Disease relevance of Alphaxalone

• Alphaxalone activates a Cl- conductance independent of GABAA receptors in cultured embryonic human dorsal root ganglion neurons [1].
• It was found that alphaxalone was adequatley removed from the circulation, despite a period of cardiopulmonary bypass and hypothermia, and provided suitable anaesthesia for this type of surgery [2].
• The metabolism of 14C-labelled alphaxalone, dispensed as Althesin, was studied in normal patients, patients with obstructive jaundice and patients with chronic renal disease and anuria [3].
• However, alphaxalone and tetrahydrodeoxycorticosterone failed to potentiate gamma-hydroxybutyric acid-induced absence seizures when injected into thalamic reticular nucleus [4].
• The incidence of involuntary movements and increased muscle tone was significantly greater after etomidate than following alphaxalone/alphadalone; but the involuntary movements were never marked [5].

Psychiatry related information on Alphaxalone

• Chlordiazepoxide and the steroid anesthetic, alphaxalone, also attenuated the anxiogenic-like effect of restraint stress and elevated the baseline exploratory behavior of nonstressed control groups [6].
• In addition, no changes in pain threshold were noted with alphaxalone (8 mg/kg) in the tail-flick analgesia test [7].
• The effects of alphaxalone on CRF-potentiated startle may not be generalized to all CRF-stimulated behaviours, since alphaxalone failed to disrupt CRF-stimulated locomotor activity [8].
• Etomidate in electroconvulsive therapy. A within-patient comparison with alphaxalone/alphadalone [5].
• Valproate (284 mg/kg; the dose used in combination with alphaxalone) produced significant memory deficits in mice [9].

High impact information on Alphaxalone

• Sex difference in response to alphaxalone anaesthesia may be oestrogen dependent [10].
• These results, taken together with those of Richards and Hesketh, suggest that the effect of alphaxalone may be mediated by interactions with synaptic membranes that are more specific than simply a generalized change in membrane structure, and that these interactions are affected by sex steroids [10].
• T-type Ca(2+) channels are believed to play an important role in pain perception, and anesthetic steroids such as alphaxalone and allopregnanolone, which have a 5alpha-configuration at the steroid A, B ring fusion, are known to inhibit T-type Ca(2+) channels and cause analgesia in a thermal nociceptive model (Soc Neurosci Abstr 29:657.9, 2003) [11].
• To determine whether receptor modulation by intravenous general anesthetics also was affected by these point mutations, we examined the effects of propofol, etomidate, the barbiturate methohexital, and the steroid alphaxalone on wild-type and mutant GABAA receptors expressed in human embryonic kidney 293 cells [12].
• These results further demonstrate that the actions of general anesthetics at GABA(A) receptors are influenced by receptor subunit composition, and they suggest that the effects of alphaxalone and etomidate are mediated by different binding sites on the receptor complex [13].

Chemical compound and disease context of Alphaxalone

• The use of Cremophor EL to solubilize steroids such as alphaxalone led to unacceptable hypersensitivity reactions and consequent withdrawal of this anaesthetic [14].

Biological context of Alphaxalone

• 2. The animals were anaesthetized with sodium pentobarbitone which, as assessed by the effects on the circadian rhythm of plasma ACTH and corticosterone, appeared to be a better anaesthetic than either urethane or alphaxalone for studies on the hypothalamic-pituitary-adrenal system [15].
• 3. The kinetics of the Na current were not modified by alphaxalone but, in the presence of the drug, the K current showed an apparent fast inactivation [16].
• However, higher concentrations of alphaxalone (10-100 microM) reversibly suppressed ACh-evoked currents, the IC50 for blockade being 20 microM [17].
• Protein kinase A inhibition significantly reduced alphaxalone auto-modulation at alpha1beta3gamma2L, alpha6beta3gamma2L, and alpha6beta3delta subtypes while it enhanced potentiation at alpha1beta3delta isoforms suggesting a crucial influence of receptor subunit composition and phosphorylation for steroid actions [18].
• Pressure reversal of alphaxalone/alphadolone and methohexitone in tadpoles: evidence for different molecular sites for general anaesthesia [19].

