphaxalone positively modulates gamma-aminobutyric acid (GABA) receptors in vitro. It has also been reported that positive modulation of GABA(A) receptors in the rat spinal cord can produce antinociception in vivo. This present study looks at the interaction of an intraperitoneal injection (i.p.) of the steroid anaesthetic combination Saffan (alphaxalone 9 mg/ml, alphadolone acetate 3 mg/ml) with GABA(A) receptors in the spinal cord. Full recovery from anaesthesia induced by Saffan 2 ml/kg i.p., as assessed by the rotarod test, occurred after 28.78 +/- 0.86 min. Residual antinociceptive effects were assessed by application of electrical current at two skin sites (neck and tail) and also tail withdrawal from noxious heat. Residual antinociception was observed at both skin sites assessed by the electrical test but not when assessed by noxious heat. The antinociceptive effects in the tail but not the neck were suppressed by intrathecal administration of GABA(A) antagonists (bicuculline and SR-95531). In a separate group of experiments alphaxalone and alphadolone were given i.p. individually at the same doses that were given when formulated in Saffan. Alphaxalone produced sedative and anaesthetic effects with no antinociception. Alphadolone caused no sedation but it did cause antinociceptive effects equal in magnitude to those produced by Saffan. We conclude that Saffan produces antinociception in rats when given i.p. by an interaction with spinal GABA(A) receptors. Furthermore, this antinociception is due to the alphadolone content of the neurosteroid anaesthetic and not the alphaxalone.

Topics: Alfaxalone Alfadolone Mixture; Anesthetics; Animals; Bicuculline; GABA Antagonists; GABA-A Receptor Antagonists; Male; Nociceptors; Pain Measurement; Pregnanediones; Pyridazines; Rats; Rats, Wistar; Receptors, GABA-A; Reference Values; Spinal Cord; Steroids; Time Factors

Topics: Anesthesia Recovery Period; Anesthesia, Intravenous; Anesthetics, Combined; Animals; Birds; Female; Male; Pregnanediones

Topics: Anesthesia; Anesthesia, Inhalation; Anesthesia, Intravenous; Anesthetics, Intravenous; Animals; Birds; Drug Therapy, Combination; Isoflurane; Preanesthetic Medication; Pregnanediones; Xylazine

The effects of ketamine, etomidate, alphaxalone and alphadolone acetate on nodal sodium and potassium currents of frog myelinated nerve fibre have been examined. The four general anaesthetics reversibly depressed ionic currents, although they tended to be more effective in blocking potassium than sodium current. The potassium current was reduced by etomidate and alphaxalone in a time-dependent manner. This was not found for ketamine and alphadolone acetate. In addition to blocking effects on sodium current, etomidate, alphaxalone and alphadolone acetate, but not ketamine, induced a negative shift of steady-state sodium inactivation-voltage curves. Collectively, the general anaesthetics appeared to alter specifically and differentially sodium and potassium channel-gating systems. The simplest interpretation of these results suggests that the compounds produce state-dependent blocks of ionic channels, and that there are general anaesthetic receptor sites located on the channel proteins themselves. Furthermore, potassium and sodium channels may contain several types of receptor sites, through which anaesthetics could exert their different actions.

Topics: Action Potentials; Anesthetics, Intravenous; Animals; Axons; Dose-Response Relationship, Drug; Etomidate; Ion Channel Gating; Ketamine; Membrane Potentials; Nerve Fibers, Myelinated; Potassium; Potassium Channels; Pregnanediones; Rana esculenta; Sodium; Sodium Channels; Time Factors

