Search

Most previous assays for thiopental are time-consuming due to laborious sample extraction steps prior to analysis using gas chromatography or high pressure liquid chromatography. Here, we describe the first high-throughput liquid chromatography - tandem mass spectrometry (LC-MS/MS) method for quantification of thiopental concentrations in samples of human plasma. Robotic on-line solid phase extraction (SPE) was used to elute the analytes of interest from samples of human plasma (50μL) loaded onto C18 SPE cartridges to which were added aliquots (50μL) of internal standard solution (thiopental-d5 100ng/mL) and 0.5% formic acid in water (100μL). Cartridges were washed using 10% methanol in ammonium acetate buffer (50mM, pH 7) before elution with mobile phase comprising 0.1% formic acid in water and acetonitrile with a flow rate of 0.55mL/min using a 7.2min run time. The analytes were separated on a C18 XTerra ® analytical column. Mass spectrometry detection was performed using a QTrap 5500 mass spectrometer (AB Sciex) with negative ionisation. The multiple reaction monitoring (MRM) transitions for thiopental and the internal standard were 241→58, and 246→58, respectively. The calibration curve was linear over a range of 6-600ng/mL. Thiopental was stable in human plasma samples for at least 36h in the autosampler, as well as after three cycles of freeze and thaw, and after 3h storage at room temperature. The absolute recovery and matrix effect were 102% and 6.9%, respectively, and the within-run and between-run precision and accuracy were ≤15%. Our method is fully-validated and satisfies the requirements of the 2012 European Medicines Agency (EMEA) guideline for Bioanalytical Method Validation., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Introduction: Thiopental is a thiobarbiturate given in the case of brain injuries to reduce intracranial pressure and to manage cerebral ischemia. A pharmacokinetic model has been described previously in critically ill patients with a different therapeutic strategy. New treatment options prompted us to investigate if drug-drug interactions occur. A new model is proposed describing the influence of concomitant administration of esomeprazole on the distribution of thiopental., Method: The study population comprised 52 critically ill patients (body weight 47.1-114 kg) aged 18-78 years who had been admitted into the critical care unit for treatment of intracranial hypertension. A total mean dose of 282.8 ± 172.7 mg/kg was given in 96 ± 72 h. Pharmacokinetic analysis was performed by using a nonlinear mixed-effect population model., Result: A one-compartment open model with first-order elimination identified two covariates, namely, body weight on clearance and volume of distribution, and the administration of esomeprazole on volume of distribution. The mean values (% relative standard error) for total clearance (CL) and for central volume of distribution (Vd) in patients with and without concomitant esomeprazole were 5.3 L/h (9.2 %) and 256.1 (6.4 %) and 153.2 l (19.2 %), respectively., Conclusion: Based on these results, we conclude that concomitant administration of esomeprazole increases the volume of distribution and the half-live of thiopental. This drug-drug interaction should be considered when a target concentration has to be reached.

Thiopental is an ultra-short-acting barbiturate, used as an induction agent during general anesthesia and to manage intra cranial pressure in traumatic brain injuries. Because of its rapid onset of action, the potential for accidental or intentional abuse of thiopental is high. In this paper, a case is presented in which a 25-year-old female deliberately injected a fatal dose of thiopental. A method is developed for the evaluation of thiopental levels in the post-mortem blood (PMB) by simple and rapid HPTLC. Three different extraction procedures were compared for optimum recovery of thiopental from spiked blood samples. The effect of pH on the extraction yield of thiopental over a pH range of 5-6.5 was examined. An average analytical recovery of 90.5% was achieved from an ethyl acetate extract at pH 5.5. Chromatographic separation was achieved on silica gel 60F254 plates with an optimized mobile phase consisted of hexane-dichloromethane-ethyl acetate in the ratio 7.5:2:0.5 (v/v). Densitometric detection was carried out at 290nm in absorbance mode. No significant chromatographic interference was observed from other drugs used to diagnose the brain death. Calibration curve for thiopental in blood were linear from 1 to 100μgml(-1) with r(2)=0.994. The detection limit was 0.5μgml(-1) and its lower limit of quantification was 1.5μgml(-1). The method showed excellent intra-assay precision (R.S.D. 1.07-6.28%) and inter-assay precision (R.S.D. 0.39-1.43%) for spiked blood samples at concentration of 1, 10, and 50μgml(-1). The toxicological analysis revealed high concentrations of thiopental in PMB (204.75μgml(-1) ±0.34), which is of immense help to conclude that the death occurred due to fatal doses of thiopental., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The suicide of a 43-year-old male by intravenous injection of cisatracurium, a non-depolarizing neuromuscular blocking agent, and thiopental, an ultra-short-acting barbiturate, is presented. Systematic toxicological screening by gas chromatography-mass spectrometry (GC-MS), liquid chromatography (LC)-diode-array detection, and LC-MS-MS confirmed the presence of thiopental. A large peak in the GC-MS chromatogram was matched by the Pfleger-Maurer library as corlumine, but neither atracurium neither its metabolite, laudanosine, were detected. To confirm the absence or the presence of laudanosine in the blood sample, an ultra-performance liquid chromatography-MS-MS method for cisatracurium and laudanosine quantification was developed. The calibration range was 2.5-500 ng/mL for laudanosine and 10-500 ng/mL for cisatracurium. The biases were lower than 12.3%. Intraday and interday precisions, expressed as coefficient of variation, were lower than 13.3%. This method allowed to confirm the presence of laudanosine and measurement of laudanosine in all samples. The femoral blood concentration was therapeutic (0.46 μg/mL). This case report documents a possible analytical pitfall and describes a simple and fast method for cisatracurium determination. Moreover, the purpose of this case report was to document the postmortem redistribution of cisatracurium and laudanosine, which could help make it possible to interpret tissue or cardiac blood concentrations in forensic cases where femoral blood is not available.

Background and Objectives: Thiopentone, a short-acting barbiturate, has been introduced as premedication for intubation in newborn infants. The objectives of this study were to assess the pharmacokinetics of thiopentone in newborn infants, and to unravel whether placental transfer of the drug should be taken into account if administered to infants exposed to it during delivery., Methods: Plasma concentrations were assessed with high-pressure liquid chromatography in samples from delivering mothers (n=27) receiving a median dose of 5.5 mg/kg (range 3.8-7.7) thiopentone for Caesarean section in gestational week 37.6 (range 25.7-41.4) and from corresponding umbilical cord blood (n=28). In infants (n=30) born at 35.4 weeks gestation (range 27.9-42.0) undergoing surgery at a median postnatal age of 24.5 h (range 4-521), repeated blood levels were assessed after administering a dose of 3 mg/kg thiopentone on clinical indication before intubation (seven samples per infant from 5 min to 48 h after administration)., Results: The umbilical/maternal concentration ratio was 0.7, the mean concentration of thiopentone was 55.7 micromol/l (SD+/-15.3) in mothers and 39.3 micromol/l (SD+/-12.5) in venous cord blood. In newborn infants undergoing surgery, the terminal half-life of thiopentone was 8 h (interquartile range (IQR) 2.5-10.8), and clearance 0.092 l/min per kg/postnatal age in days (IQR 0.02-0.1)., Conclusions: Thiopentone might be used as premedication for short-lasting intubation after birth, for example, for surfactant administration. During the first 4 h after birth the dose needs to be adjusted for maternal dosage as well as for the weight of the infant.

