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Discusses the abstract of the article "Propofol Concentration Changes in Cerebrospinal Fluid After the Drug Infusion," by R. Kalitynski submitted at the 27th Congress of The Scandinavian Society of Anesthesiology and Intensive Care Medicine.

Discusses the abstract of the article "Propofol Concentration in Human Cerebrospinal Fluid-- Free and Bound Form of the Drug," by R. Kalitynski and colleagues submitted at the 27th Congress of The Scandinavian Society of Anesthesiology and Intensive Care Medicine.

The phospholipid class and fatty acid composition of Legionella bozemanae were determined using thin-layer chromatography, gas-liquid chromatography, and matrix-assisted laser desorption ionization-time of flight mass spectrometry. Phosphatidylcholine, phosphatidylethanolamine, and diphosphatidylglycerol were the predominant phospholipids, while phosphatidyl-N-monomethylethanolamine, phosphatidylglycerol, and phosphatidyl-N,N-dimethylethanolamine were present at low concentrations. With the use of the LC/MS technique, PC16:0/15:0, PC17:/15:0, and PE16:1/15:0 were shown to be the dominant phospholipid constituents, which may be taxonomically significant. Two independent phosphatidylcholine synthesis pathways (the three-step methylation and the one-step CDP-choline pathway) were present and functional in L. bozemanae. In the genome of L. bozemanae, genes encoding two potential phosphatidylcholine forming enzymes, phospholipid N-methyl transferase (PmtA) and phosphatidylcholine synthase (Pcs), homologous to L. longbeachae, L. drancourtii, and L. pneumophila pmtA and pcs genes were identified. Genes pmtA and pcs from L. bozemanae were sequenced and analyzed on nucleotide and amino acid levels. Bacteria grown on an artificial medium with labelled choline synthesized phosphatidylcholine predominantly via the phosphatidylcholine synthase pathway, which indicates that L. bozemanae phosphatidylcholine, similarly as in other bacteria associated with eukaryotes, is an important determinant of host-microbe interactions., (Copyright © 2010 Elsevier GmbH. All rights reserved.)

The composition of phospholipids from the cellular envelope of Legionella lytica grown on artificial medium was determined by two-dimensional thin-layer chromatography. Phosphatidylcholine, phosphatidylethanolamine, and phosphatidyl-N-monomethylethanolamine were the predominant phospholipids, while diphosphatidylglycerol, phosphatidylglycerol, and phosphatidyl-N,N-dimethylethanolamine were present at low concentrations. A trace amount of lipids carrying glycosyl residues was also observed. The fatty acids and their distribution in individual phospholipids were characterized using liquid chromatography/mass spectrometry (LC/MS), matrix-assisted laser desorption ionization-time of flight, and gas chromatography/MS methods. The characteristic feature of L. lytica phospholipids was the presence of an unbranched chain (which differentiates this bacterium from Legionella pneumophila) and branched iso and anteiso fatty acids as well as cis-9,10-methylenehexadecanoic acid. According to spectroscopic LC/MS data, the localization of saturated and unsaturated fatty acid residues on phosphorylglycerol was determined. Some aspects of the significance of phosphatidylcholine, one of the main phospholipids in L. lytica, are addressed and taxonomic implications of the data are discussed.

Aim: It is generally assumed that only unbound drugs can reach the site of action by diffusing across the membranes and exerting pharmacological effects by interacting with receptors. Recent research has shown that the percentage of free drugs may depend on the total drug concentration. The aim of the paper is to verify whether the mentioned dependence reported for propofol also takes place in plasma and human serum albumin samples in the presence of intralipid-the medium used as a vehicle for propofol infusions and a parenteral nutrition agent., Methods: Artificial plasma samples and human plasma were spiked with intralipid or ethanolic solutions of propofol. The samples were then assayed for free propofol concentration using ultrafiltration and high performance liquid chromatography with fluorimetric detection., Results: The decrease of the total drug concentration results in free propofol fraction increase, irrespectively of the used type of propofol solvent and sample type. The addition of intralipid causes the lowering of the overall free drug fraction with respect to the samples spiked with ethanolic solutions of the drug., Conclusion: The presence of intralipid does not influence the phenomenon of free propofol fraction rise at low total drug concentration. Such a rise cannot be ignored in clinical conditions when the drug is applied for sedative, antiemetic or other low-dosage purposes.

The development of analytical techniques for estimation of free drug concentration is crucial for the needs of modern pharmacology. Up to now, many different methods of free drug assay have been used. The methods involving isolation of free drug from a sample are most frequently applied because they can be easily adopted for the processing of real samples. Among the methods that do not require free drug isolation only the adsorption method could be promising in application to samples of this kind. The successful use of the adsorption method is possible only if two requirements are fulfilled: (I) the chosen adsorbent does not bind proteins from the sample and (II) the processes of adsorption of the assayed drug on the adsorbent used and on the protein should be independent. This paper discusses the possibilities of application of the adsorption method for determination of free drug concentration using propofol as the model drug. The presented results show that the fulfillment of the above conditions may be very difficult if not impossible not only for propofol, but for other drugs as well.

Drugs exist in blood in two forms: free and bound to proteins and blood cells. It is generally assumed that only the unbound form of a drug exerts pharmacological activity as it is able to diffuse across the membranes and reach the site of action. Since for the majority of drugs their free fraction is usually constant, the therapeutic effect of the drug is most often correlated with its total concentration. However, in case of some disease states (e.g. renal or hepatic disorders) the protein concentration may change dramatically, resulting in clinically significant change of free drug fraction. The results presented in the paper prove that, in case of propofol, an increase of free fraction occurs with a decrease of total drug concentration. This dependence is observed both in vitro (in artificial and native human plasma) and in vivo. Free propofol fraction, which in clinical conditions ranges from 1 to 3%, at very low total propofol concentrations (below 0.01 microgml(-1)) tends to reach 100%. This increase of free drug percentage is discussed in terms of its possible reasons as well as its potential clinical relevance.

