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The Pre-Concept Design (PCD) of the Balance of Plant (BoP) systems of the EU-DEMO power plant is described in this paper for both breeding blanket (BB) concepts under assessment, namely the Water Cooled Lithium Lead (WCLL) BB and the Helium Cooled Pebble Bed (HCPB) BB. Moreover, the results of a preliminary evaluation of a number of BoP variants are discussed. This paper outlines the steps of the BoP design development, highlighting the project objectives and the strategy for their achievement under the very challenging requirements which include, among others, the intermittent nature of the DEMO plasma heat source. The main achievements during the PCD Phase will be reported together with the development plan for the Concept Design (CD) Phase to reach a mature (feasible) BoP concept for DEMO., peer-reviewed

A Target Enabling Componentdescribing C16CF3C synthesis

A Target Enabling Component describing C8CF3C

DEMO will be a fusion power plant demonstrating the integration into the grid architecture of an electric utility grid. The design of the power conversion chain is of particular importance, as it must adequately account for the specifics of nuclear fusion on the generation side and ensure compatibility with the electric utility grid at all times. One of the special challenges the foreseen pulsed operation, which affects the operation of the entire heat transport chain. This requires a time-dependant analysis of different concept design approaches to ensure proof of reliable operation and efficiency to obtain nuclear licensing. Several architectures of Balance of Plant were conceived and developed during the DEMO Pre-Concept Design Phase in order to suit needs and constraints of the in-vessel systems, with particular regard to the different blanket concepts. At this early design stage, emphasis was given to the achievement of robust solutions for all essential Balance of Plant systems, which have chiefly to ensure feasible and flexible operation modes during the main DEMO operating phases – Pulse, Dwell and ramp-up/down – and to adsorb and compensate for potential fusion power fluctuations during plasma flat-top. Although some criticalities, requiring further design improvements were identified, these preliminary assessments showed that the investigated cooling system architectures have the capability to restore nominal conditions after any of the abovementioned cases and that the overall availability could meet the DEMO top-level requirements. This paper describes the results of the studies on the tokamak coolant and Power Conversion System (PCS) options and critically highlights the aspects that require further work.

BackgroundProlonged catheter use is controversial because of the risk of catheter-related infection, but the extent to which the risk increases over time remains unknown. We thus assessed the time-dependence of catheter-related infection risk up to 15 days.MethodsOur analysis was based on the German Network for Regional Anesthesia, which includes 25 centers. We considered 44,555 patients who had surgery between 2007 and 2014 and had continuous regional anesthesia as well as complete covariable details. Cox regression analysis was performed and adjusted for confounding covariables to examine the relationship between catheter duration and probability of infection-free catheter use.ResultsAfter adjustment for confounding factors, the probability of infection-free catheter use decreases with each day of peripheral and epidural catheter use. In peripheral catheters, it was 99% at day 4 of catheter duration, 96% at day 7, and 73% at day 15. In epidural catheters, it was 99% at day 4 of catheter duration, 95% at day 7, and 73% at day 15. Only 31 patients (0.07%) had severe infections that prompted surgical intervention. Among these were five catheters that initially had only mild or moderate signs of infection and were left in situ; all progressed to severe infections.ConclusionsInfection risk in catheter use increases over time, especially after four days. Infected catheters should be removed as soon as practical.

Dural puncture, paraesthesia and vascular puncture are the most common complications of epidural catheter insertion. Their association with variation in midline needle insertion depth is unknown. This study evaluated the risk of dural and vascular punctures and the unwanted events paraesthesia and multiple skin punctures related to midline needle insertion depth. A total of 14,503 epidural catheter insertions including lumbar (L1–L5; n = 5367), low thoracic (T7–T12, n = 8234) and upper thoracic (T1–T6, n = 902) insertions, were extracted from the German Network for Regional Anaesthesia registry between 2007 and 2015. The primary outcomes were compared with logistic regression and adjusted (adj) for confounders to determine the risk of complications/events. Results are presented as odds ratios (OR, [95% confidence interval]). Midline insertion depth depended on body mass index, sex, and spinal level. After adjusting for confounders increased puncture depth (cm) remained an independent risk factor for vascular puncture (adjOR 1.27 [1.09–1.47], p = 0.002) and multiple skin punctures (adjOR 1.25 [1.21–1.29], p

Background Obesity is believed to increase the risk of surgical site infections and possibly increase the risk of catheter-related infections in regional anesthesia. We, therefore, analyzed the influence of obesity on catheter-related infections defined within a national registry for regional anesthesia. Methods The German Network for Regional Anesthesia database with 25 participating clinical centers was analyzed between 2007 and 2012. Exactly, 28,249 cases (13,239 peripheral nerve and 15,010 neuraxial blocks) of patients ≥ 14 years were grouped in I: underweight (BMI 13.2–18.49 kg/m2, n = 597), II: normal weight (BMI 18.5–24.9 kg/m2, n = 9272), III: overweight (BMI 25.0–29.9 kg/m2, n = 10,632), and IV: obese (BMI 30.0–70.3 kg/m2, n = 7,744). The analysis focused on peripheral and neuraxial catheter-related infections. Differences between the groups were tested with non-parametric ANOVA and chi-square (P