Unlabelled: Thiopental may be used for sedation before intubation in newborn infants. A boy, born at 33 weeks of gestation (gw); birth weight 2435 g, was prescribed thiopental 3 mg/kg before intubation. He developed temporary hypotension and oxygen desaturation, and remained unconscious for longer than expected with a suppressed electroencephalography for 48 h. Serum thiopental concentration was 82, 59, 42 and 32 micromol/L after 20 min and 6, 24 and 68 h respectively. Serum concentrations from five newborn infants at the same time points after intubation with the same thiopental dose were used as reference values, and indicated a 10-fold overdose in the index case. The cause of the overdose could not be identified. The infant recovered; cerebral magnetic resonance imaging at the age of 42 gw and psychomotor development at 2 years were normal. These results show that thiopental concentrations are variable in neonates and there is a high risk of dosage error as no specific paediatric formulation is available., Conclusion: Well-designed procedures and continuous education are required to prevent errors and adverse events during drug delivery to newborn infants. To develop a safe method of administration for thiopental, an extended pharmacokinetic and pharmacodynamic study in neonates is warranted.

Background: Several drugs may affect the diagnosis of brain death by depressing the electroencephalographic signal. Serum levels of these drugs must be below their respective therapeutic ranges., Methods: A high performance liquid chromatography-based fast and simple method was developed for determination of thiopentone, pentobarbitone, phenobarbitone, methohexital and propofol in serum and validated according to international recommendations., Results: Separation of extracted analytes was performed on a reversed phase column [Agilent Zorbax SB C18, 5 microm, 4.6 x 250 mm; mobile phase 50% 50 mM NaH(2)PO(4) pH 4.6 mixed with 35% (v/v) acetonitrile and 15% (v/v) methanol]. Calibration curves were linear throughout the selected ranges (microg/mL, thiopentone 0.25-50, pentobarbitone 0.25-25, phenobarbitone 2.5-50, methohexital 0.125-2.50, propofol 0.25-5.0). The standard deviations for the regression line, recovery, imprecision and accuracy results were all highly satisfactory. The lower limits of quantification for propofol, thiopentone and pentobarbitone were set at 0.25 microg/mL, for phenobarbitone 2.5 microg/mL, and for methohexital 0.125 microg/mL, which are below the lowest pharmacologically relevant serum concentrations. Intra- and inter-day coefficients of variation were less than 10% throughout as determined with six replicates., Conclusions: The method presented is suitable for drug monitoring to help enhance the reliability of the diagnosis of brain death.

A postal survey was conducted to determine how thiopental is used in UK neurosurgery critical care units. Thirty units were contacted and 26 replied. Thiopental is used in 23 units. The majority (60%) of these units govern the use of thiopental with protocols or guidelines and 74% use cerebral monitoring to guide dosage. When patients have had thiopental, 20 units delay brain stem testing, two will not perform tests and one unit incorporates cerebral angiography into their protocol. Twelve units use serum thiopental assays in their brain stem testing procedures, but there is wide variation in the interpretation of the results. We found inconsistency and confusion surrounding brain stem testing in this patient group, raising the possibility of misdiagnosis of brain stem death.

Brain death diagnosis may be confounded by centrally acting drugs. The certainty of brain death diagnosis can be enhanced by demonstrating that the concentrations of such drugs are well below the therapeutic range. A combined high-performance liquid chromatography-based method was developed for the benzodiazepines midazolam, 1-hydroxymidazolam, 1-hydroxymidazolam glucuronide, diazepam, and nordiazepam and for the barbiturates thiopentone and pentobarbitone in serum or plasma of critically ill patients. The lower limits of detection of the assays for benzodiazepines and barbiturates were 2.5 ng/mL and 0.05 microg/mL. The lower limits of the working ranges of these assays were set at 25 ng/mL and 0.5 microg/mL, respectively, and are below the lowest pharmacologically active plasma concentrations of these drugs. Intra- and interday coefficients of variations were less than 2.5% and 11.0% throughout, as determined with six replicates (n = 6). These assays were accurate in that the relative difference between actually measured and expected concentration never exceeded 12%. Utilization of these assays will render the diagnosis of brain death more reliable.

Reaction between iodine and azide ion induced by mercaptopyridines and mercaptopyrimidines was utilized as a detection system in TLC and HPTLC. The developed plates were sprayed with a freshly prepared mixtures of sodium azide and starch solution adjusted to pH 5.5, and exposed to iodine vapour. The spots became visible as white spots on violet-grey background. The iodine-azide detection system has been proved to be the most favourable and enabled to detect quantities per spot in the range of 1-20 pmol (HPTLC) and 1-60 pmol (TLC). The iodine-azide tests were compared with other visualizing techniques commonly used in planar chromatography (iodine vapour and UV254). The developed method was applied to detection of thiopental in biological samples.

Novel miniaturized polyurethane (PU) membrane sensors in an all-solid state graphite support were developed, electrochemically evaluated and used for the assay of thiopental drug. The thiopental (T) sensors are based on the formation of ion-association complexes of thiopental with copper(II) and cobalt(II)-bathophenanthroline (bphen) counter anions as electroactive materials dispersed in a polyurethane matrix. The sensors show a linear response for thiopental over the range of 1 x 10(-1) - 5 x 10(-5) M thiopental at 25 degrees C over the pH range 6 - 11 with anionic slopes of -28.7 and -28.3 mV decade(-1) with Cu- and Co-bphen thiopental membrane sensors, respectively. These sensors exhibit a fast response time (25 - 45 s), a low detection limit (5 x 10(-6) M), a long lifetime (7 weeks) and good stability. The selectivity coefficients for thiopental sensors relative to the number of interfering anions, were investigated. These sensors were used for the direct potentiometry of thiopental in a pharmaceutical formulation and human serum. Results with mean accuracy of 99.8 +/- 0.5% of nominal were obtained, which compare well with data obtained using spectrophotometric (UV-Vis) and British Pharmacopoeia (BP) methods.

Background: Emotional information has the ability to alter the formation and strength of a memory ('memory modulation'). Memory modulation by negative emotion is mediated by the amygdala. It is not known how gamma aminobutyric acid (GABA)ergic drugs affect the processes involved in memory modulation. This study investigates whether memory for negative emotional stimuli is more refractory to the effects of GABAergic drugs., Methods: Eighty-three healthy volunteers were shown a randomized sequence of 60 visual stimuli consisting of negative, positive and neutral emotive pictures, while receiving a controlled infusion of thiopental (n=31), propofol (n=31), dexmedetomidine (n=10) or placebo (n=11). After a 5 h retention interval, when drug concentration was negligible, subjects performed a recognition task with 'old' pictures randomly mixed with 'new' pictures. Drug effect was calculated as the proportionate reduction in recognition for images of each emotional valence., Results: Forty-eight subjects were included in a within-subject logistic dose-response model analysis. In the thiopental group there was a smaller drug effect seen for negative vs positive images (proportional memory reduction from baseline 0.27 (SD 0.20) vs 0.56 (0.25), P<0.001, n=20 included in analysis). A similar trend was seen in the propofol group (0.25 (0.28) vs 0.54 (0.30), n=10), but this did not attain statistical significance. No trend was seen in the dexmedetomidine group (0.33 (0.26) vs 0.24 (0.22), n=7)., Conclusions: Over a specific dose range of thiopental (target serum concentration 2-7 micro g ml(-1)), impairment of explicit memory for images with negative emotional valence is less than that for images with positive emotional valence. There is a strong possibility that propofol (target serum concentration 0.3-2.4 micro g ml(-1)) causes a similar effect. Modulation of visual memory by negative emotional content continues at sub-anaesthetic concentrations of GABAergic drugs associated with explicit memory impairment.