Prolonged, stable, non-recovery anaesthesia is required for the assessment of the effects of novel compounds on the cardiovascular system. A comparison of injectable anaesthetic agents and combinations (thiobarbital, fentanyl-fluanisone and midazolam, propofol, fentanyl-fluanisone and propofol, and alphaxalone/alphadolone) was made in laboratory rats and the following parameters assessed over 3 h: blood pressure, heart rate and rhythm, respiration rate and depth, analgesia, ease of induction and maintenance of anaesthesia. It was found that propofol, with fentanyl-fluanisone premedication, provided stress-free induction, easily controlled anaesthesia, good analgesia and muscle relaxation for surgery, for up to 3 h duration. Heart rate, blood pressure and respiration remained stable and within normal limits during this time. The other anaesthetics/combinations assessed did not rate as highly in these respects. Propofol, following fentanyl-fluanisone premedication, would appear to be a useful and safe anaesthetic for use in rodents, which avoids significant effects on heart rate or blood pressure.

Topics: Anesthesia, Intravenous; Anesthetics; Animals; Blood Pressure; Butyrophenones; Female; Fentanyl; Heart Rate; Male; Midazolam; Pentobarbital; Pregnanediones; Propofol; Rats; Respiration; Thiopental

The effect of 4 anaesthetic regimens on blood pressure and survival was investigated during repeated episodes of cerebral ischaemia in the rat induced by diathermy of the vertebral arteries and reversible occlusion of the carotid arteries. The best results were obtained with inspired halothane with neuromuscular blockade and artificial ventilation, followed in order by halothane, intravenous alphaxolone/alphadolone, and intraperitoneal urethane with spontaneous ventilation.

Topics: Anesthetics; Animals; Arterial Occlusive Diseases; Brain Ischemia; Carotid Artery Diseases; Disease Models, Animal; Drug Combinations; Halothane; Male; Neuromuscular Blocking Agents; Pregnanediones; Rats; Rats, Inbred Strains; Respiration, Artificial; Retrospective Studies; Urethane

In this study we have investigated the influence of preparative surgery on the potency with which a range of injectable anaesthetics depressed nociceptive withdrawal reflexes in anaesthetized, spinalized rats. Drug effects were compared on 2 different preparations, each requiring differing degrees of preparatory surgery. Recordings were made in each case of unitary motoneurone responses to controlled noxious stimuli. The dose-dependent effects of the general anaesthetics alpha-chloralose (20-80 mg/kg i.v.) and alphaxalone/alphadolone (0.5-2 mg/kg) and of the dissociative anaesthetic ketamine (0.5-16 mg/kg) were studied. When the degree of surgical intervention was increased, the reflex response to a uniform mechanical pinch stimulus was facilitated. This enhanced response was more susceptible to the reflex depressant actions of all the compounds studied.

Topics: Action Potentials; Anesthetics; Animals; Chloralose; Dose-Response Relationship, Drug; Ketamine; Male; Motor Neurons; Nociceptors; Physical Stimulation; Pregnanediones; Rats; Rats, Inbred Strains; Reflex; Spinal Cord; Surgical Procedures, Operative

The anaesthetic induction agents thiopentone, propofol and alphaxalone-alphadolone were administered to cats intravenously and ketamine and xylazine-ketamine-atropine were administered intramuscularly in order to determine their effects on gastric pressure, lower oesophageal sphincter pressure, and barrier pressure. Manometric measurements were made with a non-perfused catheter tip pressure transducer. All the anaesthetic induction agents decreased the tone of the lower oesophageal sphincter but the reduction was least with ketamine. Lower oesophageal sphincter tone was significantly higher in cats anaesthetised with either xylazine-ketamine-atropine or propofol than in cats anaesthetised with either thiopentone or alphaxalone-alphadolone. Despite a higher gastric pressure in the cats anaesthetised with ketamine rather than with the other drugs except propofol, the barrier pressure was also significantly higher in cats anaesthetised with ketamine than in cats anaesthetised with any of the other drugs except xylazine-ketamine-atropine. The risk of gastrooesophageal reflux seemed to be higher with alphaxalone-alphadolone than with thiopentone if the lower oesophageal sphincter pressure and gastric pressure are used as indicators of likely reflux.