Objective: Investigation of the propofol concentration changes in cerebrospinal fluid (CSF) after the termination of the drug infusion., Methods: Nine patients (American Society of Anesthesiologists classes I-III) scheduled for elective intracranial procedures were studied. Propofol was applied in the form of target control infusion. During anesthesia, fractional doses of fentanyl and cisatracurium were administered as necessary. After tracheal intubation, the lungs were ventilated to achieve normocapnia with an oxygen-air mixture (fraction of inspired oxygen = 0.33). Arterial blood and CSF samples (from an intraventricular drain) were taken simultaneously at the end of propofol infusion and then at 15, 30, 45, 60, 90, and 120 minutes after the end of infusion., Results: A pronounced decrease of the anesthetic concentration in plasma (P < 0.001) was observed during the first 15 minutes after infusion termination, followed by further yet slower decrease of the drug concentration. At the end of propofol infusion, the concentration of propofol in CSF was 65.59 ng/mL (SD, 26.91 ng/mL) and remained almost stable for approximately 30 minutes; afterward, a slow decrease of CSF propofol concentration was observed., Conclusion: The statement that CSF can be regarded as a significant route for drugs delivery to the brain is disputable for propofol. The obtained results show that, in contrast to the situation from induction of anesthesia, back transport of the drug from CSF to blood is markedly slower, supporting the thesis about propofol transport from blood to CSF by passive diffusion.

Free drug assay in physiological fluids is getting more and more attention nowadays. The principal reason is the fact that the unbound drug form is responsible for the therapeutic or toxic effects of its application. Unbound drug concentration significantly depends on the extent of its binding by plasma. This article describes the influence of different factors on unbound propofol concentration. These factors are presence of infusion fluids in blood, type of anticoagulant, sample storage time and plasma freezing. The following conclusions result from the experiments carried out: 1. The lowest free drug fractions are observed in samples containing carbohydrate infusion fluids. The free drug percentage is virtually independent of its total concentration in the range of clinically relevant concentrations. 2. There is no evident anticoagulant influence (heparin, citrate, EDTA and oxalate) on free propofol level in plasma samples. 3. Longer storage of plasma at 4 degrees C causes a slight rise of free propofol concentration in heparinised plasma and no evident changes in plasma containing citrate. 4. Plasma freezing induces the increase of free drug concentration both for citrate and heparin. These findings are valuable both for clinicists and pharmacologists, and important for chemical analysts.

Background: Propofol is one of the most frequently applied intravenous anesthetics. Although it has been used for a long period, its pharmacokinetics, especially central nervous system pharmacokinetics, are not fully recognized., Objective: Investigation of the relationships between total propofol concentration in blood, total propofol concentration in cerebrospinal fluid (CSF), free propofol concentration in blood, and free anesthetic concentration in CSF in patients undergoing elective neurosurgery and anesthetized with propofol., Methods: Eleven patients scheduled for elective intracranial procedures were studied. Propofol was applied in the form of target control infusion. During anesthesia, fractional doses of fentanyl and cisatracurium were administered as necessary. After tracheal intubation the lungs were ventilated to achieve normocapnia with an oxygen-air mixture (Fi O2 = 0.33). CSF and blood were taken at the moment of intraventricular drainage application., Results: The unbound propofol concentration in plasma is 1.12% (SD 0.61%; SEM 0.18%) of the total concentration in plasma, and the free propofol concentration in plasma is 71.6% (SD 61.0%; SEM 18.4%) of the total CSF propofol concentration. The free anesthetic concentration in CSF is 30.9% (SD 15.7%; SEM 4.7%) of the total CSF propofol concentration, and 61.8% (SD 34.9%; SEM 10.5%) of the free propofol concentration in plasma., Conclusion: The relationship between unbound drug concentrations in plasma and in CSF determined in this study leads to the postulate that propofol is transported from blood to CSF by passive diffusion.

Aims: The aim of this study was to define the relationship between unbound propofol concentrations in plasma and total drug concentrations in human cerebrospinal fluid (CSF), and to determine whether propofol exists in the CSF in bound form., Methods: Forty-three patients (divided into three groups) scheduled for elective intracranial procedures and anaesthetized by propofol target control infusion (TCI) were studied. Blood and CSF samples (taken from the radial artery, and the intraventricular drainage, respectively) from group I (17 patients) were used to investigate the relationship between unbound propofol concentration in plasma and total concentration of the drug in CSF. CSF samples taken from group II (18 patients) were used to confirm the presence of the bound form of propofol in this fluid. The CSF and blood samples taken from group III (eight patients) were used to monitor the course of free and bound CSF propofol concentrations during anaesthesia., Results: For group I patients the mean (and 95% confidence interval) total plasma propofol concentration was 6113 (4971, 7255) ng ml(-1), the mean free propofol concentration in plasma was 63 (42, 84) ng ml(-1), and the mean total propofol concentration in CSF was 96 (76, 116) ng ml(-1) (P < 0.05 for the difference between the last two values). For group II patients the fraction of free propofol in CSF was 31 (26, 37)%. For group III patients the fraction of free propofol in CSF during TCI was almost constant (about 36%)., Conclusions: The unbound propofol concentration in plasma was not equal to its total concentration in CSF and cannot be directly related to the drug concentration in the brain. Binding of propofol to components of the CSF may be an additional mechanism regulating the transport of the drug from blood into CSF.