To follow up an investigation which studied effects of antenatal dexamethasone therapy on neonatal respiratory performance in multifetal gestations, neonatal serum steroids were determined by HPLC. A major peak (X) whose retention time coincided with that of dexamethasone was observed in many, but not all, serum samples. However, there was no correlation between the neonates whose serum samples displayed this X-peak and the mothers who had actually received the steroid therapy, indicating that the X-substance was not dexamethasone. An alternate mobile phase was employed which separated the X-substance and dexamethasone validating the indication. Among ten clinical conditions of the neonate birth, the X-substance was found to correlate only with the mothers who had the cesarean operation for delivery, suggesting that the substance was not necessarily a steroid. Four anesthetic agents used for cesarean operations were studied; the X-substance was identified as thiopental using a LC/MS technique. This was based on the same retention times, the same negative ions at m/z 240.9 and the same daughter ions at m/z 100.8 between the two substances. Thus, caution must be exercised when HPLC is employed to study serum steroids of patients who have previously been exposed to thiopental. Moreover, recent reports have shown that thiopental affects certain metabolic reactions in the rat; the present findings also suggest a need for further investigations of thiopental effect on neonates.

Background: A hypoperfusion-reperfusion human model is observed during and soon after laparoscopic surgery. The aim of the study was to research the preventive effects of etomidate, thiopental, and propofol in induction on hypoperfusion- reperfusion phenomenon during laparoscopic cholecystectomy., Methods: Thirty-six consecutive ASA I-II patients were randomized into three groups of 12 patients each. Anaesthesia was induced with etomidate in group 1, thiopental in group 2, and propofol in group 3. Venous blood samples were obtained at different time points for measurement of plasma malondialdehyde (MDA) levels. Arterial blood and gastric juice samples were obtained for the calculation of gastric intramucosal pH (pHi). Also changes in aminotransferases, alkaline phosphatase and total bilirubin levels were assessed., Results: There was a significant decrease in pHi at 1 min before desufflation (BD) and 20 min after desufflation (AD) compared with before insufflation (BI) in all groups. Plasma level of MDA was significantly increased in group 1 at 1 min BD and 20 min AD compared with before induction of anaesthesia (baseline). Malondialdehyde levels were decreased significantly in group 3 and increased non-significantly in group 2 at the same time points. Also AST and ALT levels were significantly increased in both groups 1 and 2 at 24 h postoperatively., Conclusion: Propofol with antioxidant activity may offer many advantages by scavenging reactive oxygen species and their metabolites in case of anticipated hypoperfusion-reperfusion phenomenon, such as would occur in laparoscopic surgery., (Copyright 2004 Acta Anaesthesiologica Scandinavica)

Study Objective: To evaluate the potential of compounds commonly used in anesthesia practice to affect the intracellular oxidant-antioxidant homeostasis of peripheral blood lymphocytes at clinically relevant concentrations; and to study the changes in reactive oxygen species production and measure the mitochondrial glutathione content., Design: Prospective, in vitro study., Setting: Experimental medical research laboratory at a University Hospital., Measurements: Lymphocytes were isolated from the peripheral blood of 15 healthy donors and incubated for 12 hours at 37 degrees C with the following drug concentrations: thiopental sodium 20 mmoL/mL, droperidol 130 micromol/mL, propofol 60 mmoL/mL, and succinylcholine 17 mmoL/mL. Reactive oxygen species (ROS) generation was determined by hydroethidine and 2',7'-dichlorofluorescein diacetate methods. Mitochondrial glutathione level was assessed using monobromobimane staining., Measurements and Main Results: Thiopental-treated lymphocytes exhibited an overgeneration of ROS, but no change was detected in mitochondrial glutathione quantity. Propofol and droperidol could not induce any perturbative effect on the oxidative state of T cells, whereas succinylcholine was found to markedly affect lymphocyte oxidative state both by impairing glutathione content and promoting exaggerated production of ROS., Conclusion: Drugs commonly used in anesthesia practice may significantly alter the oxidative state of peripheral T cells. This mechanism could contribute to the immune suppression that occurs transiently in the early postoperative period.

Background: Some limitations of traditional ("mamillary") compartmental pharmacokinetic models of anaesthetic related drugs arise from representing the blood as a central compartment. Recirculatory pharmacokinetic models overcome these limitations. It is proposed that the simplest recirculatory model has only two compartments, and that understanding the properties of this model is a useful introduction to recirculatory pharmacokinetic concepts., Methods: The compartments of the model are the lungs and the remainder of the body. The traditional rate constants (e.g. k12 and k21) are replaced by terms that include cardiac output. Drug infusion is into the lung compartment, and drug clearance is from the "body" compartment. The "total" drug concentrations can be thought of as the sum of the first-pass and recirculated drug concentrations at any time. Equations for both first-pass and total drug concentrations in arterial and mixed venous blood are presented. The effects of cardiac output and injection time on these concentrations were analysed., Results: The first-pass arterial concentrations were shown to make a significant contribution to the total concentrations for high-clearance drugs and/or bolus drug administration. There was an inverse relationship between these first-pass concentrations and cardiac output, and a direct relationship with bolus injection rate. Thus, the total arterial concentrations are affected by these factors in these circumstances., Conclusions: The two-compartment recirculatory model is the simplest tool available for elaborating recirculatory pharmacokinetic concepts. The recirculatory approach may provide a conceptual framework of drug disposition that better matches the clinical experience of anaesthetists.

Background: Modeling of pharmacokinetic parameters and pharmacodynamic actions requires knowledge of the arterial blood concentration. In most cases, experimental measurements are only available for a peripheral vein (usually antecubital) whose concentration may differ significantly from both arterial and central vein concentration., Methods: A physiologically based pharmacokinetic (PBPK) model for the tissues drained by the antecubital vein (referred to as "arm") is developed. It is assumed that the "arm" is composed of tissues with identical properties (partition coefficient, blood flow/gm) as the whole body tissues plus a new "tissue" representing skin arteriovenous shunts. The antecubital vein concentration depends on the following parameters: the fraction of "arm" blood flow contributed by muscle, skin, adipose, connective tissue and arteriovenous shunts, and the flow per gram of the arteriovenous shunt. The value of these parameters was investigated using simultaneous experimental measurements of arterial and antecubital concentrations for eight solutes: ethanol, thiopental, 99Tcm-diethylene triamine pentaacetate (DTPA), ketamine, D2O, acetone, methylene chloride and toluene. A new procedure is described that can be used to determine the arterial concentration for an arbitrary solute by deconvolution of the antecubital concentration. These procedures are implemented in PKQuest, a general PBPK program that is freely distributed http://www.pkquest.com., Results: One set of "standard arm" parameters provides an adequate description of the arterial/antecubital vein concentration for ethanol, DTPA, thiopental and ketamine. A significantly different set of "arm" parameters was required to describe the data for D2O, acetone, methylene chloride and toluene - probably because the "arm" is in a different physiological state., Conclusions: Using the set of "standard arm" parameters, the antecubital vein concentration can be used to determine the whole body PBPK model parameters for an arbitrary solute without any additional adjustable parameters. Also, the antecubital vein concentration can be used to estimate the arterial concentration for an arbitrary input for solutes for which no arterial concentration data is available.