Psoas blocks are an alternative to femoral nerve blocks and have the potential advantage of blocking the entire lumbar plexus. However, the psoas muscle is located deeply, making psoas blocks more difficult than femoral blocks. In contrast, while femoral blocks are generally easy to perform, the inguinal region is prone to infection. We thus tested the hypothesis that psoas blocks are associated with more insertion-related complications than femoral blocks but have fewer catheter-related infections.We extracted 22,434 surgical cases from the German Network for Regional Anesthesia registry (2007-2014) and grouped cases as psoas (n = 7593) and femoral (n = 14,841) blocks. Insertion-related complications (including single-shot blocks and catheter) and infectious complications (including only catheter) in each group were compared with χ tests. The groups were compared with multivariable logistic models, adjusted for potential confounding factors.After adjustment for potential confounding factors, psoas blocks were associated with more complications than femoral blocks including vascular puncture 6.3% versus 1.1%, with an adjusted odds ratio (aOR) of 3.6 (95% confidence interval [CI], 2.9-4.6; P0.001), and multiple skin punctures 12.6% versus 7.7%, with an aOR of 2.6 (95% CI, 2.1-3.3; P0.001). Psoas blocks were also associated with fewer catheter-related infections: 0.3% versus 0.9% (aOR of 0.4; 95% CI, 0.2-0.8; P = 0.016), and with improved patient satisfaction (mean ± SD 0- to 10-point scale score, 9.6 ± 1.2 vs 8.4 ± 2.9; P0.001). Results from a propensity-matched sensitivity analysis were similar.Psoas blocks are associated with more insertion-related complications but fewer infectious complications.ID NCT02846610.

Major requirements for a future fusion power plant are to ensure the extraction of the fusion power for electricity production and to provide the whole T necessary to sustain the thermonuclear reaction during the plant lifetime. Blanket first wall and divertor targets have to be designed to sustain high heat flux in small surface regions facing the plasma; thick structures have to surround the plasma to capture the neutron energy and protect vacuum vessel and magnets. All these components have to be efficiently cooled to respect strong additional requirements to ensure an efficient operational regime for the power conversion system. The neutrons generated by the plasma have to be used for T generation; for this scope blankets are filled by Li compounds in solid or liquid form. To reach the tritium self-sufficiency the blanket needs an accurate and clever design of the breeder zone and an accurate material selection. Furthermore, recovery time of T that has to become available for the fuel cycle have to be minimised, avoiding large inventories in reactor and in the fuel processing plant. The development of these technologies is the key issues for the development of a first generation of fusion devise after ITER.

Summary Background : Clinical studies suggest low-dose ketamine may have preemptive effects on postoperative pain in adults. The objective of this study was to determine whether intraoperative low-dose S-ketamine reduces postoperative pain and morphine consumption in children undergoing major urological surgery. Materials : Thirty children scheduled for major urological surgery were included in this prospective study. Anesthesia was performed as total intravenous anesthesia (TIVA) with alfentanil and propofol. Fifteen patients additionally received an intravenous bolus of S-ketamine (0.2 mg·kg−1) followed by a continuous infusion of 5 μg·kg−1·min−1, which was stopped immediately after skin closure (Ketamine Group). Another 15 patients received an infusion of saline (Control group). After transfer to the PACU, pain intensity was evaluated using a numeric rating scale (NRS). First patient controlled analgesia (PCA) request, cumulative morphine consumption and pain intensities within the first 72 h were compared. Results : Morphine consumption was not significantly different during the first 72 h (Control: 0.4 mg·kg−1, 0.24–0.51 mg·kg−1, Ketamine: 0.32 mg·kg−1, 0.19–0.61 mg·kg−1; median, 25–75% percentile; n.s.). However, differences were found in pain intensity during the first postoperative hour (Control: 4.0, 3.2–4.6, Ketamine: 2.5, 1.3–3.5; median, 25–75% percentile; P

Aims We studied the development of acute tolerance to the EEG effect of midazolam and the new benzodiazepine Ro 48-6791. Methods Nine young (24–28 years) and nine elderly (67–81 years) male volunteers received midazolam and Ro 48-6791 computer-controlled, targeting linearly increasing plasma concentrations for 30 min (targeted slopes: 40 and 20 ng ml−1 min−1 for midazolam, 3 and 1.5 ng ml−1 min−1 for Ro 48-6791, for young and elderly, respectively) and a constant concentration for the following 15 min. After recovery, the same infusion scheme was repeated. Plasma concentrations of midazolam, Ro 48-6791 and its metabolite Ro 48-6792 were determined from arterial blood samples. The hypnotic effect was assessed using the median frequency of the EEG power spectrum. Results The concentration–effect relationship in each infusion cycle could be described by a sigmoid Emax model. The half-maximum concentration EC50 was higher in the second infusion cycle compared with the first one (midazolam, 47% (2.3–91.6%) and 37% (5.3–69.5%); Ro 48-6791, 22% (−2.8% to 44.6%) and 43% (3.4–82.4%) for young and elderly; mean and 95% confidence interval). The complete time course of the EEG median frequency could be described by an interaction between the parent drug in an effect compartment and a hypothetical competitive drug in an additional tolerance compartment. For Ro 48-6791, the use of its metabolite Ro 48-6792 as competitive compound also gave appropriate results. Conclusion Midzolam and Ro 48-6791 showed acute tolerance to the EEG effect which might be caused by competitive interaction with the metabolite.

