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RESUMEN: La población actual del departamento del Cauca es el resultado de la mezcla de tres poblaciones parentales (europea, amerindia y africana). En este estudio se determinó la composición genética de 306 residentes del departamento mediante la utilización de 34 variantes autosómicas, 9 variantes en el cromosoma X, 6 en el ADNmt y 8 en el cromosoma Y. Los análisis de las variantes autosómicas y del cromosoma X revelaron que la población europea y la amerindia han contribuido en mayor proporción al actual acervo genético de la población estudiada. Los resultados de las variantes en el ADNmt y del cromosoma Y sugieren un fuerte sesgo sexual (flujo génico asimétrico) en el proceso de mezcla, en el que los cruces interétnicos fueron principalmente entre los colonizadores europeos y las mujeres nativas ABSTRACT: The contemporary population of the Province of Cauca is the result of the admixture between three parental populations (European, Amerindian and African). Genetic composition was determined in 306 residents of the Province with the use of 34 autosomal markers, 9 markers in chromosome X, 6 and 8 mtDNA in chromosome Y. Autosomal and X chromosome data indicate that both European and Amerindian populations have contributed to a greater extent to the current genetic pool of the population. The mtDNA and the Y chromosome data, indicate a strong sexual bias (asymmetrical gene flow) in the admixing process, where interethnic crosses were mainly between European men and native women. COL0006723

The endocrine response is an important component of the physiological response to blood loss. There is some variability in reported levels of certain hormones during hemorrhage such as the stress hormone adrenocorticotrophic hormone (ACTH). Therefore, the effect of two anesthetic agents, ketamine and saffan, on ACTH and β-endorphin levels during hemorrhage was assessed in 12 minipigs. The animals were divided into two groups, group I saffan and group II ketamine (n=6). Pigs were subjected to a continuous fixed volume hemorrhage under one of the above anesthetics while spontaneously breathing. Blood pressure and heart rate responses were recorded together with β-endorphin and ACTH levels both before and at 10, 20, 30, 40 min after the onset of bleeding. ACTH levels were higher in the ketamine-anesthetized pigs and rose significantly faster with falling blood pressure than ACTH measured in pigs under saffan anesthesia. In contrast, the hemorrhage induced β-endorphin increase was not significantly different between the two anesthetic groups. These results indicate that choice of anesthetic agent is important when investigating the hormone response to hemorrhage and may account for the variable hormone levels in the published literature to date.

Summary Three possible factors predisposing to Althesin hypersensitivity, namely total dose, method of administration, either by bolus dose or infusion, and pregnancy have been studied in patients receiving the drug for the first time. Of 137 patients given Althesin, four exhibited clinical signs of mild hypersensitivity, while C3 conversion alone, indicative of a subclinical reaction, was seen in a further six patients. No reactions were observed in two control groups in whom anaesthesia was induced with thiopentone. Neither the total dose nor method of administration appeared consistently to influence the incidence of reactions, but eight of the ten patients producing an altered response to Althesin were pregnant.

Background Long-term behavioral, immunologic, and neurochemical alterations have been found in primates exposed to adverse early rearing. Methods Bonnet macaque ( Macaca radiata ) mother–infant dyads were exposed to uncertain requirements for food procurement (variable foraging demand, VFD) for a few months. Ten years later, these offspring and age- and gender-matched control subjects were studied using proton magnetic resonance spectroscopic imaging (MRSI). Results In anterior cingulate, VFD-reared subjects displayed significantly decreased N -acetylaspartate (NAA) resonance and significantly increased glutamate–glutamine–γ-aminobutyric acid (Glx) resonance relative to the stable neurometabolite creatine (Cr). Across all subjects, NAA/Cr and Glx/Cr ratios in the anterior cingulate were negatively correlated ( r = −.638, p = .014). In the medial temporal lobe, the ratio of choline-containing compounds to Cr was significantly increased in VFD subjects. Conclusions These findings indicate that adverse early rearing in primates has an enduring impact on adult MRSI measures considered reflective of neuronal integrity and metabolism, membrane structure and glial function, and cerebral glutamate content, and that these alterations occur in the same brain regions implicated in trauma-related psychiatric disorders.