Studies of factors affecting the initial disposition of drugs with a rapid onset of effect following i.v. administration have used antipyrine as a surrogate for lipophilic drugs because it lacks cardiovascular effects. The present study tested the assumption that antipyrine is a useful surrogate for the flow-dependent tissue distribution of the lipophilic drug thiopental by comparing the recirculatory pharmacokinetic models of antipyrine and thiopental disposition after concomitant administration to five dogs anesthetized with 1.5% halothane. The pharmacokinetics of indocyanine green, a marker of the intravascular behavior of antipyrine and thiopental, and antipyrine in these dogs was nearly identical to that described previously in dogs anesthetized with 1.5% halothane but not given thiopental. The total volume of distribution of the highly lipophilic drug thiopental was more than 60% larger than that of antipyrine, 53 versus 33 liters, respectively. Nonetheless, the initial distribution kinetics of the two drugs, including the pulmonary tissue volume and the volume of the nondistributive pathway as well as the clearance to it, were nearly identical. As a result, the fraction of cardiac output involved in distribution of the two drugs to peripheral tissues was similarly identical, although the distribution of cardiac output between clearance to the rapidly equilibrating tissues and clearance to the slowly equilibrating tissues differed slightly. This study validates the assumption that antipyrine is a useful surrogate for lipophilic drugs in pharmacokinetic studies in which physiologic stability is desirable to meet the assumption of system stationarity.

The effects of glutathione (GSH) and glutathionesulfonic acid sodium salt [N-(N-gamma-L-glutamyl-L-beta-sulfoalanyl)glycine sodium salt, GSO3Na], which is a minor metabolite of GSH, on the pharmacokinetics of thiopental sodium were investigated in rats. The concomitant use of GSO3Na with thiopental sodium significantly increased the tissue-to-plasma concentration ratio (Kp) of thiopental sodium 60 min after its administration in the heart, lung, brain, liver, kidney, and spleen, while GSH did not affect them. On the other hand, the Kp value of thiopental sodium 5 min after its administration with concomitant GSO3Na decreased significantly only in the spleen. Neither GSO3Na nor GSH changes the pharmacokinetic parameters of thiopental sodium. Significant change of the binding ratio of thiopental sodium to bovine serum albumin (BSA) was not observed by the addition of less than 5-fold GSO3Na. About 50% of thiopental sodium was bound to the brain, lung or liver, however, no significant change of this binding ratio was observed by the concomitant use of GSO3Na. The partition coefficient of thiopental sodium apparently increased by the concomitant use of GSO3Na but not by GSH. This phenomenon seemed to be concerned with a mechanism to increase the Kp values of thiopental sodium in the tissues. The increment in the drug distribution to tissues with concomitant GSO3Na observed in this study is useful information for the application of drug combinations as a biodistribution promoter.

The cerebral and systemic kinetics of intravenous thiopentone (250 mg over 2 minutes, n=5) and propofol (100 mg over 2 minutes, n=6) were determined in sheep anaesthetized with halothane (2.0%) and mechanically ventilated to an end-expired carbon dioxide tension of 40 mmHg. The sheep were previously instrumented with arterial and sagittal sinus (effluent from the brain) blood sampling catheters. Systemic kinetics were inferred from the time-course of the arterial blood concentrations, and cerebral kinetics from the time-course of the arterio-sagittal sinus concentration difference across the brain. Under halothane anaesthesia, the peak arterial concentrations of each drug occurred at the end of the two-minute infusion, and was 42.3 mg/l and 12.3 mg/l for thiopentone and propofol, respectively. Propofol had a significantly larger systemic clearance (3.19 l/min) than thiopentone (0.99 l/min). The brain concentrations of propofol equilibrated more slowly with the arterial concentrations than those of thiopentone. The extraction ratio across the brain near the end of the infusions (1.5 min) were 0.85 and 0.46 respectively. These data were also compared to analogous previously published data for initially conscious sheep. The systemic kinetics of thiopentone were little affected by halothane anaesthesia. For propofol, halothane anaesthesia was associated with a statistically significant reduction in clearance (50% of awake), a slower initial half-life (247% of awake), and the emergence of a second slower half-life in some sheep. The cerebral kinetics of both drugs were subtly altered by halothane anaesthesia.

Background: Thiopental is an anaesthetic drug that is largely used in both short-term and long-term infusion. After long-term infusion of thiopental, non-linear and inter-individual-dependent pharmacokinetics occur because of the saturation and/or induction of the metabolism. Clinical monitoring is important so that therapeutic adjustments can be made in many of the different pharmacological treatments, especially when long-term infusion is required. We describe a new, rapid HPLC method for the determination of plasma thiopental., Methods: Sample preparation involved precipitation of plasma proteins using a mixture of methanol, zinc sulfate and ethylene glycol, and containing the internal standard 5-ethyl-5-p-tolyl-barbituric acid. After adding trichloroacetic acid, the sample was centrifuged and the supernatant was injected into a C(18) reversed-phase column. The mobile phase used was water-methanol-acetonitrile (50:40:10, v/v). The eluent was monitored at 290 nm., Results: The calibration curve was linear from 0.2 to 100 microg/mL. Precision, calculated as the coefficient of variation (%), was in the range of 3.62-0.70% for the within-day assay and 5.77-1.51% for the between-day assay. The absolute recoveries obtained from supplemented samples were never less than 100%., Conclusions: This technique shows good reliability and seems to be suitable for a very fast and simple therapeutic monitoring of plasma thiopental.

Background: Thiopental and propofol are highly lipid-soluble, and their entry into the brain often is assumed to be limited by cerebral blood flow rather than by a diffusion barrier. However, there is little direct experimental evidence for this assumption., Methods: The cerebral kinetics of thiopental and propofol were examined over a range of cerebral blood flows using five and six chronically instrumented sheep, respectively. Using anesthesia (2.0% halothane), three steady state levels of cerebral blood flow (low, medium, and high) were achieved in random order by altering arterial carbon dioxide tension. For each flow state, 250 mg thiopental or 100 mg propofol was infused intravenously over 2 min. To quantify cerebral kinetics, arterial and sagittal sinus blood was sampled rapidly for 20 min from the start of the infusion, and 1.5 h was allowed between consecutive infusions. Various models of cerebral kinetics were examined for their ability to account for the data., Results: The mean baseline cerebral blood flows for the "high" flow state were over threefold greater than those for the low. For the high-flow state the normalized arteriovenous concentration difference across the brain was smaller than for the low-flow state, for both drugs. The data were better described by a model with partial membrane limitation than those with only flow limitation or dispersion., Conclusions: The cerebral kinetics of thiopental and propofol after bolus injection were dependent on cerebral blood flow, despite partial diffusion limitation. Higher flows produce higher peak cerebral concentrations.

Thiopental is a racemate of equimolar R- and S-thiopental enantiomers that have different potencies in laboratory experiments. We measured concentrations of R- and S-thiopental in plasma, tissues and brain microdialysate of rats after computer-controlled infusion of thiopental i.v. to a plasma concentration of 40 micrograms ml-1 for 20 min in two pharmacokinetic studies. In study 1, animals were found to maintain their target plasma concentrations, which then decayed biphasically after infusion. Brain microdialysate concentrations of both enantiomers increased from about 3% of corresponding plasma concentrations at 1 min to 9% at 20 min. In study 2, thiopental concentrations were found to be highest at 20 min in CNS tissue, at 30 min in muscle and at 60 min in fat. Tissue:plasma distribution coefficients of R-thiopental were greater than those of S-thiopental when calculated from total or unbound plasma concentrations. We found no pharmacokinetic evidence to support differences between the thiopental enantiomers in rates of equilibration across the blood-brain barrier after infusion of rac-thiopental.