BACKGROUND AND OBJECTIVE: Knowledge of the pharmacodynamic interaction between remifentanil and propofol is important to permit optimal dosage strategies. We studied this pharmacodynamic interaction using the median power frequency of the processed electroencephalogram as a control parameter for feedback-controlled dosing of propofol. METHODS: Twenty-one patients were given total intravenous anaesthesia with remifentanil and propofol. During three target-controlled infusion regimens, the target concentrations of remifentanil (5, 10, 15 ng mL(-1)) and propofol dosing were automatically adjusted to keep the median power frequency in the range 2 +/- 0.5 Hz. In each patient and during each remifentanil target concentration, four arterial propofol/remifentanil concentration pairs were measured. The type of interaction was tested using the relative distance from the line of additivity and the isobole was modelled using Bernstein splines. RESULTS: The results from 13 patients were used for data analysis. The measured remifentanil concentrations during the three targets were (mean +/- SD): 3.6 +/- 0.9, 8.1 +/- 2.5 and 12.4 +/- 2.8 ng mL(-1). The corresponding propofol concentrations were 2.64 +/- 0.86, 2.13 +/- 0.58 and 2.09 +/- 0.58 microg mL(-1). The data were best described with an additive type of interaction and the isobole was estimated using: ((c)Remifentanil/64.2 ng mL(-1)) + ((c)Propofol/2.61 microg mL(-1)) = 1. CONCLUSIONS: Within the studied concentration range, remifentanil and propofol showed an additive type of pharmacodynamic interaction on the electroencephalogram.

Fragestellung. Opioide tragen zu postoperativer Ubelkeit und Erbrechen (PUE) bei. Durch eine intraoperative Analgesie mit S-(+)-Ketamin kann auf die Gabe von Opioidanalgetika verzichtet und der postoperative Opioidverbrauch moglicherweise reduziert werden.Ziel der Studie waren die Erfassung der Inzidenz und Intensitat von PUE nach einer totalen intravenosen Anasthesie (TIVA) mit S-(+)-Ketamin-Propofol (K-P-Gruppe) bzw.Alfentanil-Propofol (A-PGruppe) und die Erfassung des Aufwachverhaltens. Methodik. Es erhielten 145 Patienten (18–70 Jahre,ASA I-III) eine TIVA mit K-P oder A-P.Dabei wurden Aufwachzeiten,PUE, Schmerzintensitat und Akzeptanz des Narkoseverfahrens verglichen. Ergebnisse. Die Aufwachzeiten in der K-P-Gruppe waren verlangert. Die Inzidenz an PUE war vergleichbar (26% bzw. 22% fur K-P vs. A-P); die Intensitat war mit einer VAS

Especially for medical disciplines like anesthesiology, which represent only a small economic market, drug development is a cost intensive and with respect to financial aspects a high risk task. This situation requires methods, which in the early stages of the drug development process of an interesting compound allow the establishment of a reliable and valid data set, in order to make decisions on the continuation or discontinuation of a project. Given a compound out of the group of benzodiazepines as an example this paper represents todays methods of integrated pharmacokinetic-pharmacodynamic modelling as well as the special computer aided strategies of drug dosing as powerful tools in the anaesthetic drug development process. It is shown that one can generate data concerning differences in drug requirement and drug duration in the therapeutic dose range between different groups of possible patients, e.g. young and elderly, as early as the early phase II. It is concluded that these clinical pharmacological tools and the high resolution data generated by them facilitate the Go/No-Go decision to proceed to phase III and enhance the likelihood of passing phase III successfully.

The objectives of this study were to explore, by a modelling approach, in nine young (24-28 yr) and nine elderly (67-81 yr) male subjects, the pharmacokinetics and pharmacodynamics of Ro 48-6791, a new water soluble benzodiazepine. A microprocessor-controlled i.v. infusion pump generated linearly increasing arterial plasma concentrations until predetermined EEG and clinical end-points were attained. This concentration was maintained for 15 min and thereafter the infusion was discontinued. Haemodynamic and respiratory variables were monitored continuously. At full reorientation of the subject, a second infusion cycle was started under the same conditions to investigate the reproducibility of the concentration-effect relationship. The plasma concentration-time profiles of Ro 48-6791 were fitted accurately to an open three-compartment model. Plasma concentrations of Ro 48-6792, an N-dealkylated metabolite, accumulated during the course of the study. Pharmacokinetic variables of Ro 48-6791 were similar for both groups. The largest differences between young and elderly subjects, respectively, were found for clearance (mean 85 (SD 23) vs 71 (15) litre h-1) and k12 (11 (7) vs 7 (3) h-1). The concentration-median EEG frequency relationship was described with a sigmoid Emax model. Elderly subjects showed slightly increased drug sensitivity compared with young subjects (EC50 72 (25) and 44 (15) micrograms litre-1 in young and elderly subjects, respectively). The concentration-response data of the second infusion cycle deviated from the fitted curve suggesting either development of acute tolerance to the EEG effects of Ro 48-6791 or a role for drug metabolites. Because of the differences in sensitivity and clearance, lower doses of Ro 48-6791 should be administered to elderly compared with young subjects in order to achieve similar effects.