Topics: Anesthetics; Animals; Cats; Esophagogastric Junction; Female; Ketamine; Male; Pregnanediones; Pressure; Propofol; Random Allocation; Stomach; Thiopental; Xylazine

Topics: Anesthetics; Animals; Cat Diseases; Cats; Drug Combinations; Female; Laryngeal Edema; Pregnanediones

The synthetic steroids alphaxalone and alphadolone are combined for use as a veterinary anesthetic and marked under the trade name Saffan. This study evaluated the anticonvulsant activity of Saffan in 2 rat models of epilepsy: maximal electroshock and subcutaneous pentylenetetrazol seizures. Neurological deficit was tested in each animal just prior to the seizure test to differentiate selective antiepileptic effects from nonselective anticonvulsant or anesthetic activity. In both seizure models Saffan induced anticonvulsant activity only at doses associated with neurological deficit.

Topics: Anesthetics; Animals; Anticonvulsants; Electroshock; Male; Pentylenetetrazole; Postural Balance; Pregnanediones; Rats; Rats, Inbred Strains; Seizures; Steroids

1. Alphaxalone and alphadolone acetate were found to inhibit histamine release from rat mast cells induced by concanavalin A by blocking the calcium channels of the cells. 2. They also both inhibited the release induced by A23187, but only alphaxalone inhibited the release induced by compound 48/80. 3. It is concluded that the inhibitory effects of these compounds were not due to their anesthetic properties, but may have been due to their inhibition of steps of the release cascade that open calcium channels and subsequent steps.

Topics: Anesthetics; Animals; Calcimycin; Calcium; Concanavalin A; Drug Interactions; Histamine Release; In Vitro Techniques; Male; Mast Cells; p-Methoxy-N-methylphenethylamine; Pregnanediones; Rats; Rats, Inbred Strains; Receptors, Concanavalin A

Sixty coldwater and warmwater fish ranging in weight from 2 to 35 kg were injected intramuscularly with the hypnotics alphaxalone-alphadolone and metomidate hydrochloride and the non-depolarising muscle relaxant gallamine triethiodide using a laser-aimed underwater dart gun. Alphaxalone-alphadolone produced sufficient sedation for easy netting within five to 20 minutes at doses between 0.3 and 0.5 ml/kg, with induction being somewhat faster in warmwater species. The pattern of induction was similar with metomidate but required doses of 40 to 60 mg/kg. The muscle relaxant gallamine triethiodide showed promise as a practical agent for the capture and handling of large fish by virtue of its smooth induction of paralysis at doses between 1 and 3 mg/kg and its reversible supplementation with orally administered metomidate hydrochloride.

Topics: Anesthetics; Animals; Fishes; Gallamine Triethiodide; Imidazoles; Immobilization; Injections, Intramuscular; Lasers; Pregnanediones

This report describes 75 cases of reliable 1-2-hour surgical anesthesia of newborn to adult squirrel monkeys, with rapid induction and recovery, using a single intramuscular dose of alphaxolone-alphadolone (doses between 11.5 and 30 mg/kg body weight).

Topics: Age Factors; Anesthesia; Anesthetics; Animals; Body Temperature; Cebidae; Dose-Response Relationship, Drug; Female; Injections, Intramuscular; Male; Pregnanediones; Reference Values; Respiration; Saimiri

Testosterone and androstenedione were measured in the plasma of mature tom-cats before, during and after anesthesia with thiopentone, ketamine, xylazine and alphaxolone/alphadolone. Samples were collected via an indwelling jugular catheter at 30 min intervals before anesthesia (5 samples) and during the recovery phase (8 samples), and at intervals of 15 min during anesthesia (7 samples). Thiopentone and ketamine anesthesia significantly depressed testosterone and androstenedione concentrations during and after anesthesia. Xylazine significantly increased testosterone concentrations during anesthesia but they returned to pre-anesthetic concentrations during recovery. Androstenedione concentrations were significantly depressed during the recovery phase from xylazine anesthesia. Alphaxolone/alphadolone anesthesia had no significant effect of testosterone concentrations but significantly increased and androstenedione concentrations during anesthesia and recovery. Testosterone and androstenedione concentrations in cats were significantly altered by these 4 commonly used anesthetics and this must be taken into account if hormone concentrations are measured while cats are anesthetised.