Effective plasma concentrations of propofol, thiopentone and ketamine were determined at different endpoints in a study with randomized, crossover design in nine New Zealand White rabbits. A continuous infusion was used (30 ml/h) with concentrations of 10 mg/ml for propofol, 25 mg/ml for thiopentone and 20 mg/ml for ketamine. The endpoints were loss of the righting reflex, loss of purposeful reactions to tail clamping (as an example of a peripheral pain stimulus) or to intranostril insufflation of ammonia vapour (as an example of a central reflex stimulus), and the recovery of these reflexes and reactions. According to the ED50 values the potency ratios of propofol, thiopentone and ketamine were at the loss of righting reflex 1:1.8:1.2, at the loss of reaction to ammonia vapour 1:1.5:1.6, and at the loss of reaction to tail clamping 1:1.5:3.9, respectively. Recovery was significantly faster after propofol than after thiopentone and ketamine. Measuring the effective plasma concentrations of intravenous anaesthetics provides a method of relating dose to effect, but there still remains a variable gap between plasma concentration and effect.

Bullfrogs (Rana catesbeiana) anesthetized with a large dose of thiopental (42.8 mg/kg) retained movement responses to nociceptor stimuli despite an average plasma drug level of 51 mg/l, of which 63% was bound to plasma proteins. This concentration, when corrected to include only unbound and uncharged drug, was 2-fold greater than those reported to abolish nociceptor response (NR) during surgical anesthesia in man. The median anesthetic dose (AD50) for loss of the righting reflex was 11.2 mg/kg by s.c. injection into the abdominal lymph sac; however, at 54.0 mg/kg, all frogs retained NRs, although otherwise deeply anesthetized. The ratio of NR-blocking dose to light AD was thus > 4.8, as compared to < 2 in mammalian studies. Whole body levels of thiopental determined at 3 h after intralymphatic injection showed that about half the injected drug had been eliminated by this time and that termination of anesthesia was chiefly due to drug elimination. Even though the pharmacokinetics of thiopental appears to differ markedly in frogs and men, the poor analgesia seen in the present study frequently has been reported during clinical barbiturate anesthesia. Since this deficiency is much more pronounced in the bullfrog than in man, its neurophysiological basis might profitably be studied using the bullfrog as a model; however, the high mortality associated with deep thiopental anesthesia in the frog should preclude its use as a practical anesthetic in amphibia.

1. To better understand the pharmacology of the thiopentone enantiomers, we studied their quantitative electroencephalographic effects and their distribution into vital tissues. 2. Adult Wistar rats were infused with rac-, R- or S-thiopentone at 4 mg kg(-1)min(-1) until death ensued. The EEG signal was acquired continuously; serial arterial plasma and terminal tissue thiopentone concentrations were measured enantiospecifically. Relevant drug tissue : plasma distribution coefficients and plasma concentration-EEG effect relationships were determined. 3. Doses (mg kg(-1)) (mean+/-s.e.mean) for anaesthesia (toe pinch) and lethality (respiratory failure), respectively, decreased in the order R-thiopentone (55.8+/-2.4 and 176.2+/-11.2)> rac-thiopentone (39.3+/-2.1 and 97.5+/-3.9)> S-thiopentone (35.6+/-1.9 and 74.2+/-5.2); plasma drug concentrations (microg ml(-1)) decreased in the order R-thiopentone (66.3+/-4.5 and 89.8+/-5.2)> rac-thiopentone (56.7+/-2.0 and 77. 8+/-2.8)> S-thiopentone (55.0+/-1.9 and 64.1+/-2.8). 4. Initial EEG activation was similar for all thiopentone forms. Plasma drug concentrations for the same extent of EEG deactivation reflected the potency order. 5. After infusion of rac-thiopentone, tissue : plasma distribution coefficients were higher for R- than for S-thiopentone in brain and visceral regions, but not in fat or muscle. After infusion of the separate enantiomers, the relative heart : brain distribution ratio was for S-thiopentone was double that for R-thiopentone. 6. The therapeutic index of R-thiopentone (3.16+/-0. 14) was more advantageous than either rac-thiopentone (2.52+/-0.13) or S-thiopentone (2.10+/-0.14), possibly due to the relatively greater distribution into CNS tissues than heart. The data suggest that R-thiopentone could make a satisfactory single enantiomer substitute for rac-thiopentone.

A gas chromatographic-mass spectrometric (GC-MS) assay for the determination of thiopental and its main metabolite pentobarbital in human plasma is presented in this study. The sample preparation consists only in the addition of the internal standard barbital and an acidic extraction with ethyl acetate. Analytical separation is accomplished on a RTX-1 15 m x 0.25 mm capillary column with a film thickness of 0.5 micron. The effluent is observed by a mass selective detector operating in the single ion monitoring mode. The limits of detection are 5 ng/ml for pentobarbital and 10 ng/ml for thiopental, the intra-day variabilities are 2.2% and 4.0% and the inter-day variabilities are 3.3% and 7.1% at concentrations of 5 micrograms/ml, respectively. Applying this assay, the stability of thiopental and pentobarbital in human plasma was tested at concentrations of 5 micrograms/ml each. Thiopental is stable in human plasma at least over 41 days stored at -20 degrees C and 5 degrees C, respectively. A decay of about 2%/day is observed under storage at ambient temperature (19-20 degrees C). Pentobarbital is stable under all storage conditions. Methanolic solutions of thiopental are stable for 83 days under storage at 5 degrees C. Aqueous solutions of thiopental-sodium are stable for at least 23 days under storage at 5 degrees C or ambient temperature.

Using capillary zone electrophoresis (CZE) with a 75 mM phosphate buffer at pH 8.5 containing 5 mM hydroxypropyl-gamma-cyclodextrin (OHP-gamma-CD) as chiral selector, the separation of the enantiomers of thiopental and its oxybarbiturate metabolite, pentobarbital, is reported. Enantiomer assignment was performed via preparation of enantiomerically enriched fractions using chiral recycling isotachophoresis (rITP) processing of racemic barbiturates and analysis of rITP fractions by chiral CZE and circular dichroism spectroscopy. Thiopental and pentobarbital enantiomers in plasma were extracted at low pH using dichloromethane and extracts were reconstituted in acetonitrile or 10-fold diluted, achiral running buffer. The stereoselectivity of the thiopental and pentobarbital metabolism was assessed via analysis of 12 plasma samples that stemmed from patients undergoing prolonged or having completed long-term racemic thiopental infusion. The data obtained revealed a modest stereoselectivity with R-(+)-thiopental/S-(-)-thiopental and R-(+)-pentobarbital/S-(-)-pentobarbital plasma ratios being < 1 (P < 0.05 compared to data obtained with racemic controls) and > 1 (P < 0.001), respectively. The total S-(-)-thiopental plasma concentration was found to be on average about 24% higher compared to the concentration of R-(+)-thiopental, whereas the total R-(+)-pentobarbital plasma level was observed to be on average 29% higher compared to the S-(-)-pentobarbital concentration.

Barbiturate coma is initiated in brain-injured patients whenever elevated intracranial pressure remains unresponsive to other therapeutical strategies. However, barbiturates alter cortical activity resulting in difficulties in clinical evaluation. Therefore, we investigated the impact of long-term thiopental administration on responsiveness to exteroceptive stimuli in relation to pharmacokinetics of thiopental in CSF and serum. Long-term infusion increases thiopental levels which remain elevated for 6 and 9 days in CSF and serum, respectively, after termination of its administration. Prolonged unresponsiveness to exteroceptive stimuli correlates with persisting thiopental in CSF and serum. Thus, quantitative analysis of thiopental in serum becomes indispensable in predicting the length of drug-induced neurological impairment and in avoiding misinterpretation of the neurological status.