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±91ml min -1 for midazolam (mean ± SD; P

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 NON-MEM® 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 pCO 2 was analysed every 6 min. Results. The model-dependent pharmacokinetic parameters of eltanolone were characterized by a high total clearance (1.75±0.221 min -1 ), small volumes of distribution (Vc=7.7 ± 3.4 I; Vdss=92 ± 22 1) and relatively short half-lives (t 1 / 2α = 1.5±0.6 min; t 1/2β =27±5 min; t 1/2γ =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

The need for better anaesthetic agents has 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 which has been released in Germany a few months ago. This compound has reached the highest degree of intraoperative 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 blood and tissue nonspecific esterases. 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, 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 by 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 soluble 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 Target-Controlled Infusions (TCI), there has been recently introduced the so called 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.

Viele klassische Fuhrungsmodelle, die heute gelehrt werden, stammen aus den 60er und 70er Jahren des 20. Jahrhunderts. Es erscheint nicht ubertrieben, wenn man formuliert, dass diese „in die Jahre gekommen“ sind. Hierzu passend wird von prominenter Seite – Hamel – kritisiert, dass die gangigen Managementpraktiken in Unternehmen aus der Mitte des 20. Jahrhunderts stammen und veraltet seien. Insofern erscheint es an der Zeit, nach neueren Perspektiven, Instrumenten und Ansatzen der Fuhrung zu fragen. Der Uberblick uber diesen Band argumentiert entlang von insgesamt neun thesenartig formulierten Mythen zum Thema Fuhrung. Mit diesen Mythen werden Verweise auf die Artikel gegeben. Mythen reduzieren in mehrdeutigen Situationen die Komplexitat, dies allerdings zum Preis der Einseitigkeit, denn sie gehen mit Simplifizierung und Stereotypisierung einher, so dass eine mogliche Sichtweise zur allein richtigen erklart wird. Insofern geht es in dem Artikel zum einen darum, irrefuhrende Fehlannahmen zur Diskussion zu stellen und zum anderen einen Uberblick uber die 33 (weiteren) Artikel des Bandes zu geben.

Eine gute Fuhrungskraft zeichnet sich durch ein Hochstmas an „strategischer Orientierung“ aus – so konnte man manche Aussage zugespitzt darstellen. Das Balance-Modell der Fuhrung verabschiedet sich von dieser linearen Sichtweise. In dem Modell werden acht Spannungsfelder fur Fuhrungskrafte beschrieben, die so gestaltet werden mussen, dass die sich jeweils ergebenden gegensatzlichen Anforderungen gleichzeitig verfolgt werden. Einseitigen Orientierungen und sog. Uberzeichnungen von Kompetenzen kann so vorgebeugt werden. Diese acht fur Fuhrungskrafte relevanten Spannungsfelder sind: (1) Strategie vs. Tagesgeschaft; (2) Selbermachen vs. Delegieren; (3) Nahe vs. Distanz; (4) Team vs. Individuum; (5) Reflexion vs. Umsetzung; (6) Optimierung vs. Innovation; (7) Offenheit vs. Positionierung; (8) Autonomie vs. Integration. In dem Artikel wird beschrieben, wie in einem schnell wachsenden Unternehmen der Balanceansatz der Entwicklung eines masgeschneiderten, unternehmensweiten Kompetenzmodells zu Grunde gelegt wurde, um dem starken Wachstum und den damit einhergehenden Veranderungsprojekten gerecht zu werden. Das Balance-Modell der Fuhrung kann als Diagnoseinstrument und als Instrument der Gestaltung von Personal- und Organisationsentwicklungsprozessen eingesetzt werden.

Excitation functions of the 16O+16O system decaying by α and 8Be(g.s.) emission to low-lying states of the respective 28Si and 24Mg residual nuclei have been measured from Ec.m. = 18.35–31.0 MeV. All experimental results are reproduced satisfactorily by Hauser-Feshbach model calculations, if transmission coefficients for potential-barrier penetration are used for all cluster decay channels as well as for the entrance channel. Calculations using optical-model transmission coefficients are systematically at variance with the data, which is explained in terms of exit-channel angular momentum limitation.

The production of pi-0 and eta-mesons has been studied in the reactions Ne-20 + Al at 350 MeV/u and Ar-40 + Ca at 1.0 GeV/u. Rapidity distributions and transverse momentum spectra have been measured and are compared to thermal distributions.

γ-multiplicityMγ and missing charge ΔZ from fragment-fragment coincidences have been measured for fissionlike events in the reactions32S+58,64Ni at 160 and 180 MeV bombarding energies. The experimental data have been compared with a Monte Carlo simulation of the sequential decay of primary fragments assumed to be in thermal equilibrium. Statistical-model calculations have been performed with different assumptions on the spin distribution of the composite system decaying in two symmetric fragments. The experimentalMγ data are well described by model calculations with spin values inside the fusion region. Those spin values are close to the first moments of the angular-momentum distributions for fusion-fission of the compound nucleus as computed by statistical model using finite-range corrected fission barriers. Model calculations describe also well the experimental ΔZ values for the32S+58Ni reaction but overestimate the data relative to the64Ni target, evidencing difficulties in the complete reconstruction of the sequential decay of the reaction products.