Hyperreflexia is a common feature of spinal cord injury (SCI), and changes in reflex excitability have been reported to be useful in assessing treatments in animal models of cord damage. However, spinal reflexes are known to be dependent on anesthetic level. As a preliminary to its use in SCI, the excitability of the Hoffman reflex (H reflex) has been assessed under several commonly used anesthetics. The H reflex was recorded in the distal foot muscles (dorsal interossei) of adult rats, while the lateral plantar nerve was stimulated. Five different anesthetics were used: ketamine, halothane, Nembutal, Etomidate, and Saffan. Recording and stimulating electrodes were inserted directly through the skin to minimize the surgical procedure for each experiment, allowing repeated recording to be made in the same animal on a weekly basis. Suppression of the H reflex was tested using twin-pulse stimulation. Halothane and ketamine produced suppression of the H response when interpulse intervals were shortened to less than 1 s. The H-reflex suppression profiles recorded under Etomidate, Saffan, and Nembutal anesthesia were less sensitive to the stimulation rate, with little reduction until intervals were 200 ms or less. The suppression profiles of halothane and ketamine resemble that seen in unanesthetized humans, whereas that under the other anesthetics tried here resembles that observed in spinal-cord-injured animals. The results suggest a preferential action of some anesthetics on descending pathways involved in reflex modulation and the importance of assessing reflex excitability under anesthetics such as ketamine or halothane.

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.

A patient who exhibited a severe reaction to an intravenous agent on one occasion was given a similar anaesthetic on a subsequent occasion without incident. Intradermal testing was carried out and the results are tabulated and discussed.

A study has been carried out into the effects of clinically important antisickling and anaesthetic substances and ionophoric antibiotics on the activities of (Na+, K+)- and (Ca+2, Mg2+)-ATPases of the human erythrocyte membrane. In general, these drugs, with the exception of nystatin, inhibit both types of enzymic activities but with varying degrees of efficacy. (Ca2+, Mg2+)-ATPases was more sensitive to the lipophilic anaesthetics and (Na+,K+)-ATPase to the ionophoric antibiotic, amphotericin B. These results are explained in the light of the partition coefficients of these drugs in erythrocyte membranes, their effects on the fluidity of the erythrocytes membranes, the changes they induce in the permeability properties of erythrocytes and the subsequent effect of procaine on sickling of erythrocytes, and their potential interaction with specific membrane components.

1. Systemic administration of phenethylamine-derived, 5-hydroxytryptamine(2) (5-HT(2)) receptor agonists inhibits the firing of midbrain 5-HT neurones, but the 5-HT receptors involved are poorly defined, and the contribution of peripheral mechanisms is uncertain. This study addresses these issues using extracellular recordings of 5-HT neurones in the dorsal raphe nucleus of anaesthetised rats. 2. The 5-HT(2) receptor agonists DOI ((+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride) and DOB ((+/-)-2,5-dimethoxy-4-bromoamphetamine hydrobromide), caused a dose-related (10-100 micro g kg(-1) i.v.) inhibition of 5-HT neuronal activity, with the highest dose reducing firing rates by80%. 3. Pretreatment with the 5-HT(2) receptor antagonist ritanserin (1 mg kg(-1) i.v.) completely blocked the action of DOI. The 5-HT(2A) receptor antagonist MDL 100,907 (0.2 mg kg(-1) i.v.) blocked the action of both DOI and DOB. In comparison, the 5-HT(2B/C) receptor antagonist SB 206553 (0.5 mg kg(-1) i.v.) caused a small, but statistically significant, shift to the right in the dose response to DOI and DOB. 4. Pretreatment with the peripherally acting 5-HT(2) receptor antagonist BW 501C67 (0.1 mg kg(-1) i.v.) had no effect on the DOI-induced inhibition of 5-HT cell firing, but completely blocked the DOI-induced rise in mean arterial blood pressure. 5. These data indicate that the inhibition of 5-HT cell firing induced by systemic administration of DOI and DOB is mediated predominantly by the 5-HT(2A) receptor-subtype, but that 5-HT(2B/C) receptors also play a minor role. Moreover, central and not peripheral mechanisms are involved. Given evidence that 5-HT(2) receptors are not located on 5-HT neurones, postsynaptic 5-HT feedback mechanisms are implicated.

A safe means of anaesthetizing common marmosets ( Callithrix jacchus) for a study using magnetic resonance imaging (MRI) to investigate cerebral ischaemia was required. Continuous infusion of alphaxalone/alphadalone was used to anaesthetize 37 marmosets for non-recovery and recovery experiments. This was found to give safe, reliable anaesthesia when coupled with pulse oximetry and electrocardiographic (ECG) monitoring.

The akinesia of Parkinsonism is relieved by pallidotomy and subthalamic nucleotomy, but not by thalamotomy. Therefore, this disabling symptom probably depends upon connections other than the pallidalthalamocortical tracts, possibly efferents of the medial pallidum descending to the upper brainstem. We have previously demonstrated akinesia in the normal monkey following radiofrequency lesioning in the region of the pedunculopontine nucleus (PPN), one of the primary targets for descending pallidal outflow. Here, we confirm that selectively destroying neurones in the PPN area, whilst sparing fibres of passage, results in an akinetic state in normal macaques.