Four commonly used barbiturates (phenobarbital, butalbital, pentobarbital and thiopental) were analyzed in human serum using supercritical fluid extraction (SFE) and negative ionization LC/ESI-MS/MS. Barbital was used as the internal standard. Carbon dioxide SFE was performed at 40 degrees C and 500 atm, with a total extraction time of 35 min. The analytes were collected off-line in a liquid trap containing absolute methanol. Samples were then concentrated by vacuum centrifugation. The high performance liquid chromatography separation utilized gradient elution with a total analysis time of 21 min. The precursor and major product ions for the four barbiturates were monitored on a triple quadrupole mass spectrometer with negative ion electrospray ionization (ESI) in the multiple reaction monitoring mode as follows: (1) thiopental (m/z 241.20-->58.00), (2) phenobarbital (m/z 231.10-->188.0), (3) pentobarbital (m/z 225.10-->181.90) and (4) butalbital (m/z 222.80-->179.90). In the case of phenobarbital, pentobarbital and butalbital, the most abundant product ion arises from the loss of 43 u (HCNO loss). However, in the case of thiopental, the most abundant product ion was observed at m/z 58.0 (the [M-183]-ion, or NCS-). Mechanisms for the formation of the collision induced dissociation reaction products of these barbiturates are proposed.

The electroencephalographic (EEG) effects of thiopentone have been used extensively in the pharmacodynamic and pharmacokinetic modelling of drug effects in the central nervous system (CNS). Thiopentone has a biphasic (enhancement followed by inhibition) effect on nocifensive reflexes that occurs in a dose range similar to that which activates the EEG. In this study we have used rats chronically instrumented with hippocampal EEG (hEEG) electrodes to simultaneously characterize the effects of thiopentone on the hEEG and nocifensive reflex thresholds. Enhancement of these two measures of CNS effect correlated well with plasma thiopentone concentrations of 10-30 micrograms ml-1 (35-75 mumol litre-1) but maximal reflex enhancement occurred at concentrations of 3 micrograms ml-1 (11 mumol litre-1) less than the peak hEEG effect. The results validate the usefulness of nocifensive reflex thresholds for measurement of the CNS effects of thiopentone at subanaesthetic concentrations.

Purpose: To characterize the pharmacodynamic relationships between plasma pentobarbitone and thiopentone concentrations and nocifensive reflexes during emergence from anaesthesia., Methods: Forty-nine rats were studied. Plasma barbiturate concentrations were measured with high performance liquid chromatography. Nocifensive reflexes were assessed with the hindlimb withdrawal latency (WL) to heat and the somatic motor response threshold (SMRT) to tail pressure. In Protocol I, SMRT, WL, sedation, and the presence of paw-licking and the righting reflex were assessed in unrestrained rats before and every 10 min for two hours after an intraperitoneal injection of pentobarbitone (30 mg.kg-1). Plasma pentobarbitone kinetics were determined in a separate group of rats. In Protocol II, SMRT and drug concentrations were measured concurrently in partially restrained animals before and for 35 min after a computer-controlled i.v. bolus of thiopentone. In Protocol III the SMRT-plasma thiopentone relationship was determined during increasing and decreasing plasma thiopentone concentrations., Results: Enhancement of both nocifensive reflexes was observed in the unrestrained animals. Enhancement of SMRT was maximal [175% (153-197) of control values] at a mean plasma thiopentone concentration of 11 (9-13) micrograms.ml-1. The SMRT-plasma thiopentone curve showed a mean efflux-influx difference in plasma thiopentone concentration of 4(2.3-5.7) micrograms.ml-1., Conclusions: Barbiturate-associated nocifensive reflex enhancement occurs in unrestrained animals with both thermal and pressure stimuli. The SMRT-plasma thiopentone concentration relationship during emergence from anaesthesia was similar to that observed previously during induction. The thiopentone plasma concentration-SMRT plot showed an equilibrium delay similar to that previously described by others for thiopentone at an electroencephalographic effect site.

A simple assay method for the measurement of thiopental by reversed-phase high-performance liquid chromatography (HPLC) with ultraviolet absorbance detection was developed. The method involved a protein precipitation with methanol. Carbamazepine was used as internal standard. The mobile phase was acetonitrile-water (32:62, v/v). The elution was isocratic and the column temperature was ambient. Linear detection response was obtained for concentrations ranging from 1-100 microg ml(-1). Recovery from plasma averaged 88%. Precision, expressed as coefficient of variation (%), was in the range of 0.2-8%. Percent recovery was at least 93%. Stability studies showed that plasma samples should be processed as promptly as possible. This method has been used in therapeutic monitoring and for the determination of pharmacokinetic parameters of thiopental in patients treated with a high dose over a long time to decrease intracranial pressure.

We studied the performance of a target-controlled drug infusion device, computer-assisted continuous infusion (CACI). Forty-one volunteers received one of midazolam (n = 11), propofol (n = 10), thiopental (n = 10), or fentanyl (n = 10) in sedative concentrations. Concentrations were kept constant for 45-70 min at five sequential target concentrations in each subject. Twenty-six subjects had arterial sampling and 15 had venous sampling to determine drug concentrations. Median performance errors, median absolute performance error (MDAPE), wobble, divergence, and median absolute constancy error (MDACE), defined as error around mean actual concentration at each target, were calculated. CACI demonstrated significant performance errors, which were different among drugs. MDAPE (5%-95% confidence interval) ranged from 22.9% (12.1%-39.6%) for propofol to 82.2% (36.0%-183.0%) for midazolam. Although performance errors could be large, CACI was able to maintain a constant serum concentration over time very successfully. The MDACE ranged from 5.6% (3.9%-17.3%) for fentanyl to 11.2% (8.9%-20.4%) for propofol. Few differences occurred between arterial and venous sampling, although when they occurred, arterial samples indicated larger errors. It is concluded that CACI is very successful at maintaining constant serum concentrations of these drugs at sedative concentrations. Arterial sampling should be used when the performance characteristics of an infusion device are being tested. However, venous sampling may be adequate to determine serum concentrations when a pseudo-steady state has been achieved.

Aims: Thiopentone is administered as a racemate (rac-thiopentone) for induction of anaesthesia as well as for neurological and neurosurgical emergencies. The pharmacokinetics and pharmacodynamics of rac-thiopentone have been extensively studied but the component R-(+)- and S-(-)- enantiomers, until very recently, have been largely ignored., Methods: The present study analyses the pharmacokinetics of R-(+)- and S-(-)-thiopentone in 12 patients given rac-thiopentone intravenously for induction of anaesthesia and five patients given a prolonged infusion of rac-thiopentone used for treatment of intracranial hypertension., Results: The mean total body clearance (CLT) and apparent volume of distribution at steady-state (Vss) showed trends towards higher values for R-(+)- than for S-(-)-thiopentone in both patient groups; CLT and Vss of unbound fractions of R-(+)- and S-(-)-thiopentone, however, did not show these trends. The time courses of R-(+)- and S-(-)- thiopentone serum concentrations were so similar that EEG effect could not be attributed to one or other enantiomer. Serum protein binding for S-(-)-thiopentone was greater than for R-(+)-thiopentone (P = 0.02) and 24 h urinary excretion of R-(+)-thiopentone was greater than for S-(-)-thiopentone (P = 0.03). In one patient, concomitant measurement of CSF and serum thiopentone concentrations found that serum: CSF equilibration of unbound fractions of both enantiomers was essentially complete., Conclusions: The study was unable to determine any pharmacokinetic difference of clinical significance between the R-(+)- and S-(-)-thiopentone enantiomers and concludes that minor differences in CLT and Vss could be explained by enantioselective difference found in serum protein binding.