The backward-angle yield from 12 C + 24 Mg has been studied with the technique of inverse kinematics, using 24 Mg beams with energies from 90 to 126 MeV. In the different exit channels with 5 ⩽ Z ejectile ⩽9 the Q -integrated differential cross sections d σ d θ are consistent with isotropy at 130° ⩽ θ c.m. ⩽ 165°, which is taken as signature of orbiting. The most probable exit energies in the strongly predominant even- Z channels as a function of bombarding energy give evidence for complete damping at angular momenta close to the critical ones for fusion. The results for the weakly populated odd- Z channels suggest that the conditions of damping are affected by the large negative ground-state Q -values. Structures are observed in the Q -value spectra and in the excitation functions at given Q . The former are identified with high-spin states close to the yrast lines, which are shown to be selectively populated due to the matching conditions for deep-inelastic reactions in light heavy-ion systems. An additional selectivity for natural-parity transitions gives evidence for the conservation of the dinuclear parentage. Narrow fluctuations observed in the excitation functions for fixed narrow Q -windows are attributed to the overlapping of unbound states of the intermediate complex. In the Q -integrated excitation functions these fluctuations cancel, but weak gross structure of a few MeV width remains visible. A statistical analysis of the narrow fluctuations yields coherence widths around 400 keV, corresponding to lifetimes of the intermediate dinucleus around 2 × 10 −21 s.

In der Psychiatrie wurde schon relativ fruh erkannt, dass ein groserer Anteil — nach heutigem Erkenntnisstand 10–30% (Marneros 1995; Olbrich et al. 1999) — der psychotischen Erkrankungen, die seit 1933 nach dem von Kasanin gepragten Begriffschizoaffektiv genannt werden, diagnostisch nicht eindeutig der Schizophrenie oder der Depression zugeordnet werden konnten. Dennoch wurde diese Erkrankung erst in jungster Zeit in den international bedeutsamen Klassifizierungssystemen »Diagnostisches und statistisches Manual psychischer Storungen« (DSM-III-R, 1987, und DSM-IV, 1998) und »Internationale Klassifikation psychischer Storungen« (ICD-10, 1993) hinreichend befriedigend beschrieben. Verglichen mit diesem Fortschritt der deskriptiven Psychiatrie um begriffliche Klarung liegt die psychoanalytische Psychosenforschung trotz ihrer bemerkenswerten Erfolge in der Beschreibung der Psychodynamk schizophrener (u. a. Benedetti 1983, 1987; Mentzos 1991, 1992; Schwarz 1993, 2000; Hartwich u. Grube 2003) und affektiver psychotischer Zustande (u. a. Jacobson 1971; Mentzos 1995; Boker 1999, 2001; Boker u. Hell 2002) in der Betrachtung schizoaffektiver Storungen zuruck. Angesichts dessen kann der vorliegende Versuch, einen Beitrag zu einer psychodynamischen Theorie der schizoaffektiven Psychose zu liefern, nur hypothetischen Charakter haben. Das Gleiche gilt auch fur eine kurzlich vorgelegte umfassendere Arbeit (Hering 2004). Meine Uberlegungen gehen von den Definitionen des DSM-III-R, DSM-IV und der ICD-10 aus: Wahrend einer ersten Episode des gesamten Krankheitsverlaufes liegen depressive und/oder manische Stimmungen »gleichzeitig« mit schizophrenietypischen Symptomen vor. In einer zweiten Phase imponieren Erscheinungen, die eindeutig und ohne Beimischung affektiver Symptome das Kriterium der Schizophrenie erfullen. Ferner werden die Erkenntnisse der Psychoanalyse zur Schizophrenie und zur affektiven Storung vergleichend herangezogen. Schlieslich grunden die Hypothesen auf einer langjahrigen psychoanalytisch orientierten und sozialpsychiatrischen Arbeit mit schizoaffektiv erkrankten Menschen.

The aim of this study was to investigate efficacy and tolerability of propofol, remifentanil and cisatracurium or mivacurium in routine anesthetic practice.A total of 6,161 patients scheduled for abdominal or orthopedic surgery were included in this open multicenter phase IV study. Perioperative hemodynamics as well as induction, recovery and discharge times, anesthetics, frequency of PONV and side-effects were studied.Quality of induction and maintenance of anesthesia were evaluated by anesthesiologists to be good or very good in 88%. 86% of the patients assessed anesthesia as good or very good. Adverse events were reported for 28 patients (0.45%), with hypotension and bradycardia being most frequent. Recovery was evaluated by anesthesiologists to be good or very good in 88%, surgeons and nursing staff assessed the TIVA as good or very good in 90%. Most frequent postoperative complaints were pain (16.7%), nausea (6.1%), shivering (3.1%) and vomiting (0.7%).The study showed that total intravenous anesthesia using propofol, remifentanil and cisatracurium or mivacurium is safe, tolerable and effective and has a high degree of acceptance.

Background and objective: For total intravenous anaesthesia an opioid is often combined with a hypnotic. A supra-additive interaction has been reported for clinical signs such as loss of consciousness or loss of the eyelash reflex. This study investigated the type of interaction of alfentanil and propofol on the electroencephalogram. Methods: Twenty patients scheduled for abdominal surgery were enrolled in the study. Anaesthesia was induced and maintained with alfentanil and propofol. Each patient received a target-controlled infusion of alfentanil. Three target concentrations of 150, 225 and 300 ng mL -1 were applied to each patient in random order. Propofol was added to the alfentanil infusion by a feedback system. The set point was the range of 1.5-2.5 Hz median frequency of the electroencephalogram. Four arterial blood samples were taken within the last 20 min of each period. The mean drug concentrations were used to determine the type of interaction and an isobole was estimated by fitting Bernstein spline functions to the data. Results: In 17 patients, all three alfentanil target concentrations could be administered. The test for supra-additivity as well as the isobole construction resulted in an additive type of interaction. The line of additivity c A /c A0 + c P /c P0 = 1 was best fitted for the values (standard deviation) c A0 = 1240 (51) ng mL -1 and c P0 = 5.21 (0.36) μg mL -1 . Conclusions: The type of interaction between alfentanil and propofol on the electroencephalogram in the investigated dose range is additive. This gives the freedom and need to select the appropriate dosing ratio of alfentanil and propofol by other considerations.

