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Description / Table of Contents: Abstract During the last five years several authors have reported largely satisfactory results, using the steroid intravenous anaesthetic eltanolone (pregnanolone) for induction of anaesthesia after administering a bolus dose. Until now, however, no investigations have been undertaken, dealing with the infusion pharmacokinetics of eltanolone after arterial blood sampling and using slow induction to quantify the concentration-effect relationship. Secondary objectives were to assess the haemodynamic and respiratory effects. Material and methods. Eltanolone emulsion was administered to 12 healthy male volunteers using a computer-controlled infusion device. Linearly increasing serum concentrations were generated for two consecutive times with an anticipated slope of 0.075 μg ml−1 min−1 and with a targeted concentration of 2 μg ml−1. During and following the infusion, EEG was recorded and clinical signs were assessed as measure of the hypnotic effect. Thus, the time intervals from start of infusion until the volunteers fell asleep, until they did no longer respond to loud verbal commands, until loss of the corneal reflex and until the appearance of burst suppression patterns in the EEG were recorded. The latter sign was used as endpoint for the infusion. After the cessation of the infusion the time intervals until the disappearance of burst suppression and the reappearance of the clinical signs were recorded until full orientation was regained. Arterial blood samples were frequently drawn up to 720 min following the cessation of the last infusion cycle. Eltanolone serum concentrations were measured by a specific GC-MS assay. Pharmacokinetics were analysed with NONMEM® by an open three compartment model. The serum concentrations were correlated with the corresponding clinical signs to quantify the concentration-effect relationship. Blood pressure, heart rate and oxygen saturation were measured continuously and the arterial pCO2 was analysed every 6 min. Results. The model-dependent pharmacokinetic parameters of eltanolone were characterized by a high total clearance (1.75±0.22 l min–1), small volumes of distribution (Vc=7.7±3.4 l; Vdss=92±22 l) and relatively short half-lives (t1/2α =1.5±0.6 min; t1/2β=27±5 min; t1/2γ=184±32 min) (Table 2). The clinical signs revealed a good hypnotic effect, resulting in burst suppression periods in the EEG after 19 min during the first and 15 min during the second infusion cycle. The slow induction enabled a thorough observation of the induction phase. During the first infusion cycle cessation of counting occurred after 7.7±1.3 min (mean±SD), reaction to verbal contact was lost after 10.4±1.3 min and the corneal reflex was lost only in about one half of the volunteers after 17.9±2.8. During recovery, the corneal reflex reappeared 9.4±2.4 min after stop of infusion, first reactions to loud verbal commands were recorded after 24.2±4.3 min and full orientation was regained after 34.7±6.2 min. During the second cycle all signs disappeared faster and were regained later (Table 3). The correlation between clinical signs and corresponding serum concentrations revealed, that in both cycles the disappearance occurred at clearly higher concentrations than the reappearance (Fig. 2). The decrease of the systolic arterial pressure showed a maximum of 31% compared to the baseline values, which was statistically significant (P〈0.05). Diastolic arterial blood pressure decreased of about 10%, while heart rate increased significantly of about 24% (P〈0.05) (Fig. 3 and 4). Oxygen saturation remained stable with values between 96 and 100% with the exception of one volunteer. Apnoea was not recorded during the entire observation period. The median value of all pCO2 analyses was 41 mmHg with a range of 25–60 mmHg. The only serious undesirable effect was a seizure during awakening in one volunteer which coincided with polyspike waves in his raw-EEG recordings (Fig. 5). Conclusions. Eltanolone proved to be a potent hypnotic. With regard to haemodynamics and respiration it caused relatively modest reactions. The quantification of the concentration-effect relationship revealed a time lag between serum concentration and corresponding effect that seems to exceed the effect-hysteresis of thiopentone and propofol. This hysteresis restricts the control of the substance, if the effect has to be changed rapidly, and leads to a delayed recovery. Together with its possible proconvulsant properties and increased reports of urticaria this meanwhile led to the cessation of the clinical investigations with eltanolone.