1. Whole-cell patch-clamp recordings were used to investigate the effects of the anaesthetic Saffan on the electrophysiological properties of sympathetic preganglionic neurones (SPNs) in rat spinal cord slices. 2. Saffan (1-54 microM) abolished or reduced the frequency of spontaneous action potential firing and abolished spontaneous, sub-threshold membrane potential oscillations. Saffan caused dose-dependent decreases in input resistance and depending upon the initial resting membrane potential, either a depolarization, a hyperpolarization or no change in membrane potential. 3. Responses to Saffan were blocked by the GABAA receptor antagonists bicuculline (5-20 microM) and picrotoxin (20 microM), but not by the glycine receptor antagonist strychnine (20 microM) indicating that they were mediated by GABAA receptors. 4. Changes in the properties of SPN action potentials were also observed. In the presence of Saffan the amplitude and duration of the action potential after-hyperpolarization were reduced and larger depolarizations were required in order to evoke trains of action potentials. 5. To examine the effects of Saffan on electrotonic coupling between SPNs, experiments were performed with the Na+ channel blocker QX-314 in the intracellular solution and antidromic oscillations were evoked by ventral root stimulation. Saffan failed to abolish antidromic oscillations, but reduced their amplitude and duration. This indicates that the abolition of spontaneous membrane potential oscillations was not a direct effect on the coupling between SPNs, but was a result of the abolition of spontaneous activity by Saffan. 6. The responses to Saffan occurred within the plasma concentration range of Saffan during anaesthesia, suggesting that the electrophysiological properties of SPNs may be altered during anaesthesia with Saffan. This would be expected to lead to changes in sympathetic tone and in the integration of sympathetic output.

Objective : To test the hypothesis that increased cardiac output with continuous positive airway pressure (CPAP) leads to increased myocardial metabolic cost. Design : Prospective, repeated-measures, laboratory studies. Setting : University-affiliated hospital animal research laboratory. Subjects : Eight sedated pigs that had been previously instrumented for collection of hemodynamic data. Interventions : Application of CPAP at 0, 5, 10, and 15 cm H 2 O and recovery under conditions of normal blood volume (normovolemia) and after administration of hetastarch 35 mUkg (hypervolemia). Measurements and Main Results : We measured mean arterial pressure, cardiac output, systemic vascular resistance index, the first derivative of the left ventricular pressure at a left ventricular pressure of 50 mm Hg, rate-pressure product, left ventricular tension-time index, stroke work index, myocardial pressure-myocardial segment length area, coronary artery blood flow and coronary vascular resistance, and myocardial oxygen consumption (four pigs). With normovolemia, cardiac output decreased with CPAP (4.9 ± 1.2 Umin at CPAP of 0 cm H 2 O to 4.5 ± 1.3 Umin at CPAP of 15 cm H 2 O, p

Total intravenous anaesthesia is a form of anaesthesia which is more often used in human medicine for high risk patients. The case reports of two cats with a severe dyspnoe are presented. Both patients received anaesthesia with the steroid anaesthetic agent Saffan for 19 and 25 hours, respectively. Saffan is a well-tolerated agent with little side effects. Dosage and monitoring results are presented.

The application of human pediatric equipment for measuring respiratory function in nonhuman primates is rapidly gaining popularity in the evaluation of anti-asthma drugs. An important difference between primate procedures and the human clinical situation is the requirement for anesthesia for some techniques because of poor animal compliance. We studied the actions of three potential maintenance anesthetic agents-thiopental, saffan, and propofol-and their effects on a range of cardiovascular parameters under conditions of a broncho-provocation test in rhesus monkeys. The spasmolytic effect of saffan on bronchial smooth muscle was investigated in smooth muscle preparations in vitro and in the rhesus monkey in vivo. Thiopental proved to be a useful sedating agent for this application. Saffan proved to be a bronchodilator in vitro, but the sedative dose was lower than that required to induce appreciable bronchodilator activity in vivo. In comparison, propofol was not appropriate for this application because of the poor sedative effect at nonbronchodilator doses.

An animal model with selective cardiac autonomic denervation was developed in neonatal swine for the purpose of future studies concerning the possible role of abnormal cardiac innervation in the etiology of sudden infant death syndrome. Twenty-six 4- to 8-day old piglets were randomly assigned to one of the following treatment groups: right stellate ganglionectomy (RSG), left stellate ganglionectomy (LSG), right cardiac vagotomy (RCV), and sham-operated control group. Piglets were anesthetized with Saffan and mechanically ventilated on room air. The thoracic wall was opened, and the sternum was divided, permitting exposure of pleura, heart, and lungs. After completion of one of these operative procedures, the thoracic wall was closed in layers. On successful recovery from anesthesia and extubation, piglets were returned to their sows. Postoperative administration of antibiotics was performed during the first week. Electrocardiograms were recorded once a week over an 8-week period. The sham-operated control group had a postnatal increase in QTc and decrease in heart rate. The RSG group had significantly longer QTc than the sham-operated control group QTc, whereas the RCV group had significantly shorter QTc interval than sham-operated controls. Surgical complications caused the death of two piglets (hemorrhage in one and aspiration in the other), infection caused the death of one piglet 2 weeks after surgery, and three died of unknown causes (one from the RSG group and two from the RCV group). The cause of death for these three animals could not be determined (necropsy was not revealing) because they were not monitored at the time of their demise.(ABSTRACT TRUNCATED AT 250 WORDS)

