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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.

The effect of Althesin, an anesthetic comprising two steroids, on regional cerebral function was determined by measurement of regional cerebral glucose utilization. Rats were anesthetized with an intravenous dose of 4, 8, or 20 mg total steroid/kg. These doses produced anesthesia for 12, 18, and 37 min, respectively. There were no physiologically significant effects of Althesin (20 mg/kg) on body temperature, blood pH, or blood gases. Blood pressure and heart rate decreased slightly after administration of Althesin. Althesin had a profound effect on glucose consumption in many, but not all, cerebral structures. The forebrain (especially cerebral cortex) was affected most, while the hindbrain was much less so or not at all. This pattern of functional depression is in accord with the minimal effects observed on physiologic variables. The effects of Althesin differ from those of other known anesthetics and suggest a unique mechanism. The possibility of action through naturally occurring steroid receptors is considered.

The aim of this work was to study in mammals the ability of high pressures to reverse the anesthesia produced by a wide range of general anesthetics. Dose-response curves were obtained using mice at pressures ranging from 1 to 125 atm for five agents, namely alpha-chloralose, ethylcarbamate, phenobarbital and, for comparison, nitrogen and argon. The increase of ED50 was found to be a linear function of pressure in each case, but the proportionate increases in ED50 with pressure were greater for the three non-inhalation agents than for the two gases. Thus, the ratio of ED50 at 100 atm to that at 1 atm was 1.74 for alpha-chloralose, 1.68 for ethylcarbamate, and 1.54 for phenobarbital. On the other hand, the corresponding ratios for argon and nitrogen were only 1.36 and 1.34. The potencies of three short-acting agents (trichloroethanol, ketamine, and alphadione) were shown to increase with decreasing pressure, although ED50 values could not be obtained. It is concluded that pressure reverses the actions of a wide variety of anesthetics in mice. The results of this study are not inconsistent with either the fluidized lipid membrane or the critical volume hypotheses of anesthetic action.

Curves relating renal sympathetic nerve activity and mean arterial pressure were derived in conscious rabbits during ramp changes in mean arterial pressure, elicited by perivascular balloon inflation. The renal sympathetic nerve activity-mean arterial pressure relationship consisted of a high-gain sigmoidal region about resting, where renal sympathetic nerve activity rose or fell in response to moderate falls and rises of mean arterial pressure. With larger pressure rises, renal sympathetic nerve activity first fell to a lower plateau and then reversed at even higher mean arterial pressure. When mean arterial pressure was lowered below resting, renal sympathetic nerve activity rose to an upper plateau and then reversed abruptly toward resting at low mean arterial pressure. Both arterial and cardiac baroreceptors exerted substantial inhibitory influences on renal sympathetic nerve activity at all pressure levels. These effects appeared additive over the central high gain region of the curve, but beyond this region there were non-additive interactions. The latter were affected considerably by alfathesin anesthesia. In other experiments, we studied the effects of sustained alterations in resting mean arterial pressure induced by infusing nitroprusside and phenylephrine, which produced rapid resetting of the renal baroreflex. The latter could be accounted for, in part, by resetting of the threshold of the arterial baroreceptors and in part by contributions from other afferents, probably the cardiac receptors. During resetting associated with nitroprusside-induced falls in resting blood pressure, high-gain reflex adjustments in renal sympathetic nerve activity to moderate changes in mean arterial pressure were preserved, but during resetting associated with phenylephrine-induced rises in resting mean mean arterial pressure, the resting renal sympathetic nerve activity lay on the lower curve plateau, resulting in reduction in the apparent gain of the reflex renal sympathetic nerve activity response to moderate changes in mean arterial pressure.

