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BACKGROUND: AZD3043 is a positive allosteric modulator of the γ-aminobutyric acid type A receptor, with sedative and anesthetic properties. We describe a population pharmacokinetic (PK) model of arterial and venous concentrations of AZD3043 and the pharmacodynamic effects on bispectral index (BIS) in healthy volunteers. METHODS: Arterial and venous plasma concentrations of AZD3043 and BIS were measured in 2 clinical studies in 125 healthy volunteers, where AZD3043 was given as a 1-minute bolus (1-6 mg/kg), a 30-minute infusion (1-81 mg/kg/h), or 0.8 + 10, 1 + 15, 3 + 30, and 4 + 40 (mg/kg bolus + mg/kg/h infusion for 30 minutes). Population PK/pharmacodynamic analysis was performed with NONMEM. RESULTS: A recirculatory model, comprising a series of 5 compartments for the transit of drug between venous and arterial plasma, 2 peripheral distribution compartments, and 1 compartment for the nondistributive transit of drug from arterial to venous plasma, described the PK of AZD3043. Systemic clearance was high (2.2 L/min; 95% confidence interval, 2.12-2.25), and apparent volumes of distribution were low, leading to a short elimination half-life. The apparent volumes of distribution of the arterial and peripheral compartments increased with increasing administered dose, giving a total apparent volume of distribution of 15 L after the lowest dose and 37 L after the greatest dose. A sigmoid maximum effect (Emax) model with an EC50 of 15.6 µg/mL and a γ of 1.7 described the relationship between AZD3043 effect-site concentrations and BIS. The between-subject variability in EC50 was 37%. An effect compartment model, with a half-life of the equilibration rate constant ke0 of 1.1 min, described the delay in effect in relation to the arterial plasma concentrations. CONCLUSIONS: AZD3043 had a high clearance and a low apparent volume of distribution, leading to a short half-life. However, the apparent volume of distribution was dose dependent (P < 0.001), leading to an increased

Pain is the most common symptom following laparoscopic cholecystectomy (LC) and might delay discharge from hospital after day surgery. A patient’s ability to manage stressful situations can be assessed by the sense of coherence (SOC) and has been proposed to predict health. The aim of this study was to investigate predictors of average pain the first postoperative week after LC, and predictors of changes in perceived health, with special reference to individual coping resources measured by the Sense of Coherence Scale. Furthermore, a test–re-test was performed on SOC to evaluate the stability in the context of LC surgery. Method: Seventy-three patients completed questionnaires about SOC, health status, pain, anxiety, symptom occurrence and symptom distress preoperatively, postoperative day 1–7 and after 1 and 6 months following LC. Results: By multiple regression, 23% of the variability in pain intensity could be explained by the variables age, SOC and education. Age was the strongest predictor. Further, 19% of the change in health between day 7 and 1 month could be explained by the two variables symptom distress the first postoperative day and SOC. The test–re-test of SOC had a correlation coefficient (r) of 0.55. Forty-six patients (63%) remained within ± 10% of their preoperative SOC score at 6 months, 11 patients (15%) decreased and 16 patients (22%) increased their SOC values. Conclusion: SOC was found to be a significant but weak predictor of pain intensity the first week after LC. Furthermore, patients scoring low SOC values experienced a delay in their health improvement. SOC was more unstable over time than previously suggested. Further, interventional studies are needed to clarify if SOC might be a clinically useful measure to identify vulnerable patients undergoing LC surgery.

BACKGROUND: In previous work, extravascular expansion was observed to be enhanced by isoflurane anesthesia in sheep when a crystalloid bolus was administered. The aim of the current study was to further elaborate these investigations to humans and to explore the use of population kinetics in the analysis of fluid shifts. METHODS: Eleven healthy volunteers participated in two experiments each, either awake or isoflurane anesthetized, during which they received 25 ml/kg saline, 0.9%, intravenously over 20 min. Plasma dilution data were derived from repeated sampling of hemoglobin concentration, and population pharmacokinetic analysis was conducted using the WinNonMix 2.0.1 software (Pharsight Corporation, Mountain View, CA). Plasma hormones were measured, and hemodynamic values were monitored. RESULTS: Fluid infusion during isoflurane anesthesia was followed by a higher cardiac output, lower arterial pressure, and lower urinary excretion as compared with the awake protocol (P < 0.05). Albumin dilution was greater than hemoglobin concentration-derived plasma dilution, which indicates a transcapillary leak of albumin. A two-compartment model with an isoflurane-depressed, intercompartmental distribution parameter predicted that more than 50% of the infused volume was retained in the peripheral compartment at 180 min in both protocols. Isoflurane markedly increased the plasma levels of renin and aldosterone, whereas vasopressin was mostly unchanged. CONCLUSION: Fluid retention after rapid infusion of 0.9% saline was prominent in both awake and isoflurane-anesthetized subjects. Altered kinetics of infused 0.9% saline during isoflurane anesthesia was expressed as reduced clearance and a slower distribution, resulting in a small but significant increase in fluid accumulation in the body fluid compartments. These changes may be due to the associated decreasing of mean arterial pressure and increased release of renin and aldosterone.