Gonadotropin-releasing hormone (GnRH) and oxytocin both stimulate the secretion of luteinizing hormone (LH), although with different characteristics. Therefore, interaction between oxytocin and GnRH in the control of LH may be postulated. We developed models for investigating whether oxytocin can modulate GnRH action on LH in vivo. Pentobarbitone is known to pharmacologically isolate the pituitary from hypothalamic GnRH. We found that after pentobarbitone anesthesia of female rats at proestrus, oxytocin caused a synergistically enhanced LH response to administered GnRH (p < 0.04). In a second series of experiments, female proestrous rats were anesthetized with althesin. This anesthetic allows transport of endogenous GnRH from the hypothalamus to the pituitary. In control animals, which received no exogenous hormone, there was a surge in the mean LH concentration on the evening of proestrus, indicating the presence of endogenous GnRH activity. Thus, the novel model enables detection of interactions of administered hormones with endogenous GnRH. Administration of GnRH plus oxytocin in the afternoon of proestrus caused a reduction (p < 0.01) in the mean level of LH observed in the evening. The reduction was larger than if GnRH alone was administered. Following althesin anesthesia, rats sometimes had low LH levels on the afternoon of proestrus. There was a statistically significant difference between the number of rats that received oxytocin plus GnRH and had low LH levels and the number with low LH levels in the control group (p < 0.02). Neither of the hormones administered alone had a significant effect. Thus, it appears that oxytocin accentuated the effect of GnRH in reducing LH concentrations in althesin-anesthetized rats. If althesin anesthesia was embloyed one estrous cycle (4 days) before hormone administration, there was no difference in the evening LH surge observed in control and experimental groups. However, oxytocin synergistically enhanced the acute LH response to exogenous GnRH (p < 0.03). Our results demonstrated interaction of oxytocin with GnRH in vivo, revealing potential for complex modulation by oxytocin of GnRH control of LH.

Steroids produce anaesthesia besides producing the well known metabolic and hormonal effects. A number of anaesthetic steroids have been synthesized and tried clinically. Hydroxydione, althesin, minaxolone and pregnanolone are among those studied in detail. They act through GABAergic mechanism and are known to be advantageous over barbiturates.

The effect of physostigmine, a cholinesterase inhibitor, on the loss of consciousness induced by three different intravenous induction anesthetics, namely midazolam, etomidate and althesin at ED50, was studied in three comparable groups of patients. Ten min before induction, the first and second groups received physostigmine 8 micrograms/kg and 16 micrograms/kg, respectively, and the third group received 2 ml of saline solution. Physostigmine 16 micrograms/kg resulted in a significant decrease in the percentage of unconscious patients with midazolam (from 50% to 10%), but it did not modify the incidence with etomidate or althesin. Physostigmine at doses of 8 micrograms/kg and 16 micrograms/kg could cause 6.7% and 10% nausea, respectively. Although the mechanism of the drug interaction of physostigmine and midazolam is unclear, physostigmine could be used clinically to reverse post-anesthetic somnolence induced by midazolam.

The effects of anaesthetic agents on pressor effect of NG-nitro-L-arginine (L-NNA), a potent inhibitor of nitric oxide (NO) synthesis, were examined in rats. I.v. bolus of L-NNA (1-32 mg/kg) in conscious rats dose dependently increased mean arterial pressure (MAP) to a maximum value of 53 +/- 2 mmHg at 16 mg/kg with ED50 value of 4.7 +/- 0.9 mg/kg. The effects of a single i.v. bolus dose (32 mg/kg) of L-NNA were examined in conscious rats and rats anaesthetised with pentobarbital, chloralose, ketamine, althesin (mixture of alphaxalone and alphadolone), urethane, enflurane or halothane. In conscious rats, peak MAP (51 +/- 3 mmHg) was reached 10 min after i.v. injection and the effect lasted more than two hours. The magnitudes of peak MAP differed under the influence of anaesthetic agents with the following rank order: althesin greater than conscious = pentobarbital = chloralose = ketamine = urethane greater than enflurane much greater than halothane (in which there was negligible change in MAP). The onsets were delayed in rats anaesthetised with pentobarbital, althesin, chloralose and enflurane but not altered with ketamine and urethane compared to that in conscious rats. Therefore, L-NNA caused intense and prolonged pressor response in conscious rats and rats anaesthetised with the i.v. anaesthetic agents pentobarbital, chloralose, ketamine, althesin and urethane. MAP effect of L-NNA was markedly attenuated by the inhalation anaesthetics halothane and enflurane.