Topics: Androstenedione; Anesthesia, Intravenous; Anesthetics; Animals; Animals, Domestic; Cats; Ketamine; Male; Pregnanediones; Testosterone; Thiopental; Time Factors; Xylazine

Alphaxalone is considered the anaesthetic of choice in neuroendocrine reproductive studies in female rats, since it appears to have little, if any, effect on release of gonadotrophin-releasing hormone. There has been less study of the effects of this anaesthetic on the male reproductive neuroendocrine axis, however. Accordingly, the time-dependent effects of alphaxalone, as well as of urethane and ketamine, on the increased levels of LH in castrated rats were determined. Each anaesthetic was administered i.p. and each depressed LH levels significantly compared with those in castrated unanaesthetized rats killed by decapitation (controls). The effect of the anaesthetics was noted 15 min after administration and persisted at 30 and 60 min in animals anaesthetized with alphaxalone and urethane. Only in ketamine-anaesthetized animals did serum concentrations of LH finally rise to concentrations not significantly different from those in control rats. Thus alphaxalone, though useful in female neuroendocrine studies, is as profoundly disruptive as other anaesthetics on the male rat hypothalamic-pituitary reproductive unit.

Topics: Anesthetics; Animals; Depression, Chemical; Ketamine; Luteinizing Hormone; Male; Orchiectomy; Pregnanediones; Rats; Rats, Inbred Strains; Urethane

Tadpoles were used to study quantitative interactions between high pressure and two intravenous anaesthetics, alphaxalone/alphadolone and methohexitone. The potencies of the two agents were decreased by high pressure but to different extents. The maximum effect was seen in the pressure range 70-130 atmospheres absolute (ATA). The increases in the normobaric anaesthetizing concentration (ED50) required at 100 ATA were alphaxalone/alphadolone:405 +/- 5 (s.d.)%; methohexitone:658 +/- 80 (s.d.)%. For both alphaxalone/alphadalone and methohexitone, the curves obtained when the increase in ED50 was plotted against increasing pressure showed plateaux at pressures above 70 ATA. These data support the concept of the two intravenous drugs causing general anaesthesia by the occupation of separate molecular 'sites' with different but finite capacities.

Topics: Amphibians; Anesthesia, General; Anesthetics; Animals; Atmospheric Pressure; Carbon Dioxide; Dose-Response Relationship, Drug; Hydrogen-Ion Concentration; Methohexital; Oxygen Consumption; Pregnanediones

Topics: Anesthesia, Intravenous; Animals; Birds; Dose-Response Relationship, Drug; Ketamine; Pregnanediones; Thiazines; Xylazine

Topics: Adolescent; Anesthetics; Brain; Brain Injuries; Coma; Drug Therapy, Combination; Electroencephalography; Humans; Intracranial Pressure; Male; Monitoring, Physiologic; Pregnanediones; Thiopental

Previous studies indicate that the threshold of the jaw opening reflex (JOR) evoked by tooth-pulp stimulation is much lower in cats subjected to minimal surgical trauma and a short period of anaesthesia than in animals prepared for stereotaxic recording from the brainstem. Experiments have been carried out to determine whether the higher JOR thresholds observed in the latter group of cats could be attributed to the duration of the anaesthesia or the greater surgical trauma to which they were subjected. The effects on the JOR evoked by tooth-pulp stimulation of brief episodes of noxious and high intensity electrical stimulation of other tissues have been studied in anaesthetized cats. In lightly anaesthetized, control animals, the reflex threshold was usually below 100 microA, 0.1 ms and maintained anaesthesia did not affect this. Alphaxalone/alphadolone, methohexitone and alpha-chloralose produced similar results. Noxious or high intensity electrical stimuli applied to a paw, a pinna or the scalp caused either no change or a decrease in the JOR threshold of cats lightly anaesthetized with alphaxalone/alphadolone. With deeper anaesthesia, these same conditioning stimuli caused a maintained increase in JOR threshold which could be reversed by decreasing the anaesthetic dose. The results suggest that the high threshold of the JOR observed in earlier experiments was not due to anaesthesia but may have been caused by trauma.