Especially for medical disciplines like anesthesiology, which represent only a small economic market, drug development is a cost intensive and with respect to financial aspects a high risk task. This situation requires methods, which in the early stages of the drug development process of an interesting compound allow the establishment of a reliable and valid data set, in order to make decisions on the continuation or discontinuation of a project. Given a compound out of the group of benzodiazepines as an example this paper represents todays methods of integrated pharmacokinetic-pharmacodynamic modelling as well as the special computer aided strategies of drug dosing as powerful tools in the anaesthetic drug development process. It is shown that one can generate data concerning differences in drug requirement and drug duration in the therapeutic dose range between different groups of possible patients, e.g. young and elderly, as early as the early phase II. It is concluded that these clinical pharmacological tools and the high resolution data generated by them facilitate the Go/No-Go decision to proceed to phase III and enhance the likelihood of passing phase III successfully.

Background In the last 4 y, several authors have reported largely satisfactory results using the new steroid intravenous anesthetic eltanolone (pregnanolone) to induce anesthesia. Until now, however, no investigations have addressed the infusion pharmacokinetics of eltanolone or used electroencephalographic effect data for full pharmacodynamic modeling. Thus the authors conducted a study to evaluate the pharmacokinetic and pharmacodynamic properties of eltanolone after infusion in healthy volunteers. Methods Eltanolone emulsion was administered to 12 healthy men using a computer-controlled infusion device. Linearly increasing serum concentrations were generated for two consecutive infusions with an anticipated slope of 0.075 microgram.ml-1.min-1 and a targeted concentration of 2-2.5 micrograms/ml. During and after the infusion, electroencephalographic data were recorded as a continuous pharmacodynamic parameter to measure the hypnotic effect. In addition, blood pressure, heart rate, pulse oximetry, clinical signs of anesthesia, and any undesirable effects were recorded. The appearance of burst suppression periods in the raw electroencephalographic wave form was used as an end point for the infusion. Arterial blood samples were drawn frequently until 720 min after the cessation of the last infusion cycle. Eltanolone serum concentrations were measured using a specific gas chromatography-mass spectrometry assay. Nonlinear regression analysis was used to relate a power spectral parameter of the electroencephalograph (median frequency) to the serum concentration using a sigmoid Emax model, including an effect compartment to minimize possible hysteresis. Population pharmacokinetics were analyzed using an open three-compartment model. Results The pharmacokinetic model parameters of eltanolone were characterized by a high total clearance (1.75 +/- 0.22 l/min), small volumes of distribution (Vc = 7.65 +/- 3.40 l; Vdss = 91.6 +/- 22 l), and relatively short half-lives (t1/2 alpha = 1.5 +/- 0.6 min; t1/2 beta = 27 +/- 5 min; t1/2 gamma = 184 +/- 32 min). With regard to the pharmacodynamic model parameters, eltanolone proved to be a potent hypnotic agent (Cp50 = 0.46 +/- 0.09 microgram/ml). The hypnotic effect coincided with a remarkable hysteresis between serum concentration and biophase, determined by an equilibration half-life of 8 min (ke0 = 0.087 +/- 0.013 min-1). All volunteers breathed spontaneously during the entire observation period and showed no clinically relevant hemodynamic changes. One volunteer experienced a convulsion while awakening. Conclusions Eltanolone is a new potent steroid-type hypnotic agent with rapid elimination characteristics. Although it is short-acting, the remarkable hysteresis limits the control and might complicate administration of eltanolone if it is used as a component of a complete intravenous anesthesia regimen. Furthermore, it involves the potential disadvantage of drug accumulation and it prolongs recovery if larger-than-necessary doses are used to induce anesthesia rapidly.

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.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 microgram ml-1 min-1 and with a targeted concentration of 2 micrograms 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.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 (t1/2 alpha = 1.5 +/- 0.6 min; t1/2 beta = 27 +/- 5 min; t1/2 gamma = 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. The correlation between clinical signs and corresponding serum concentrations revealed, that in both cycles the disappearance occurred at clearly higher concentrations than the reappearance. The decrease of the systolic arterial pressure showed a maximum of 31% compared to the baseline values, which was statistically significant (P0.05). Diastolic arterial blood pressure decreased of about 10%, while heart rate increased significantly of about 24% (P0.05). 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. (ABSTRACT TR

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; P0.005) and the central volume of distribution to be 20.5 +/- 7.1 vs. 7.9 +/- 3.0 l, respectively (P0.005). 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 (P0.05). The recovery period for Ro 48-6791 was reduced by 66% (P0.005) in the young and 45% (P0.01) 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 (P0.001). Comparing both age groups, the doses necessary to cause similar effects were reduced by one half for both compounds in the elderly (P0.001). 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.