The effects of partial denervation, partial denervation with additional nervous blockade with bupivacaine, and total denervation achieved by amputation and replantation of the ear on traumatic vasospasm were studied in the rabbit. The central ear artery was exposed and compressed in a standardized fashion. The inner diameter was determined by in vivo microscopy using transillumination with cold light. The resulting spasm was assessed in terms of its duration, intensity (reduction of initial diameter), and severity (integrated change in diameter over time). None of the types of denervation had any influence on the vasospasm. The results suggest that the vasospasm is a local phenomenon of the vascular smooth muscle and is not modified by the nervous system.

The release of luteinizing hormone (LH) in response to electrical stimulation of septal nuclei (the diagonal band of Broca, DBB, and dorsal septal nucleus) and the subcallosal fornix has been studied in gonadectomized female cats. The cats were anesthetized with Althesin. Electrodes were placed on the medial and lateral aspects of the subcallosal fornix and paired bipolar stimulating electrodes were aimed at the DBB or dorsal septal nucleus. The effect of electrical stimulation of these regions on the secretion of LH was studied by radioimmunoassay of LH in serial blood samples taken before, during and after stimulation. Stimulation in the DBB or in the dorsal septal nucleus resulted in a peak of LH release during stimulation followed by further spontaneous peaks. All peaks showed an exponential decline. The frequency of spontaneous peaks following stimulation could reach the level found in unanesthetized cats. Stimulation of the subcallosal fornix produced a significant depression in the amplitude of LH release. The effects of DBB, dorsal septal and fornix stimulation are all exerted, we suggest, by projections to LHRH containing neurons in the preoptic region.

Magnetic resonance imaging was applied to measure the volumes of spleens and lymph nodes of mice infected with three different leukemia retroviruses (LP-BM5 murine leukemia virus, Friend, and Rauscher) in vivo. Anesthesia by rapid intraperitoneal injection of Saffan was sufficient for magnetic resonance imaging and could be repeated at appropriate intervals. Eleven frontal magnetic resonance images through the abdomen with a center-to-center distance of 1.5 mm between adjacent slices were acquired simultaneously. To optimally demarcate spleens from the surrounding tissues, the magnetic resonance images were mildly T2-weighted for mice infected with LP-BM5 murine leukemia virus and mildly T1-weighted for those infected with Friend and Rauscher virus. Measurements requiring only 3 to 4 hours in groups of 24 to 28 mice were accomplished by using a standardized holder (i) accommodating two animals in the supine position and (ii) ensuring reproducible positioning in the magnetic resonance-instrument, and (iii) by reducing the number of phase-encoding steps of mildly T2-weighted magnetic resonance images from 256 to 128. Volumes of spleens and inguinal lymph nodes were calculated from the respective cross-sectional areas. The weights and magnetic resonance image-derived volumes of spleens and inguinal lymph nodes correlated well (r greater than 0.95). Despite large variations in the extent of splenomegaly and lymphadenopathy at any given time, the progression of the disease could easily be followed by repeating magnetic resonance imaging at intervals. Thus, statistically relevant results can be obtained in an infection model requiring the use of only a few animals.

1. The effects of general anaesthetics were investigated on neuronal sensitivities to transmitter substances, which were determined by iontophoretic applications of acetylcholine, glutamate, N-methyl-D-aspartate (NMDA) and gamma-aminobutyrate (GABA) during intracellular recording in in vitro slice preparations of neocortex (guinea-pig). 2. In most of the 65 neurones studied, perfusion of isoflurane (0.5-2.5 minimum alveolar concentration (MAC)) or Althesin (25-200 microM) and, in some cases, halothane (0.5-2 MAC), markedly reduced the depolarizing responses and associated membrane conductance changes evoked by dendritic applications of acetylcholine, glutamate, NMDA and GABA. 3. The order of depression was acetylcholine greater than glutamate or NMDA much greater than GABA. This selectivity could also be assessed from the EC50 for the isoflurane-induced depression of the just-maximal responses to acetylcholine, which was 0.9 MAC compared with an EC50 = 1.9 MAC for the suppression of glutamate responses. The selectivity was less pronounced in the case of the actions of Althesin, where the EC50s were 75 microM for the depression of acetylcholine responses and 90 microM for the depression of glutamate responses. 4. The hyperpolarizing responses observed when GABA was applied near the perikaryon in 7 neurones, were slightly reduced (approximately 15%) in 4, and unchanged in 3 neurones during anaesthetic application. 5. The pronounced depression of the responsiveness to the putative arousal transmitters and an observed blockade of acetylcholine-induced potentiation of glutamate actions suggest that anaesthetics produce unconsciousness, at least in part, by interfering with subsynaptic mechanisms of neocortical activation.