Description / Table of Contents: Abstract The objectives of the present study were to compare in a randomized double-blind crossover study design the concentration-effect relationships of Ro 48-6791, a new benzodiazepine agonist, and midazolam, following infusion in young and elderly male volunteers. Therefore, linearly increasing plasma concentrations were generated by computer controlled infusion pumps to achieve a deep hypnotic effect. The endpoint of the infusion was defined by loss of response to loud verbal commands and a median frequency of the recorded EEG power spectrum below 4 Hz. Arterial blood samples were collected in regular intervals up to 6 hours after cessation of the infusion. The method of pharmacokinetic-pharmacodynamic modeling was used to quantify the concentration-effect relationship, including age related differences, already in this early phase I study. The total clearance of Ro 48-6791 was found to be 1410±380 vs. 399±91 ml min−1 for midazolam (mean±SD; P〈0.005) and the central volume of distribution to be 20.5±7.1 vs. 7.9±3.0 l, respectively (P〈0.005). The comparison between young and elderly volunteers yielded for Ro 48-6791 a statistically not significant reduction of 16% for clearance with age and a slowed distribution of 47% for midazolam (P〈0.05). The recovery period for Ro 48-6791 was reduced by 66% (P〈0.005) in the young and 45% (P〈0.01) in the elderly, respectively, in comparison with midazolam. With respect to the total doses administered, Ro 48-6791 appeared to be 2.5 times as potent as midazolam in all volunteers (P〈0.001). Comparing both age groups, the doses necessary to cause similar effects were reduced by one half for both compounds in the elderly (P〈0.001). The major advantages of Ro 48-6791 compared to midazolam were its shorter duration of action as well as the faster recovery and thus the better controllability. Further investigations would have to confirm these results in a greater number of patients. The applied method of pharmacokinetic-pharmacodynamic modeling not only allowed to quantify the efficacy of Ro 48-6791 but also provided data to augment the safety for further investigations.

Description / Table of Contents: Abstract The need for better intravenous anaesthetic agents had led to the approval or the clinical studies of new compounds, which have or are assumed to have a higher degree of controllability or an improved spectrum of undesired side effects compared to other approved anaesthetics. For the i.v.-anaesthetics different approaches have been used to achieve this. Among these are the new synthesis of a new chemical entity (NCE), the isolation of an isomer of a racemic mixture and the new galenic preparation of a known substance for i.v.-application. This review gives for all three approaches an example. Remifentanil is a NCE belonging to the group of opioids which has been released in Germany a few months ago. From the point of view of the intraoperative controllability this compound has reached the highest degree of controllability among all i.v. anaesthetics. Its context sensitive half-life, that is the effective time for drug concentration to decline by 50% (ET50) is about 3–4 min even after several hours of continuous administration. One reason for this exceptional property is that its metabolism is independent of liver and kidney function and depends almost only on unspecific esterases occurring in blood and tissues. S-(+) ketamine represents an example for the isolation of a specific isomer out of a known racemic mixture. Racemic ketamine was introduced into clinical practice in 1965. The clinical trials with the isolated S-(+) ketamine, which are finished now, showed that the racemic mixture of both isomer does not lead to an additive effect, but the action of S-(+) ketamine is weakened by the R-(--) compound. In volunteers studies it was not possible to achieve a complete loss of consciousness by administration of R-(--) ketamine only only, whereby with S-(+) ketamine one could reduce the dose with respect to the racemic mixture by a factor of two to achieve complete consciousness. This dose reduction is accompanied with a faster offset time. For broader clinical applications one would therefore expect a higher degree of controllability and a shortened recovery period. With eltanolon a substance is presented which is known as the metabolite pregnanolon of the reductive metabolic pathway of progesterone since the 50s and which is known to possess strong hypnotic potency. However, because of its low water solubility it could not be studied as an i.v. agent until in 1990 one succeeded in making a water soluable emulsion in fat. The clearance of eltanolon is ca. 25 ml/kg/min and it has a terminal half-life of about 3 hr. It has, however, a pronounced hysteresis of 8 min between blood and effect site. This unfavourable pharmacokinetic property in conjunction with observed unvoluntary spontaneous movements and increased muscle tone during application has led to the cessation of its further clinical development. With the introduction of shorter acting compounds it is also necessary to improve the traditional techniques of i.v. drug delivery like manual bolus injections or drip infusions. After more than 16 years of research and development in the field of socalled Target Controlled Infusions (TCI), there has been recently introduced the socalled Diprifusor-TCI, as a commercially available software module to control the delivery of propofol. TCI uses established pharmacokinetic data to determine infusion rates to achieve desired drug concentrations serving as the target, which can be chosen interactively. This way of dosing i.v. anesthetics is obviously not restricted to one specific compound but can be applied to any i.v.-drug if appropriate pharmacokinetic data are used.