Recovery from anesthesia was assessed in a double-bind manner in 40 healthy volunteer students after intravenous anesthesia with thiopental (6.0 mg/kg), methohexital (2.0 mg/kg), propanidid (6.6 mg/kg), or alphadione (Althesin), 85 mul/kg using a driving simulator 2,4, 6, and 8 hours after injection of the drugs. Clinical recovery was faster after propanidid and methohexital than after thiopental or alphadione. Driving performances remained significantly (P less than 0.05) worse than in a control group for 6 hours after thiopental and for 8 hours after methohexital, and reaction times 8 hours after thiopental remained worse than in the control subjects. After alphadione driving skills were impaired at 6 hours only. Propanidid produced no impairment in driving skills at any time during the experiment. It is concluded that after the doses used in this study patients should not drive or operate machinery for at least 2 hours after propanidid and for at least 8 hours after alphadione. After methohexital and thiopental patients should probably not drive for 24 hours because of the severity of the disturbances at 8 hours.

The two steroid components of Alfathesin, alfaxolone and alfadolone acetate, have been tested for porphyrin-inducing activity in chick embryo liver cell culture and for hepatic ALA-synthetase-inducing activity in the 17-day-old chick embryo. In cell culture alfoxolone was shown to have potency comparable to that of thiopental, while alfadolone acetate had low potency. In the 17-day-old chick embryo alfaxolone has a third the potency of thiopental; alfadolone acetate showed low potency. The authors conclude that an induction dose of Alfathesin would be less likely than a comparable dose of thiopental to increase ALA-synthetase activity in a patient with hereditary hepatic porphyria.

Cardiorespiratory effects of ketamine and Althesin were measured in two groups of premedicated patients with cardiac disease. The drugs were given in clinically equivalent doses with a second dose administered about 10 min after induction. The first dose of ketamine caused a marked increase in systemic and pulmonary arterial pressure, heart rate, and central venous and wedge pressures and cardiac index. The first dose of Althesin caused a decrease in systemic arterial pressure, central venous pressure, cardiac index and heart work, but little change in heart rate. The second dose of induction agent was administered before the cardiorespiratory effects of the initial dose had resolved. The second dose of Althesin caused changes similar to those following the first dose, but less marked. The changes following the second dose of ketamine were opposite to those following the first dose.

Thiopentone 4 mg/kg, Althesin 0.055 ml/kg and ketamine 2 mg/kg were compared in 157 children undergoing minor otolaryngological surgery, mostly adenotonsillectomy. Premedication was with pethidine and atropine and anaesthesia was maintained with nitrous oxide in oxygen and halothane. Tracheal intubation was facilitated with suxamethonium. In each group half of the children received pethidine 0.7 mg/kg after intubation and the remainder received saline. Ketamine increased arterial pressure after induction. The cardiovascular responses to intubation were more obvious after thiopentone and Althesin than after ketamine. Operating conditions, cardiovascular changes during operation and the course of extubation were similar in all groups. The recovery after ketamine was longer than after thiopentone and Althesin. Thiopentone was associated with significantly less vomiting immediately after operation than was Althesin and ketamine. In the period immediately after operation Althesin was associated with a higher need for analgesics compared with thiopentone and ketamine. Pethidine prolonged the recovery after thiopentone, decreased the incidence of vomiting immediately after operation associated with Althesin and increased that associated with ketamine.

The tidal volume-inspiratory duration relationship was studied during air breathing and rebreathing in conscious and anesthetized human subjects using three different intravenous agents. The results observed have been compared with similar experiments carried out in cats. Its has been shown that anesthesia provokes an increase in breathing rate associated with a decrease in tidal volume in human subjects; an opposite effect on breathing rate was observed in cats. Thus, the tidal volume-inspiratory duration relationship, although very similar in the conscious cat or human subject, is very different under anesthesia. The results were quite consistent in a given species whatever the nature of the drug used. It is suggested that modifications of the breathing rate by anesthesia, related to animal species, are caused by central effects of the drug. These effects are probably mediated by different actions on inputs to the inspiratory –off-switch” mechanisms in the two species.