Anatomical context of Alphaxalone

• Geometric requirements for membrane perturbation and anesthetic activity. Conformational analysis of alphaxalone and delta 16-alphaxalone and 2H NMR studies on their interactions with model membranes [20].
• The ability of volatile (halothane and isoflurane) and nonvolatile (alphaxalone and pentobarbital) general anesthetics to modulate radioligand binding to gamma-aminobutyric acid (GABA)A receptors was examined in an immortalized cell line (WSS-1) expressing rat alpha 1 and gamma 2 subunits [21].
• The effect of the general anesthetic propofol on t-[35S]butylbicyclophosphorothionate ([35S]TBPS) binding to unwashed membrane preparations from rat cerebral cortex was studied and compared to that of other general anesthetics (pentobarbital, alphaxalone) which are known to enhance GABAergic transmission [22].
• These effects on the inhibitory Cl(-)-conductance mechanism may be partly responsible for the depressant actions of alphaxalone on the mammalian central nervous system [23].
• The modulation of the gamma-aminobutyric acidA (GABAA) receptor by alphaxalone has been investigated by use of voltage-clamp recordings from enzymatically isolated bovine chromaffin cells maintained in cell culture [17].

Associations of Alphaxalone with other chemical compounds

• Human embryonic kidney 293 cells transiently transfected with beta 3 subunits of gamma-aminobutyric acid type A receptors from the rat exhibited a specific high affinity binding for [35S]t-butylbicyclophosphorothionate (TBPS) that could be inhibited by pentobarbital, etazolate, (+)-etomidate, alphaxalone, propofol, chlormethiazole, and Ro 5-4864 [24].
• In hippocampus, prenatal ethanol exposure enhanced the effects of flunitrazepam and alphaxalone, whereas negative modulatory effects were either decreased (FG-7142) or unchanged (pregnenolone) [25].
• 2 Concentrations of pentobarbitone, ether, methoxyflurance, trichloroethylene and alphaxalone that are known to depress synaptic transmission in the prepiriform cortex also depressed the sensitivity of prepiriform neurones to L-glutamate [26].
• The rank order of potency for general anaesthetics was propofol > etomidate = alfaxalone = ketamine > thiopental = methohexital at the fast sodium channel, and propofol > or = etomidate > alfaxalone = methohexital > thiopental > ketamine at the 5-HT3 receptor channel.(ABSTRACT TRUNCATED AT 250 WORDS)[27]
• This study determined the anesthetic potency of alphaxalone and delta 16-alphaxalone in goldfish and compared it with their effects on dipalmitoylphosphatidylcholine (DPPC) membranes and an alpha-helix polypeptide, poly(L-lysine) [28].

Gene context of Alphaxalone

• However, although maximal current activation by alphaxalone varied only slightly with the specific beta subunit isoform present, the efficacy of etomidate showed a rank order of beta3 > beta2 >>> beta1 [13].
• Alphaxalone (ALX) does not reduce CRF-potentiated startle by producing a generalized reduction in reactivity, since blockade of CRF-stimulated startle was not accompanied by an ALX-induced reduction in baseline startle amplitude and ALX does not reduce strychnine-potentiated startle [8].
• 4. At 10 microM, the steroids 5 alpha-pregnan-3 alpha-ol-20-one and alphaxalone (5 alpha-pregnan-3 alpha-ol-11,20-dione), potentiated submaximal GABA responses [29].
• Alphaxalone, a neurosteroid anesthetic, inhibits norepinephrine transporter function in cultured bovine adrenal medullary cells [30].
• The potency of TG41 at receptors containing alpha1, beta2, and gamma2L subunits was greater than that of alphaxalone, etomidate, propofol, or pentobarbital [31].

Analytical, diagnostic and therapeutic context of Alphaxalone

• The final model contained an exponential expression to account for acute functional adaptation to the EEG effect upon continuous infusion of alphaxalone [32].
• Alphaxalone was administered as a continuous intravenous infusion of 0, 1.2, 2.2, or 5.2 mg over 360 min [32].
• Proceedings: The determination of alphaxalone in human blood by gas-liquid chromatography [33].
• Alphaxalone infusion during cardiopulmonary bypass [2].
• The plasma concentrations of alphaxalone were measured with a gas chromatographic technique in six patients following a single i.v. injection of Althesin, and in five volunteers following oral administration [34].

References