Topics: Anesthetics; Animals; Cats; Dental Pulp; Electric Stimulation; Female; Jaw; Male; Methohexital; Pain; Physical Stimulation; Pregnanediones; Reflex

Two functional performance parameters (heart rate and coronary flow rate) of three groups of six isolated beating hearts obtained from rats anesthetized by inhalation of diethyl ether in air, injection intraperitoneally of sodium pentobarbital (60mg/kg) or intravenously of alphaxalone/alphadolone (15mg/kg) were compared. Differences were small, but alphaxalone-alphadolone showed lowest stable mean coronary flow rate and diethyl ether the widest variation between animals. No significant difference in function was found between ether and pentobarbital, currently the two most widely used methods. But, pentobarbital showed higher stable functional performance and least variation between animals. We conclude that pentobarbital is the most useful of these three agents for obtaining hearts for perfusion as isolated beating organs, and that alphaxalone-alphadolone is clearly less suitable.

Topics: Anesthesia; Animals; Coronary Circulation; Ether; Ethyl Ethers; Heart; Heart Rate; Pentobarbital; Pregnanediones; Rats

Allergic reactions to the intravenous drugs used in anaesthesia pose a major problem for the anaesthetist, since they represent an unpredictable and occasionally life-threatening event. Reports of 2 such cases are presented, and the incidence, assessment and prophylaxis of such reactions are discussed.

Topics: Alcuronium; Anesthesia, Intravenous; Anesthetics; Child; Drug Hypersensitivity; Female; Humans; Male; Middle Aged; Pregnanediones; Toxiferine

In a clinical study alfentanil/etomidat-short-active anaesthesia was used in 150 cats. The anaesthesia progress was compared to usual steroid anaesthesia by using clinical parameters as respiratory and pulse frequency as well as reflexes. Surgical tolerance in both anaesthesia was 6 minutes without and 7 minutes with azaperon premedication. In both anaesthesia excitations occur during waking time. They can be prevented by using a calm waking room or by premedication with azaperon (in subclinical dose of 0.25 mg/kg BW) or diazepam (in the usual dose of 0,2-1 mg/kg BW). Premedication with diazepam is preferred because it has no influence on respiration and circulation and does not intensify the anaesthesia. Indications for alfentanil/etomidat short-active anaesthesia are minor surgery, diagnostic measures and teeth treatment. In addition, alfentanil/etomidat was shown to be suitable for introducing inhalation anaesthesia particularly in old and sick animals.

Topics: Adjuvants, Anesthesia; Alfentanil; Anesthesia, Intravenous; Anesthetics; Animals; Cats; Etomidate; Fentanyl; Heart Rate; Imidazoles; Pregnanediones; Reflex; Respiration

The effect of three injectable drugs and a combination of two of them was compared in birds. The agents were ketamine hydrochloride, xylazine hydrochloride and the steroid mixture alphaxalone-alphadolone. Ketamine and xylazine were used in combination. One hundred and fifty-four species, all maintained by major zoos in the United Kingdom, were involved in the study. The results indicate that the drugs used produced more widely differing effects in the range of species studied than have previously been reported.