The original study with Althesin in the development of epilepsy was carried out in nine patients. EEG and SEEG records show that sensitivity to Althesin, which is a mixture of pregnandiol and pregnan acetate, precursors of sexual hormones, raises in the direction to the oldest brain formations. A physiological substance in provoking epilepsy was discovered.

The anaesthetic management for surgical procedures involving the larynx and/or trachea and the problem of the shared airway are outlined. The use of intravenous Althesin on 31 patients (43 administrations) is described. It is suggested that Althesin has a place in the management of these patients.

The actions of three intravenous anaesthetics, Althesin, thiopentone and ketamine have been compared on the rat isolated atria and portal vein. Although the three anaesthetics had grossly similar actions on the two preparations, i.e. depression of atrial rate and depression of the amplitude of myogenic activity in the portal vein, there were enough differences to suggest that they produced their effects by different mechanisms. These differences were particularly obvious in interactions with noradrenaline and the effects of changes in calcium ion concentration on the concentration effect relationships for the agents on the atria and portal vein. Generally Althesin was unaffected by changes in calcium ion concentration, whilst ketamine and thiopentone were affected, but in qualitatively different ways.

SUMMARY Four groups of healthy female patients were anaesthetized with either thiopentone, Althesin or nitrous oxide–oxygen with and without halothane. The concentrations of the plasma electrolytes were measured before and at varying times up to 10 min after the administration of suxamethonium 1 mg\kg. A small, but significant, biphasic increase in plasma potassium concentration was found when suxamethonium was administered to patients in whom anaesthesia was induced with thiopentone, Althesin and nitrous oxide–oxygen. The initial increase in plasma potassium concentration was greater in the Althesin group than in the other two groups. A more delayed, but sustained, increase in plasma potassium concentration was found following induction with nitrous oxide–oxygen–halothane. There were no significant changes in the plasma concentrations of sodium or chloride except in the halothane–nitrous oxide–oxygen series.

Althesin in doses which produced anesthesia (4 and 6 ml kg-1, i.p.) produced biphasic changes in plasma corticosterone levels. Plasma corticosterone showed an increase (p less than 0.05) due to the stress of injection but returned to basal levels by 30 min. Subsequent to the anesthetic effect (approximately 30 min) corticosterone levels increased markedly (p less than 0.01). Althesin's effectiveness showed time of day effects, i.e., Althesin was more effective in the A.M. Rats given 6 ml kg-1 Althesin showed graded plasma corticosterone responses to stresses of varying intensity. Blood withdrawal and surgical stress evoked significant increases in plasma corticosterone but a 2-min holding stress had no effect on plasma corticosterone levels. Instrumented rats receiving supplemental injections (i.p.) presented patterns of plasma corticosterone which were different from those receiving supplemental infusions (i.a.). Whereas plasma corticosterone levels of rats receiving the continuous infusion of Althesin remained relatively constant, corticosterone levels of those which received supplemental injections tended to increase. Collectively, these data suggest that Althesins usefulness as an experimental anesthetic is limited to those studies which are not compromised by stress-induced pituitary-adrenal activity.

The effects of phencyclidine on cerebral blood flow, cerebral metabolic rate for oxygen and carbon dioxide reactivity were compared with those of Althesin in six baboons. Under similar and stable levels (Stage 1) of electroencephalographic activity cerebral blood flow and the cerebral metabolic rate for oxygen were significantly less during the infusion of Althesin when compared with the values obtained during the infusion of phencyclidine. Reactivity to carbon dioxide was present and similar during the infusion of either drug.

Sequential plasma samples from 30 patients showing clinical signs of hypersensitivity to Althesin were investigated to determine if a specific immune response to the drug was present (as measured by classical complement pathway activation) or if a non-antibody-dependent alternative complement pathway activation was taking place. The patients were classified as those reacting on first exposure to Althesin and those who reacted adversely only on a second exposure. The alternative complement pathway, but not the classical pathway, was activated in five of the 13 first-time reactors, while in the remaining eight no complement activation was detected. In contrast, classical complement pathway activation was demonstrated in the blood samples of all 17 patients reacting on repeat exposure. Severe reactions occurred in nine of the 17 previously exposed patients compared with only one of the 13 reacting on first exposure to Althesin.

The effect of speed of injection on the hypnotic actions of thiopentone, methohexitone, propanidid and Alfathesin was studied in elective surgical patients. The sequential up-and-down technique was used to determine ED50 values. A significant reduction in ED50 was observed for doses injected over five seconds when compared with doses injected over fifteen seconds for thiopentone (64%, P=.001) and methohexitone (83%, P=.05). In the case of Alfathesin, relatively wide confidence limits were observed at all injection speeds and reduction in ED50 at fifteen seconds (63%, P=.01) was noted when compared with the ED50 at five seconds. No significant differences were noted with any of the drugs studied, for variations in infusion time between fifteen, thirty and sixty seconds. It was concluded that only at very rapid infusion rates does the speed of injection influence the potency of the commonly used induction agents.

