Radiofrequency ablation versus surgical resection for the treatment of oligometastatic lung disease.

PURPOSE: The purpose of this study was to compare efficacy and tolerance between radiofrequency ablation (RFA) and surgery for the treatment of oligometastatic lung disease. MATERIALS AND METHODS: This retrospective study reviewed patients treated in two institutions for up to 5 pulmonary metastases with a maximal diameter of 4cm and without associated pleural involvement or thoracic lymphadenopathy. Patient demographics, tumor characteristics, treatment outcome, and length of hospital stay were compared between the two groups. Efficacy endpoints were overall survival (OS), progression-free survival (PFS) and pulmonary or local tumor progression rates. RESULTS: Among 204 patients identified, 78 patients (42 men, 36 women; mean age, 53.3±14.9 [SD]; age range: 15-81 years) were treated surgically, while 126 patients (59 men, 67 women; mean age, 62.2±10.8 [SD]; age range: 33-80 years) were treated by RFA. In the RFA cohort, patients were significantly older (P<0.0001), with more extra-thoracic localisation (P=0.015) and bilateral tumour burden (P=0.0014). In comparison between surgery and RFA cohorts, respectively, the 1- and 3-year OS were 94.8 and 67.2% vs. 94 and 72.1% (P=0.46), the 1- and 3-year PFS were 49.4% and 26.1% vs. 38.9% and 14.8% (P=0.12), the pulmonary progression rates were 39.1% and 56% vs. 41.2% and 65.3% (P>0.99), and the local tumour progression rates were 5.4% and 10.6% vs. 4.8% and 18.6% (P=0.07). Tumour size>2cm was associated with a significantly higher local tumor progression in the RFA group (P=0.010). Hospitalisation stay was significantly shorter in the RFA group (median of 3 days; IQR=2 days; range: 2-12 days) than in the surgery group (median of 9 days; IQR=2 days; range: 6-21 days) (P<0.01). CONCLUSION: RFA should be considered a minimally-invasive alternative with similar OS and PFS to surgery in the treatment of solitary or multiple lung metastases measuring less than 4cm in diameter without associated pleural involvement or thoracic lymphadenopathy.

Studies on the pharmacokinetics of cisatracurium in anesthetized dogs: in vitro-in vivo correlations.

Cisatracurium undergoes primarily temperature and pH-dependent Hofmann elimination in humans. This study was conducted to describe the pharmacokinetics of cisatracurium in anesthetized dogs and determine whether its in vitro degradation rate in plasma is predictive of its in vivo elimination rate, as this is the case in humans. Nine dogs were anesthetized with pentobarbital and administered different bolus doses of cisatracurium in a randomized cross-over design. Arterial blood was collected at frequent intervals after each bolus injection. In vitro degradation rate (k(in vitro)) of cisatracurium was determined in each dog blank plasma. Plasma concentrations were determined by HPLC. Pharmacokinetic analyses were performed using two compartmental models assuming central or both central and peripheral elimination. Mean in vivo terminal elimination rate of cisatracurium (16.4 +/- 2.7 min) was twofold faster than mean in vitro degradation rate (32.9 +/- 3.7 min) in our dogs. Organ clearance was 6.12 +/- 1.69 mL/min.kg and accounted for 56 +/- 12% of the total body clearance. Apparent volume of distribution, an exit site-dependent parameter, averaged 212 or 184 mL/kg whether or not peripheral elimination was accounted for in the model. The in vitro rate of degradation in plasma is not of predictive value for the in vivo elimination rate of cisatracurium in anesthetized dogs. Organ clearance plays a more important role in the elimination of cisatracurium in dogs than in humans. Increased biliary excretion and/or presence of renal secretion are potential mechanisms that need to be explored.

Dose-dependency of pharmacokinetic/pharmacodynamic parameters after intravenous bolus doses of cisatracurium.

BACKGROUND: Pharmacokinetic/pharmacodynamic (PK/PD) parameters of neuromuscular blocking agents (NMBAs) are generally assumed to be dose-independent. To our knowledge, there are very few clinical reports where the PK/PD parameters of a NMBA were derived separately for each dose group during a formal dose-ranging study. The primary objective of this study was to challenge a potential dose-dependency of cisatracurium PK/PD parameters by conducting a well-controlled experimental study. METHODS: Eight dogs were anaesthetized with pentobarbital and mechanically ventilated. Two doses of cisatracurium (1.5xED(95) and 6xED(95)) were administered in a randomized cross-over design after an appropriate washout period. Neuromuscular function was monitored using train-of-four (TOF) stimulation. Arterial blood was sampled continuously for the first minute after cisatracurium injection and at frequent intervals thereafter. Cisatracurium plasma concentrations were determined by high performance liquid chromatography analysis. PK/PD modelling of individual data sets was performed with NONMEM using a non-parametric approach and a descriptive sigmoid E(max) model. RESULTS: Cisatracurium PKs were linear over the dose range studied. Using non-parametric PK/PD analysis, mean values for plasma-effect compartment equilibration delay (k(e0)) were 0.0600 vs 0.1278 min(-1) (P<0.05) and sensitivity (EC(50)) were 323 vs 235 ng ml(-1) (P<0.05) for the high and low doses, respectively. CONCLUSIONS: A dose-dependent effect on the PK/PD parameters of cisatracurium has important clinical implications as an accurate estimate of the EC(50) is desirable. PK/PD parameters derived after intubating bolus doses of cisatracurium would be more reliable.