Topics: Anesthesia; Anesthetics; Animals; Animals, Zoo; Birds; Drug Combinations; Female; Immobilization; Injections, Intramuscular; Injections, Intravenous; Ketamine; Male; Pregnanediones; Xylazine

The effects of pentobarbital, alpha-chloralose, alphaxalone-alphadolone, diethyl ether and chloralose-urethane anesthesia on microvascular vasomotion were studied in the hamster skin fold window preparation. All these agents paralyzed vasomotion in the arterioles causing an initial vasodilation, where diameters were above the control-unanesthetized mean values (UMD) for a period of 5-60 min and returned to UMD, and lower, after periods up to 90 min depending on the type of anesthetic. During chloralose-urethane anesthesia vasodilation lasted until the end of observation (90 min). The responses were quantitatively different as a function of vessel type, being more pronounced in the smaller terminal arterioles. Vasomotion did not recover at the end of anesthesia, when the animals awoke, and the vessels tended to remain inert for periods up to 10-20 min, at which time the activity was reestablished with the same control fundamental frequency. Small veins and venules did not exhibit vasomotion and showed various reactions that were characteristic for each anesthetic and vessel type, where vasodilation was the prevalent feature during pentobarbital anesthesia while diethyl ether had the opposite effect. Venular microvessels recovered control diameters 10-20 min after awakening.

Topics: Anesthetics; Animals; Arteries; Chloralose; Cricetinae; Ether; Mesocricetus; Microcirculation; Pentobarbital; Pregnanediones; Urethane; Vasodilation; Vasomotor System; Veins; Venules

Both animal and clinical studies have demonstrated that progesterone has antiepileptic properties. Progesterone in the immature, but not mature brain, markedly inhibits kindling. The purpose of this study was to determine if the kindling inhibition effect of progesterone is related to systemic endocrine properties. The effect of alphaxalone and alphadalone acetate, two progesterone-like compounds devoid of significant endocrine effect, were administered to both immature and mature male rats during kindling. Alphaxalone and alphadalone acetate markedly inhibited kindling in the immature rat, but had minimal effects in the mature animal. This study demonstrates that the kindling inhibition effects of progesterone are not dependent on systemic endocrine properties.

Topics: Aging; Amygdala; Anesthetics; Animals; Kindling, Neurologic; Male; Pregnanediones; Progesterone; Rats; Rats, Inbred Strains; Structure-Activity Relationship

Two experiments were undertaken to assess further the action of the steroid anaesthetic alphaxalone upon LH secretion in chronically ovariectomized female rats. For the first experiment, 31 rats were given two injections of oestradiol benzoate (20 micrograms/100 g body weight), each 72 h apart, to stimulate an LH surge 6 h after the second injection. However, one group of seven rats was anaesthetized with alphaxalone throughout the 6-h period and a second group of eight was similarly anaesthetized only for the last 2 h of the 6-h period. The steroid-stimulated LH surge was blocked in both groups of rats anaesthetized with alphaxalone. The second experiment involved a comparison of pulsatile LH secretion in animals which were either unanaesthetized (n = 8) or anaesthetized with alpha xalone (n = 9). In six out of nine rats the anaesthetic did not affect the maximum or minimum plasma LH concentrations but significantly slowed the frequency at which LH pulses were measured. In the remaining three anaesthetized rats the drug blocked pulsatile LH secretion. The experiments confirm that some secretion of LH continues during alphaxalone anaesthesia but indicate also that the drug has a more deleterious action upon the oestrogen-stimulated LH surge than believed hitherto.

Topics: Anesthetics; Animals; Castration; Estradiol; Female; Luteinizing Hormone; Pregnanediones; Rats; Rats, Inbred Strains; Secretory Rate

Cremophor Elo proved as potent as Freund's complete adjuvant for eliciting skin reactivity to bovine serum albumin in guinea pigs. It enhanced delayed hypersensitivity to sheep erythrocytes in mice while hemagglutinin antibody titers were not affected. This adjuvant activity is likely to play a critical role in hypersensitivity reactions to Cremophor-containing drugs, e.g. alphadione.