This study was conducted on 10 pediatric patients in whom intracranial hypertension stemming from head injury was reduced by high-dose thiopental administered for a prolonged period. All children showed a favorable recovery of their neurological functions. The total dose normalized to body weight averaged 335 +/- 135 mg/kg, and the mean treatment duration was 93.0 +/- 37.1 h. Data analysis was modeled for each patient to cover all the doses on the whole plasma thiopental concentration-time curve, according to a one-compartment open model. A better fit was obtained using a linear model rather than a Michaelis-Menten elimination model. Model selection was guided by evaluation of the minimum objective function, the weighted residuals, and the Akaike criterion. Thiopental pharmacokinetic parameters in pediatric patients were compared with those determined in an adult control group with similar total doses and durations of treatment. No significant difference was found between the two groups in spite of a 33% decrease of the elimination half-life in children (11.7 +/- 5.7 h) compared with adults (17.5 +/- 9.03 h). The mean values obtained were 2.42 and 2.19 ml/min/kg for total clearance and 2.18 and 2.90 L/kg for Vd in pediatric and adult groups, respectively. The linear regression of pharmacokinetic parameters in terms of age was not significant. When high doses of thiopental were administered over a prolonged period, the pharmacokinetic parameters computed for pediatric patients did not differ from those obtained in adults.

We studied 88 healthy, ASA I patients (aged 20-45 yr), to determine if nitrous oxide affects thiopentone requirements for achieving 50% probability of no movement in response to verbal commands (CP,50). Patients were allocated randomly to one of four nitrous oxide concentration groups (0%, 20%, 40% and 60%). Patients in each group were also allocated randomly to receive predetermined target plasma concentrations of thiopentone. Computer-controlled continuous infusion was used to maintain the target plasma thiopentone concentration, and this concentration was held constant for 6 min to ensure equilibration. The CP,50, value of thiopentone in the absence of nitrous oxide was 14.8 micrograms ml-1. The reduction in CP,50 by nitrous oxide was non-linear, and the interaction coefficient between nitrous oxide and thiopentone was significantly smaller than zero (P = 0.0274), indicating that nitrous oxide antagonized the ability of thiopentone to prevent response to verbal commands.

Drug therapy is usually optimized by concentration measurement in patient serum. High-performance liquid chromatography (HPLC) is one of the most important analytical techniques used for therapeutic drug monitoring (TDM) of drugs for which no immunoassay kits are available. HPLC has been frequently used for screening purposes in toxicology, too. The Merck Tox Screening System (MTSS) has been developed for the identification of substances by a combination of gradient HPLC with diode-array detection and identification with a database system. For routine TDM an isocratic HPLC system is more suitable because of shorter analysis time, better reproducibility of retention index and better precision of results. Therefore we defined a set of methods in steps of 10% of the two MTSS eluents. Three examples are shown: Amiodarone, Indometacine and Thiopental. New applications to test for other substances can be transferred to an isocratic system after a complete MTSS gradient run.

Background: In contrast to that of inhalational anesthetics, quantitation of anesthetic depth for intravenous agents has not been well defined. In this study, using rodents, the relationship between the constant plasma thiopental concentrations and the clinical response to multiple nociceptive stimuli were investigated characterizing the anesthetic state from light sedation to deep anesthesia and correlated to the degree of electroencephalogram (EEG) drug effect., Methods: Thirty rats were instrumented with chronically implanted EEG electrodes, arterial and venous catheters. A computer-driven infusion pump was used to rapidly attain and then maintain constant, target plasma thiopental concentrations ranging from 7 to 100 micrograms/ml. Three different target plasma thiopental concentrations were achieved in each rat. Electroencephalographic effects were monitored with aperiodic waveform analysis. The following nociceptive stimuli were applied: (1) unprovoked righting reflex, (2) provoked righting reflex, (3) noise stimulus, (4) tail clamping with an alligator clip, (5) constant tail pressure with an analgesiameter, (6) corneal reflex, and (7) tracheal intubation. For tail clamping, tail pressure, and intubation, either purposeful extremity movement or abdominal muscle contraction response was noted to be present or absent. The clinical responses (present or absent) were modeled using logistic regression to estimate the Cp50, the plasma thiopental concentration with a 50% probability of no response., Results: The following mean Cp50 values (95% confidence interval) were obtained: unprovoked righting reflex, 15.9 (15.1-16.6) micrograms/ml; provoked righting reflex, 21.4 (20.2-22.7) micrograms/ml; noise stimuli, 31.3 (29.7-33.0) micrograms/ml; tail clamp and limb movement, 38.3 (36.1-40.4) micrograms/ml; tail pressure and limb movement, 39.2 (37.1-41.3) micrograms/ml; tail pressure and abdominal muscle contraction, 52.5 (50.0- 55) micrograms/ml; tail clamping and abdominal muscle contraction, 56.1 (50.0-56.2) micrograms/ml; corneal reflex, 60.0 (56.6-63.4) micrograms/ml; and limb movement or muscle abdominal contraction response to intubation, 67.7 (59.2-76.1) micrograms/ml. At an EEG-effect of 9.1 and 2.2 waves/s, there was a 50% chance of limb movement response to tail clamping and tracheal intubation, respectively. There was a poor relationship between the plasma thiopental concentration and the percent increase of either heart rate or mean arterial blood pressure after applying either tail pressure or tail clamp stimuli., Conclusions: A range of nociceptive stimuli and their observed clinical responses can be used to quantitate thiopental anesthetic depth, ranging from light sedation to deep anesthesia (isoelectric EEG and unresponsive to intubation) in the rodent. Clinical response can be mapped to surrogate EEG measures.

A method for the determination of R-(+)- and (S)-(-)-isomers of thiopentone in plasma was developed. Following liquid-liquid extraction, the separation of enantiomers of thiopentone and the internal standard (racemic ketamine) was achieved by high-performance liquid chromatography on an alpha1-acid glycoprotein (AGP) column with ultraviolet detection at 280 nm. The mobile phase consisted of 20 mM KH2PO4 buffer-2-propanol-methanol (93.5:5.0:1.5) at pH 5.0. The flow-rate was 0.9 ml/min. The limit of quantification for each isomer was approximately 10 ng/ml. The assay is suitable for pharmacokinetic studies of (R)-(+)- and (S)-(-)-isomers of thiopentone, following usual bolus intravenous clinical doses of the racemic drug.

An HPLC method was developed to determine the plasma concentrations of R(+)- and S(-)-thiopentone for pharmacokinetic studies in sheep. The method required separation of the thiopentone enantiomers from the corresponding pentobarbitone enantiomers which are usually present as metabolites of thiopentone. Phenylbutazone was used as an internal standard. After acidification, the plasma sample were extracted with a mixture of ether and hexane (2:8). The solvent was evaporated to dryness and the residues were reconstituted with sodium hydroxide solution (pH 10). The samples were chromatographed on a 100 mm x 4 mm I.D. Chiral AGP-CSP column. The mobile phase was 4.5% 2-propanol in 0.1 M phosphate buffer (pH 6.2) with a flow-rate of 0.9 ml/min. This gave k' values of 1.92, 2.92, 5.71, 9.30 and 11.98 for R(+)-pentobarbitone, S(-)-pentobarbitone, R(+)-thiopentone, S(-)-thiopentone, and phenylbutazone, respectively. At detection wavelength of 287 nm, the limit of quantitation was 5 ng/ml for R(+)-thiopentone and 6 ng/ml for S(-)-thiopentone. The inter-day coefficients of variation at concentrations of 0.02, 0.1 and 8 micrograms/ml were, respectively, 4.8, 4.4 and 3.5% for R(+)-thiopentone and, respectively, 5.0, 4.3 and 3.9% for S(-)-thiopentone (n = 6 each enantiomer). At the same concentrations, the intra-day coefficients of variation from six sets of replicates (measured over six days) were, respectively, 8.0, 8.0 and 8.8% for R(+)-thiopentone and 8.8, 7.4 and 9.6% for S(-)-thiopentone. Linearity over the standard range, 0.01-40 micrograms/ml, was shown by correlation coefficients > 0.998. This method has proven suitable for pharmacokinetic studies of thiopentone enantiomers after administration of rac-thiopentone in human plasma also and would be suitable for pharmacokinetic studies of the pentobarbitone enantiomers.