The need for better anaesthetic agents has 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 which has been released in Germany a few months ago. This compound has reached the highest degree of intraoperative 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 blood and tissue nonspecific esterases. 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, 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 by 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 soluble 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 Target-Controlled Infusions (TCI), there has been recently introduced the so called 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.

An intravenous bolus dose of 0.75 mg Kg-1 eltanolone emulsion was administered to 18 unpremedicated ASA I or II patients. In addition to clinical observation and haemodynamic monitoring, EEG power spectrum and median frequency were recorded. Venous blood was collected to establish a concentration-effect relation using the median frequency as a pharmacodynamic parameter for hypnotic effect, and with analysis of data with the sigmoidal Emax model. Emax was determined as the maximal decrease of the median frequency caused by the CNS depressant effect of eltanolone. The results of seven of 15 patients with complete serum and EEG analysis could be described by a sigmoidal curve. The calculated IC50, the serum concentration producing 50% inhibition of Emax, was 0.57 micrograms mL-1. Median frequency occasionally decreased independently of eltanolone serum concentration in seven patients because interference by natural sleep was not prevented before induction or during awakening by setting continuous stimulations. In relation to the peak serum concentration, the decrease in median frequency occurred late in one patient. Nevertheless, the present study provides a preliminary estimation of the IC50 of eltanolone. From the clinical point of view, eltanolone showed satisfactory induction characteristics which warrant further evaluation.

Changes in the EEG power spectrum were studied in 50 patients (ASA status I or II), receiving either 2 mg.kg-1 of racemic ketamine or 1 mg.kg-1 of S-(+) ketamine in a randomized and double-blind manner after prior administration of 0.1 mg.kg-1 of midazolam. The patients receiving intramuscular premedication with midazolam about 45 minutes prior to induction of anaesthesia showed, in a deliberately quiet environment and mostly in the early morning, a delta dominated EEG (56% delta power) with a reduced alpha peak (17% alpha power) and an average median of 4 Hz as the baseline findings of the EEG power spectrum. The intravenous administration of midazolam led to activation of the lower beta range (13-18 Hz) and the subsequent injection of ketamine caused an increase in activity in the fast beta range (21-30 Hz), both being accompanied by a reduction of delta power from 56% to 40%. Correspondingly, an increase in the median frequency was noted. Causing nearly the same changes in EEG, S-(+) ketamine was confirmed to be twice as potent as racemic ketamine.

Activation of neutrophils by various inflammatory stimuli has been shown to play a pivotal role in septic and posttraumatic tissue injury. To further elucidate the mechanisms modulating the oxidative metabolism, we assessed superoxide production induced by N-formylmethionyl-leucylphenylalanine (FMLP) and phorbol myristate acetate and the expression of FMLP receptors of human neutrophils on several days during sepsis and after trauma. Neutrophils of septic patients isolated on days 0–4 after the diagnosis of sepsis showed a significant, more than twofold increase in specific binding of [3H]FMLP at 1, 120, and 240 nM. Scatchard plot analyses revealed that this increase in specific binding was due to an increase in the number of low- and high-affinity FMLP receptors with no changes in receptor affinity. On days 5–10 after the onset of sepsis the up-regulation of FMLP receptors on circulating neutrophils was followed by receptor down-regulation. Likewise, neutrophils from patients with trauma that was not complicated by sepsis bound significantly more [3H]FMLP than neutrophils from volunteers. However, the increase in FMLP receptors was less than that in septic neutrophils and returned earlier to normal. In accordance with the up-regulation of FMLP receptors, neutrophils obtained from patients with sepsis or after trauma on days 1–4 and days 1–2, respectively, produced significantly more superoxide anion upon stimulation with FMLP. However, after stimulation with phorbol myristate acetate, a receptor-independent activator of protein kinase C, these cells released less superoxide anion than controls. Our findings suggest that during sepsis and trauma circulating neutrophils become transiently primed for an enhanced oxidative metabolism upon stimulation with FMLP but desensitized to protein kinase C dependent stimulation.

In a randomized, double-blind study, we have examined the stereoselective disposition and pharmacodynamic characteristics of ketamine in surgical patients after i.v. administration of S(+)-ketamine 1 mg/kg body weight (25 patients) or racemic ketamine 2 mg/kg body weight (25 patients). S(+)-Ketamine was not inverted to R(-)-ketamine. After racemate administration we observed statistically significant (P < 0.01) smaller clearance and volume of distribution for R(-)-ketamine compared with S(+)-ketamine. In contrast, the pharmacokinetic variables of S(+)-ketamine were not significantly different between treatment groups. Systolic and diastolic arterial pressure and heart rate increased significantly (P < 0.005) in both groups. At 1, 3 and 15 min after S(+)-ketamine administration, significantly greater increase in systolic and diastolic pressures were observed compared with the racemate group. There was no correlation between the changes in haemodynamic variables and plasma catecholamine concentrations, which remained unaffected after administration of the medications.