Topics: Adjuvants, Immunologic; Animals; Drug Hypersensitivity; Female; Glycerol; Guinea Pigs; Hypersensitivity, Delayed; Male; Mice; Pregnanediones; Serum Albumin, Bovine

39 experiments were carried out in baboons using continuous intravenous infusion of alphaxalone-alphadolone as an anaesthetic for periods of up to 6 h. This steroid anaesthetic was found to be safe and reliable, with smooth, rapid induction, uneventful recovery, and no evidence of cumulative effect.

Topics: Anesthesia; Animals; Animals, Laboratory; Infusions, Parenteral; Papio; Pregnanediones

Alphadione, a steroidal anesthetic formulation containing alphaxalone (3 alpha-hydroxy-5 alpha-pregnane-11, 20-dione) and alphadolone acetate (21-acetoxy-3 alpha-hydoroxy-5 alpha-pregnane-11, 20-dione) in polyoxyethylated castor oil (Cremophor EL) owes its short duration of action to rapid metabolic transformation rather than the redistribution into the body fat. Treatment of rats with alphadione (1 ml/kg; intraperitoneal route) induced an increase in the cytochrome P-450 content of the liver. The difference spectra were obtained only when alphadione or alphaxalone was added to the liver microsomal suspension while neither alphadolone acetate nor Cremophor EL induced any spectral changes. The spectral dissociation constant (Ks) for alphaxalone was 2.5 X 10(-3) mM suggesting that hydroxylation of alphaxalone is a cytochrome P-450 dependent reaction.

Topics: Anesthetics; Animals; Cytochrome P-450 Enzyme System; Drug Combinations; Inactivation, Metabolic; Male; Microsomes, Liver; Pregnanediones; Rats; Rats, Inbred Strains; Spectrophotometry; Substrate Specificity

The use of alphaxalone/alphadolone in 40 reptiles of 13 species is described. In lizards and chelonians the effect of the drug combination varied from sedation to deep anaesthesia, depending on the dose. For other reasons, the effect in snakes varied, from none at all to deep anaesthesia. No fatalities occurred and there were no apparent clinical side effects in healthy reptiles. The results are discussed and attention is drawn to the apparently equivocal results in snakes.

Topics: Anesthesia; Anesthetics; Animals; Pregnanediones; Reptiles; Surgery, Veterinary

Prehospital emergency patients, especially with polytrauma and/or severe head injury need sedation for intubation and transportation. The use of relaxant drugs is dangerous under these circumstances. The "ideal drug" for this indication should not have any harmful effects on respiration, circulation, intracranial pressure, and should facilitate intubation. Short action without cumulation is desirable to make an early neurological diagnosis possible. Althesin was studied in our rescue service (ambulance and helicopter) in 133 cases (trauma n = 91, neurologic n = 18, cardiologic n = 12, intoxication n = 12), Althesin facilitated intubation in 129 cases, and was generally sufficient for sedation. Negative side effects were not seen provided althesin was correctly used. The necessity of the preceding use of an antihistaminic drug is emphasized. Althesin should not be used in patients suffering from severe cardiac disease because of its possible negative influence on cardiocirculatory function.

Topics: Adult; Anesthetics; Blood Pressure; Drug Combinations; Emergencies; Female; Heart Rate; Humans; Intubation; Male; Pregnanediones; Transportation of Patients; Wounds and Injuries

The pharmaceutical formulation of Althesin was shown to have a weak allergenic potential in the guinea pig maximization test. Alphadolone and alphaxalone acetate were found to be devoid of such potential, while the status of Cremophor EL remained equivocal.

Topics: Alfaxalone Alfadolone Mixture; Anesthetics; Animals; Drug Hypersensitivity; Female; Glycerol; Guinea Pigs; Intradermal Tests; Male; Pregnanediones

Topics: Anesthetics; Animals; Blood Pressure; Carbon Dioxide; Cats; Heart Rate; Ketamine; Oxygen; Pregnanediones; Respiration; Thiopental

Topics: Anesthetics; Animals; Cats; Drug Combinations; Pregnanediones

Alphaxalone/alphadolone (12 mg/ml) was administered by both the intramuscular and intravenous routes in an investigation of its action in newborn lambs. Useful anaesthesia was produced with an intravenous injection of 6 mg/kg bodyweight and with a divided intramuscular injection of either 9 or 12 mg/kg, one half of the dose being injected into the quadriceps mass of each hind leg. In all cases the recovery period was quiet and of short duration. Transient depressions of heart and respiratory rates were observed during anaesthesia but these were judged to be clinically acceptable. A single intramuscular injection was less effective probably because of slow absorption from the single site. The results suggest that this drug is a suitable injectable anaesthetic agent for the newborn lamb.