The binding affinities of two steroid anaesthetics, alphaxalone (Alfx) and alphadolone acetate (Alfd), for testosterone-oestradiol-binding globulin (TeBG) and corticosteroid-binding globulin (CBG) were measured in human serum. In 8 male patients, the effect of i.v. administration of Althesin (a mixture of Alfx and Alfd) on the transport of testosterone (T) and cortisol (F) was studied. Both Alfx and Alfd bind to TeBG and CBG with a relatively high affinity (10(6)M-1). A significant change in the percentage of unbound T was observed during Althesin infusion, with no change in total T concentration or in the TeBG binding parameters. The results suggest that by interaction with TeBG binding sites Alfx and/or Alfd displaced T bound to TeBG, and transiently increased the percentage of unbound T. A significant increase in the concentration of F was observed during althesin infusion, while the percentage of unbound F and the CBG binding parameters were unchanged. The dose of Alfx and Alfd used was not sufficient to alter the transport of F during brief althesin anaesthesia in men.

A study has been carried out into the effects of clinically important general anaesthetics, althesin, thiopentone and propanidid, on the transport of glucose and phosphate across the membrane of the human erythrocyte. In general these three substances all inhibit both transport processes but with characteristic inhibition profiles and varying degrees of efficacy. Glucose transport was more sensitive to the hydrophobic steroids and phosphate transport to propanidid. Some hydrophobic agents, e.g., iodobenzene and its azide, were not inhibitory. Removal of cholesterol to some extent augmented the inhibitory effects of most of these compounds (not propanidid). It is argued that these effects are due to the penetration of the anaesthetics into the lipid bilayer and either subsequent disruption of the lipid annuli surrounding the integral membrane proteins and/or direct anaesthetic-protein interaction.

Thiopentone doses corresponding to 5.238 mg x kg-1, that is 2UD95 (UD95:unconsciousness dose 95) inhibit the intensity of succinylcholine-induced fasciculations compared with UD95. Alfathesin doses corresponding to 0.570 mg x kg-1, also 2UD95 (calculated as alphaxalone at a concentration of 9 mg/ml in alfathesin), do not have any greater effect on the degree of fasciculations compared to UD95. Furthermore, neither induction agent influences the incidence, distribution and duration of succinylcholine-induced myalgias. The inhibition of the degree of fasciculations caused by thiopentone is believed to be a consequence of a postsynaptic depressant effect of thiopentone at the neuromuscular junction. The evaluation of the degree of succinylcholine-induced fasciculations must take into consideration the dose of thiopentone administered at induction of anaesthesia.

Baboons anesthetized with halothane and N2O/O2 were given an intravenous steroid anesthetic (Althesin; Glaxo Laboratories Ltd., U.K.). The drug bolus was labeled with 99mTc, and the time from central venous injection to peak radioactivity in the brain was designated drug brain arrival (DBA-peak). The electroencephalogram slowed 1.2 +/- 0.9 s after DBA-peak (P greater than 0.2), and approximately 2 s after DBA-peak, internal carotid blood flow (ICarBF) decreased and calculated internal carotid vascular resistance (ICarVR) rose. During this 2-s delay in the cerebrovascular response to the arrival of a cerebral metabolic depressant in the brain, the decrease in mean cortical Pco2 was calculated to be less than 0.26 mmHg from cortical CO2 solubility, and less than 0.32 mmHg from cortical CO2 diffusivity, which indicated that mean cortical Pco2 changes do not control cerebral blood flow (CBF). The unaltered time course of the changes in EEG, ICarBF, and ICarVR after acute cervical sympathectomy and alpha-adrenergic receptor blockade excluded the involvement of the sympathetic nervous system in the vasoconstrictor response. Intracarotid Althesin showed that the cerebral vasoconstriction was not a direct effect of the drug. The postulated link between the effects of Althesin on CBF and cerebral metabolism remains to be elucidated but is probably indirect, involving the brainstem.

In a series of patients who suffered severe histamine mediated reactions to induction agents and muscle relaxants, intradermal testing enabled the drug involved to be distinguished. The correct use of intradermal testing to give reliable results is discussed and a protocol described. Prausnitz Kustner testing was of little help in confirming the results. A number of patients tested showed high levels of immunoglobulin G (IgG) and it is believed that IgG mediated anaphylaxis may be the mechanism responsible for reactions that have been previously described as anaphylactoid or direct chemical histamine release.