BACKGROUND: Hemorrhage is commonly treated with intravenous infusion of crystalloids. However, the dynamics of fluid shifts between body fluid spaces are not completely known, causing contradictory recommendations regarding timing and volume of fluid infusions. The authors have developed a turnover model that characterizes these fluid shifts. METHODS: Conscious, chronically instrumented sheep (n = 12) were randomly assigned to three protocol groups: infusion of 25 ml/kg of 0.9% saline over 20 min (infusion only), hemorrhage of 300 ml (7.8 +/- 1.1 ml/kg) over 5 min (hemorrhage only), and hemorrhage of 300 ml over 5 min followed by infusion as noted above (hemorrhage plus infusion). A two-compartment volume turnover kinetic model containing seven model parameters was fitted to data obtained by repeated sampling of hemoglobin concentration and urinary excretion. RESULTS: The volume turnover model successfully predicted fluid shifts. Mean baseline volumes of the central and tissue compartments were 1799 +/- 1276 ml and 7653 +/- 5478 ml, respectively. Immediate fluid infusion failed to prevent hemorrhage-induced depression of cardiac output and diuresis. The model suggested that volume recruitment to the central compartment after hemorrhage was primarily achieved by mechanisms other than volume equilibration between the two model compartments. CONCLUSION: Volume turnover kinetics is a promising tool for explaining fluid shifts between body compartments after perturbations such as hemorrhage and intravenous fluid infusions. The pronounced inhibition of renal output after hemorrhage prevailed regardless of fluid infusion and caused fluid retention, which expanded the tissue compartment.

Isolation of peptides and other bioactive compounds is an important and often necessary step to get the total information about their structures. This is demonstrated by a number of different characterizations in this thesis. Bioactive peptides and small organic molecules can act as signaling substances and messengers in multicellular organisms and are fundamental to higher forms of life. The following bioactive peptides and compounds were studied. 1) Different assays can be used for detection of novel peptides. Chemical assays are simple, but still robust, and have proven successful in several cases. In this thesis, an assay was developed to detect peptides that contain tryptophan. An N-terminal dipeptide Gly-Trp is characteristic for galanin, which was cleaved off, separated and visualized. In this manner a novel form of galanin from chicken was detected and isolated. 2) Antibacterial peptides were first found in insects and later in mammals. Many of these peptides are basic, some are Pro/Arg-rich (e.g. peptide PR-39). Investigation of basic peptides from pig spleen, resulted in the isolation of a new variant form of NK-lysin, previously only detected in a cDNA library from porcine bone marrow. PR-39 was identified by a method suitable for Pro/Arg-rich peptides using ladder sequence analysis with mass spectrometry. 3) Another biological assay, involving cAMP production in cell culture of SK-N-MC cells, was used to screen peptide fractions, and resulted in the isolation of a novel form of the hormone PYY, with a phosphate group attached to the Ser-13 residue. This finding demonstrates the benefit of peptide isolation to find posttranslational modifications not directly obvious from the corresponding DNA sequence. Using nano-electrospray tandem mass spectrometry, the phosphorylated form of porcine PYY was identified and the modification localized to Ser-13. 4) Specific antibodies raised against peptides are a valuable tool in peptide chemistry. We have isolated PEC

Introduction: Total body water (TBW) is an important parameter in pathological states where the normal regulation of fluid balance is impaired (e.g., during critical illness, congestive heart failure, bum injury and renal insufficiency). Dilution of water isotopes, such as deuterium oxide (D2O), is considered die gold standard method for measuring TBW in humans. However this procedure requires skilled staff, expensive equipment and the results are seldom available in a timely fashion, which makes it less suitable for clinical applications. Ethanol is completely miscible with water and is thought to distribute into the TBW. The ethanol volume of distribution at steady state (Vss) can be estimated by pharmacokinetic analysis of the concentration-time profile. Ethanol can be measured in expired breath with high precision and this non- invasive method of analysis could provide an attractive alternative with the prospect of bedside monitoring of Vss within 4-6 hours. The aim. of this thesis was to develop an appropriate pharmacokinetic model for intravenous ethanol administration and to identify experimental factors that impact on the results. With this background, we compared Vss. determined by ethanol dilution with TBW determined by D20 dilution. The complicated absorption kinetics of ethanol (e.g. variable gastric emptying and first-pass metabolism) was avoided by use of the intravenous route of administration. Material and Methods: Forty-six healthy volunteers (20 women and 26 men) received intravenous infusions of ethanol (0.4- 0.6 g/kg body weight) in 15-60 minutes. The concentration of ethanol was measured in end-expired breath by infrared spectrometry and in blood and urine by headspace gas chromatography. Specimens of blood and breath were obtained at 5-15 min intervals for 3-6 hours post-dosing. The concentration of D20 in plasmawater was measured with isotope ratio mass spectrometry. Subjective feelings of inebriation were measured with a visual analogue scale