We studied 30 children undergoing circumcision randomly allocated to receive either thiopentone 4 mg.kg-1, propofol 2.5 mg.kg-1 or midazolam 0.5 mg.kg-1 (n = 10) IV over 30 seconds at induction of anaesthesia. Blood pressure and pulse rate during the first 15 minutes of induction were recorded by a Finapres 2300e and a Cardiocap CM-104, and changes from preinduction baseline compared between the three induction agents and the two recording instruments. Postoperatively, blood levels of the induction agents were measured and recovery from anaesthesia was assessed by clinical criteria, mood and sedation scores and psychomotor performance. The Cardiocap data revealed no statistically significant haemodynamic differences between the three induction agents. Finapres data demonstrated that propofol caused a greater decrease in mean arterial pressure when compared to thiopentone at one minute (P = 0.01) and the MAP remained significantly lower than midazolam at five minutes (P = 0.02), illustrating an advantage of continuous over intermittent non-invasive blood pressure monitoring. The midazolam group took longer to identify themselves compared to both the propofol (P = 0.005) and the thiopentone groups (P = 0.02), but there was no difference in the groups in time to eye-opening. Psychomotor performance on awakening was significantly worse in the midazolam group compared to the propofol (P < 0.03) and thiopentone groups (P < 0.02). Most children had recovered to 80% of their best, practised, unmedicated, preoperative performance four hours after awakening, irrespective of the induction agent administered. Drug blood levels correlated weakly with both methods of psychomotor assessment (r > or = 0.6). Of the three induction agents, thiopentone caused the least haemodynamic perturbation on induction, and anaesthesia induced with midazolam caused the greatest psychomotor impairment on awakening. Within one hour patients in all drug groups were equally awake, co-operative and co-ordinated.

The pharmacokinetics of thiopentone sodium administered intravenously as a single dose (11 mg/kg) were studied in acepromazine pre-medicated horses and ponies in which anaesthesia was maintained with either halothane (Group 1) or isoflurane (Group 2). The results showed that the disposition kinetics of thiopentone in horses and ponies were best described by a three-compartment open model. In plasma, a very short initial distribution phase in both horses and ponies, half-life 1.4 +/- 1.2 min (mean +/- SD) and 1.3 +/- 0.7 min, respectively, was obtained, which was followed by a second comparatively slower redistribution phase, half-life 16 +/- 12 min and 11 +/- 5 min, respectively. The volume of distribution for the drug was large, especially in the ponies which received isoflurane (1127 +/- 86 ml/kg), compared to the horses which received halothane (742 +/- 89 ml/kg). The drug had a somewhat shorter elimination half-life in the horses (147 +/- 21 min) than in than ponies (222 +/- 44 min), but no obvious difference in clearance of the drug was observed between the horses (3.5 +/- 0.5 ml/min/kg) and ponies (3.6 +/- 0.8 ml/min/kg).

Physiologically based pharmacokinetic modeling procedures employ anatomical tissue weight, blood flow, and steady tissue/blood partition data, often obtained from different sources, to construct a system of differential equations that predict blood and tissue concentrations. Because the system of equations and the number of variables optimized is considerable, physiologic modeling frequently remains a simulation activity where fits to the data are adjusted by eye rather than with a computer-driven optimization algorithm. We propose a new approach to physiological modeling in which we characterize drug disposition in each tissue separately using constrained numerical deconvolution. This technique takes advantage of the fact that the drug concentration time course, CT(t), in a given tissue can be described as the convolution of an input function with the unit disposition function (UDFT) of the drug in the tissue, (i.e., CT(t) = (Ca(t)QT)*UDFT(t) where Ca(t) is the arterial concentration, Q tau is the tissue blood flow and * is the convolution operator). The obtained tissue until disposition function (UDF) for each tissue describes the theoretical disposition of a unit amount of drug infected into the tissue in the absence of recirculation. From the UDF, a parametric model for the intratissue disposition of each tissue can be postulated. Using as input the product of arterial concentration and blood flow, this submodel is fit separately utilizing standard nonlinear regression programs. In a separate step, the entire body is characterized by reassembly of the individuals submodels. Unlike classical physiologic modeling the fit for a given tissue is not dependent on the estimates obtained for other tissues in the model. Additionally, because this method permits examination of individual UDFs, appropriate submodel selection is driven by relevant information. This paper reports our experience with a piecewise modeling approach for thiopental disposition in the rat.

The reversible effect of an induction dose of thiopental on the cerebral blood flow (CBF) was characterized by repeated 133Xe washout measurements during stable physiological conditions in anaesthetized pigs. A thiopental effect corresponding to induction of light and transient anaesthesia was confirmed by electroencephalography (EEG). The concentration (arterial plasma) -effect (-% CBF) relationship of thiopental was estimated using a sigmoidal Emax model. The injection caused a rapid 36 +/- 4.5% (mean +/- s.d.) drop in CBF, with return to baseline by 80 min. According to the pharmacodynamic model, the maximal effect of thiopental (Emax) in this experimental set-up was a 58% lowering of the CBF and the concentration at half-maximal effect (EC50) was 25 micrograms.ml-1. This study provides a complete characterization of the effect of thiopental on the CBF, including the time-course and concentration-effect relationship. A comparison to limited data in the literature suggests that the findings in the pigs constitute a fair approximation of the action of thiopental during the clinical induction of anaesthesia.

Background: alpha 2-Adrenergic agonists such as dexmedetomidine can be used to reduce the dose requirement of intravenous and volatile anesthetics. Whereas dexmedetomidine and volatile anesthetics interact pharmacodynamically (reduction of MAC), the mechanism of interaction between dexmedetomidine and intravenous anesthetics is not known., Methods: Fourteen male ASA physical status 1 patients were randomly assigned to serve as control subjects (n = 7) or to be treated with dexmedetomidine (n = 7; 100, 30, and 6 ng.kg-1.min-1 for 10 min, 15 min, and thereafter, respectively). After 35 min, in all patients, thiopental (100 mg/min) was infused until burst suppression appeared in the raw tracing of the electroencephalogram. By using concentrations of thiopental in plasma and the electroencephalogram as a continuous pharmacologic effect measure, the apparent effect site concentrations for thiopental were estimated in both groups. Three-compartment pharmacokinetics were calculated for thiopental., Results: Dexmedetomidine reduced the thiopental dose requirement for electroencephalographic burst suppression by 30%. There was no difference in estimated thiopental effect site concentrations between dexmedetomidine and control patients, suggesting the absence of a major pharmacodynamic interaction. Dexmedetomidine significantly decreased distribution volumes (V2, V3, and Vdss) and distribution clearances (Cl12 and Cl13) of thiopental., Conclusions: The thiopental dose-sparing effect of dexmedetomidine on the electroencephalogram is not the result of a pharmacodynamic interaction but rather can be explained by a dexmedetomidine-induced decrease in thiopental distribution volume and distribution clearances. Dexmedetomidine reduces thiopental distribution, most probably by decreasing cardiac output and regional blood flow.