The changes in baroreceptor-heart rate reflex properties and in hemodynamics produced by light ketamine anesthesia were studied in one group of rabbits before and after infracollicular decerebration and those produced by Althesin anesthesia in another group. Ketamine produced marked depression of baroreceptor reflex-mediated vagal effects on heart rate which was of similar magnitude in intact and pontine decerebrate rabbits; this indicates that its action was largely at or below the pons. Althesin produced much less vagal depression than ketamine in the intact rabbit but in pontine rabbits the depression was greatly enhanced. The smaller vagal depression in the intact rabbit appears to be due to a facilitatory effect through a suprapontine pathway by Althesin which partially masks its depressant effect below the pons. In the intact rabbit ketamine produced a greater rise in blood pressure than Althesin anesthesia for 1 h; the greater pressor response was due to a transient rise in total peripheral resistance (TPR) and a sustained rise in cardiac output. The difference in the blood pressure responses was mainly due to differences in action of the two anesthetics at or below the pons and only the transient rise in TPR during ketamine anesthesia was mediated through a suprapontine pathway.

Three groups of patients received Althesin, minaxolone or di-isopropyl phenol to supplement 67% nitrous oxide in oxygen. A fourth group receiving halothane to supplement nitrous oxide in oxygen acted as a control. Hepatic function tests were measured before operation and on days 1, 3, 5 and 7 after major vascular reconstructive surgery. There were significant increases to a mean value above the upper limit of normal in aspartate amino-transferase activity by day 3 in all groups. Total lactic dehydrogenase activity increased in the patients receiving Althesin, minaxolone and halothane. No change was seen in the alkaline phosphatase in any of the study groups. Gamma glutamyl transpeptidase increased in all groups, but the mean value at day 7 was not greater than the upper limit of normal. The mean activity of ornithine carbamoyl transpeptidase showed no change in any group throughout the study period. Two of the patients receiving minaxolone suffered cholestatic jaundice during the first month. These results suggest that anaesthesia with Althesin or di-isopropyl phenol results in enzyme changes similar to those seen in a comparable group of patients receiving halothane to supplement nitrous oxide in oxygen anaesthesia.

Blood from non-smoking donors was incubated with Althesin and the PO2 for half-saturation of haemoglobin at standard pH, PCO2 and temperature (P 50) was measured. The mean P 50 values of blood with blood concentrations of Althesin of 0.14 ml/dl and 0.42 ml/dl were greater (1.14 +/- 0.31 (SEM) mm Hg (P less than 0.005) and 2.22 +/- 0.35 (SEM) mm Hg (P less than 0.001), respectively) than that of control blood. These increases were dose-dependent (P less than 0.05). Erythrocyte 2,3-diphosphoglycerate (2,3-DPG) concentrations were not significantly different between the Althesin-treated and the control blood. Although a decrease in the affinity of haemoglobin for oxygen in vitro in the presence of Althesin was statistically significant, this would have no clinical significance if the drug was being used for the induction of anaesthesia only.

The increasing use of shorter-acting hypnotic agents to control intracranial pressure (ICP) following severe head injury has prompted a prospective double-blind controlled trial comparing the efficacy of etomidate and Althesin, given by i.v. infusion. Over the dose ranges used, the two drugs appeared equipotent in decreasing ICP whilst preserving cerebral perfusion pressure. However, in two patients (one in each group) ICP did not respond to hypnotic infusion, a feature noted in other studies to occur in a minority of patients. With the cessation of Althesin manufacture and the discussion about the use of etomidate infusions, it is timely to document the effectiveness of etomidate in decreasing ICP.

SUMMARY 1. Rats were prepared with chronic cannulae in the carotid artery, jugular vein and urinary bladder; they were then kept 2 days to allow recovery from surgery. 2. A steady-state continuous saline diuresis was established, then various anaesthetic agents were injected and changes in the urine flow, sodium and potassium excretion rates, GFR, ERPF, ERBF and blood pressure were measured. 3. Five groups of rats were studied: (1) control animals given saline in place of any anaesthetic agent, all parameters measured remained constant; (2) althesin (1.2 mg/kg), all parameters remained constant except for the blood pressure which decreased slightly for 5 min; (3) althesin (12 mg/kg); (4) ketamine (50 mg/kg); (5) pentothal (50 mg/kg). The above anaesthetics altered all of the measured parameters except urine output. 4. Various mechanisms for these anaesthetic agents are discussed. 5. In althesin anaesthetized rats, all the retarded renal parameters recovered within 30 min. It is concluded that for the study of renal function, if a brief anaesthesia is needed, althesin is a more suitable anaesthetic agent.

The effects on baroreflex control of heart rate, of two infusion rates of Althesin (18 and 36 micrograms kg-1 min-1 as total steroid) to supplement 66% nitrous oxide in oxygen anaesthesia, have been studied in six younger (mean age 35.5 yr) and six older (mean age 61.0 yr) patients. Steady-state anaesthesia at both infusion rates was associated with diminished baroreflex sensitivity and resetting of the reflex to allow lower arterial pressures to be maintained without tachycardia.