Since the 1940s several preclinical investigations have demonstrated the anaesthetic activity of a series of structurally related pregnanes without notable endocrine action. One of the most active of these is pregnanolone (3-alpha-hydroxy-5-beta-pregnane-20-one), which is a naturally occurring metabolite of progesterone. Pregnanolone is not soluble in water, which has prevented its use for clinical research. In 1987, however, a stable oil-in-water emulsion of eltanolone that could be used for i.v. administration in man was introduced by KABI Pharmacia, Stockholm, Sweden. METHODS. In an open study the dose of eltanolone that induces anaesthesia in 50% of the patients (AD50) was estimated according to the "up and down method" of Dixon and Massey. Respiratory and cardiovascular effects were evaluated as well as the reliability of eltanolone emulsion. The study was conducted in accordance with the Declaration of Helsinki and started after the approval of the local Medical Ethics Review Committee. In all, 31 patients of ASA risk categories I and II (male or female with non child-bearing potential) were included in the study after written informed consent had been obtained. All patients were premedicated with 5 mg midazolam i.m. about 30 min before the injection of eltanolone. Eltanolone emulsion was given i.v., usually on the back of the hand, over 20 s. In connection with the injection of eltanolone every patient was asked whether he or she felt any pain or discomfort at the injection site. As suggested by results in volunteers in a previous study the starting dose was 0.5 mg/kg body weight. Cessation of counting and loss of eyelash reflex were used as indicators of efficacy in the induction of anaesthesia. If these criteria were achieved within 120 s after the start of injection (responder) the dose for the next patient was decreased by 15%, if not (non-responder), the next patient received the same dose plus 15% (up to 1.01 mg/kg body weight). Heart rate and oxygen saturation were recorded continuously (Sirecust 404; Nellcor) from 1 min before to 10 min after the start of injection, and blood pressure was measured noninvasively 1 min before induction and then at 1, 2, 3, 5, 8 and 10 min from the start of the eltanolone injection (Sirecust 888). If oxygen saturation fell to 85% oxygen was applied by way of the face mask and the patients were ventilated if necessary. Respiratory disturbances, time to and duration of apnoea were recorded, as were involuntary movements or increase in muscle tone. Usually intubation was carried out at the end of the 10-min observation period using thiopentone, vecuronium and suxamethonium. If a patient did not fall asleep or awoke prematurely, intubation was performed in the same way and from this point pharmacodynamic parameters were no longer evaluated for the study. RESULTS. The AD50 was 0.33 mg/kg body weight, and the 95% confidence interval, 0.30-0.36 mg/kg body weight. The eltanolone dose varied from 0.25 to 0.5 mg/kg body weight. Induction was successful in 17 (of 31) patients according to the eyelash reflex as criterion and in 28 according to cessation of counting. Above 0.38 mg/kg body weight efficacy variables were achieved in all patients, while below 0.29 mg/kg body weight eyelash reflex was not lost in any patient. The mean time to loss of consciousness (cessation of counting) in the responder group was 48 +/- 12 s after the start of injection and loss of eyelash reflex was recorded after 94 +/- 13 s. In the nonresponder group eyelash reflex persisted over 120 s in all patients and counting stopped on average after 72 +/- 23 s. Three patients in this group also did not stop counting (dose: 0.29 mg/kg body weight). Blood pressure remained stable in all patients but 1 throughout the observation period. In 1 patient there was an alarming rise in blood pressure from 160/90 mmHg before to 200/100 mmHg 3 min after the injection.(ABSTRACT TRUNCATED AT 400 WORDS)

Viele der in Anasthesie und operativer Intensivmedizin verwendeten Pharmaka wie z. B. peripher wirksame Analgetika (2-Arylpropionsauren), β-Blocker, Opioide, Barbiturate sowie manche Benzodiazepine zeigen, ebenso wie Ketamin, aufgrund eines chiralen C-Atoms das Phanomen der optischen Aktivitat. Von solchen Substanzen existieren zwei Verbindungen, die sich wie Bild und Spiegelbild verhalten, weshalb sie als Enantiomere bezeichnet werden. Enan- tiomere stimmen, mit Ausnahme der Drehrichtung von linear polarisiertem Licht und der Reaktivitat gegenuber optisch aktiven Substanzen, in ihren physikalischen und chemischen Eigenschaften uberein. Hinsichtlich ihrer pharmakologischen Wirkung hat sich jedoch gezeigt, das Enantiomere sowohl pharmakodynamische als auch pharmakokinetische Unterschiede aufweisen konnen. Dies erklart sich daraus, das die unterschiedliche absolute Konfiguration der Molekule z. B. zu verschiedenen Affinitaten oder intrinsischen Aktivitaten an Rezeptoren oder auch zu anderen Rezeptorpraferenzen fuhren kann. Unterschiede in Resorption, Verteilung, Metabolismus und Elimination von Enantiomeren stellen keine Seltenheit dar [18, 19, 57, 58, 90]. Trotzdem wird die Mehrzahl dieser Pharmaka bislang klinisch als Razemat, d. h. als Verbindung, welche die beiden Enantiomere jeweils zu gleichen Teilen enthalt, eingesetzt.

Ketamin ist ein Allgemeinanasthetikum, dessen Wirkungsspektrum sowohl anasthetisch-hypnotische als auch analgetische Eigenschaften umfast. Die klinische Wirkung des Ketamins wurde von Anfang an als „dissoziative Anasthesie“ bezeichnet, womit sein charakteristischer narkotisch-kataleptischer Effekt umschrieben wird, der aus einer Koordinationsunterbrechung zwischen neokortikal-thalamischen und limbisch-retikularen Hirnstrukturen resultiert [13, 10, 46].