Topics: Anesthesia; Anesthetics; Animals; Animals, Newborn; Drug Combinations; Heart Rate; Pregnanediones; Respiration; Sheep

Topics: Anesthesia; Animals; Cattle; Drug Combinations; Goats; Injections, Intravenous; Pregnanediones; Rumen; Sheep

Gas chromatograph-mass spectrometry has been used to study the metabolism of Althesin (alphaxalone and alphadolone acetate) in man. Two metabolites, 20 alpha-reduced alphaxalone and alphadolone, as well as the two parent steroids, have been detected in the plasma during and after an infusion of Althesin. The main urinary metabolites were alphaxalone and 20 alpha-reduced alphaxalone, with smaller amounts of alphadolone, all of which were excreted mainly as the glucuronide conjugates. No alphadolone acetate was detected in the urine. In 3 patients in whom bile was collected over the 1st 24 h post-operation from an indwelling T-tube, it has not been possible using the methods described to detect in bile the presence of the parent steroids, or any of their probable metabolites.

Topics: Adult; Aged; Alfaxalone Alfadolone Mixture; Bile; Biotransformation; Female; Gas Chromatography-Mass Spectrometry; Humans; Male; Middle Aged; Pregnanediones; Time Factors

CT1341 (alphaxolone/alphadolone) (Saffan; Glaxo) at various dose rates was investigated for use as an intravenous anaesthetic agent in sheep and it was found that at least 1.65 mg/kg was required to induce anaesthesia. In an experimental group of animals the effect of CT1341 2.2 mg/kg, on PaO2, PaCO2, paH and mean arterial blood pressure was measured. The drug caused a mild respiratory acidosis accompanied by a slight decrease in PaCO2 tensions. Mean arterial blood pressure decreased by 50 per cent, 30 seconds after injection but this fall lasted for only 10 minutes. Prior administration of either atropine sulphate or mepyramine maleate failed to modify this hypotensive effect. Injection of the vehicle, Cremophor EL, alone had no effect on mean arterial blood pressure. Intracerebroventricular administration of CT1341 while producing anaesthesia failed to produce any hypotension. The drug was used for the induction of anaesthesia in 19 sheep. A mean dose of 3.0 mg/kg was found to be most useful clinically. In a further three sheep an infusion of a dilute solution (0.234 mg/kg per minute) was used to maintain anaesthesia. The most notable clinical feature in sheep was the fast, complete recovery. It is concluded that this agent is an extremely useful drug for the induction and maintenance of anaesthesia in sheep.

Topics: Anesthesia, Intravenous; Anesthetics; Animals; Pregnanediones; Sheep

Topics: Alfaxalone Alfadolone Mixture; Anesthesia, Intravenous; Animals; Blood Pressure; Bufo bufo; Cats; Electrocardiography; Pregnanediones; Rabbits; Rats

Topics: Alfaxalone Alfadolone Mixture; Animals; Bufo bufo; Cats; Muscles; Neuromuscular Junction; Pregnanediones; Rats; Synaptic Transmission

Topics: Alfaxalone Alfadolone Mixture; Anesthesia, Intravenous; Animals; Female; Lethal Dose 50; Male; Mice; Pregnanediones

Topics: Alfaxalone Alfadolone Mixture; Anesthesia, Intravenous; Animals; Guinea Pigs; Muscle, Smooth; Pregnanediones; Rabbits; Rats