Impact of peripheral elimination on the concentration-effect relationship of remifentanil in anaesthetized dogs.

BACKGROUND: This study elucidates the impact of sampling site when estimating pharmacokinetic-pharmacodynamic (PK-PD) parameters of drugs such as remifentanil that undergo tissue extraction in the biophase. The interrelationship between the concentrations of remifentanil predicted for the effect compartment and those measured in arterial, venous, and cerebrospinal fluid were investigated under steady-state conditions. METHODS: Following induction of anaesthesia with pentobarbital, an arterial cannula (femoral) and two venous catheters (jugular and femoral) were inserted. Electrodes were placed for EEG recording of theta wave activity. Each dog received two consecutive 5-min infusions for the PK-PD study and a bolus followed by a 60-min infusion was started for the steady-state study. Cerebrospinal fluid, arterial and venous blood samples were drawn simultaneously after 30, 40, and 50 min. At the end of the infusion, arterial blood samples were collected for pharmacokinetic analysis. RESULTS: Remifentanil PK-PD parameters based on theta wave activity were as follows: apparent volume of distribution at steady-state (V(ss)) (231+/-37 ml kg(-1)), total body clearance (Cl) (63+/-16 ml min(-1) kg(-1)), terminal elimination half-life (t(1/2 beta)) (7.71 min), effect compartment concentration at 50% of maximal observed effect (EC(50)) (21+/-13 ng ml(-1)), and equilibration rate constant between plasma and effect compartment (k(e0)) (0.48+/-0.24 min). The mean steady-state cerebrospinal fluid concentration of 236 ng ml(-1) represented 52 and 74% of that in arterial and venous blood, respectively. CONCLUSIONS: Our study re-emphasizes the importance of a sampling site when performing PK-PD modelling for drugs undergoing elimination from the effect compartment. For a drug undergoing tissue elimination such as remifentanil, venous rather than arterial concentrations will reflect more exactly the effect compartment concentrations, under steady-state conditions.

Interstitial muscle concentrations of rocuronium under steady-state conditions in anaesthetized dogs: actual versus predicted values.

INTRODUCTION: The objective of this study was to compare rocuronium effect (C(e)) and peripheral (C(2)) compartment concentrations predicted by pharmacokinetic-pharmacodynamic (PK-PD) modelling with those measured in plasma (C(p)) and in the interstitial fluid of muscle tissue (C(ISF,u)) by microdialysis in anaesthetized dogs. METHODS: After approval by the Animal Care Committee, eight adult male dogs with a body weight ranging from 7 to 18 kg were anaesthetized with pentobarbital. Each dog received a 2-min rocuronium infusion of 0.15 mg kg(-1) min(-1) followed by a 118-min infusion of 60 microg kg(-1) min(-1) via the right jugular vein. Arteriovenous gradient across the hindlimb was measured at 40, 60, 100 and 120 min. Three microdialysis samples were collected at 40-min intervals. Once the infusion stopped, arterial samples were collected every 2 min for the first 10 min and every 20 min for the next 120 min. Neuromuscular function was monitored using train-of-four stimulation until full recovery. Dogs were then killed and a biopsy of muscle tissue was performed (C(m)). RESULTS: At steady state, the mean C(ISF,u) value was 1353 ng ml(-1). After correction for the unbound fraction in plasma, the mean C(e,corr) and C(2,corr) were 1681 and 1481 ng ml(-1), respectively. At the terminal sampling point, C(m) was 10-fold higher than C(p). CONCLUSION: Unbound concentration of rocuronium measured in the muscle interstitial fluid under steady-state conditions confirms that parametric PK-PD modelling gives reliable estimates of effect site concentrations. Rocuronium accumulates in muscle tissue, probably by non-specific protein binding in the interstitial space.

Physicochemical properties of neuromuscular blocking agents and their impact on the pharmacokinetic-pharmacodynamic relationship.

BACKGROUND: Among the factors influencing the onset of action of neuromuscular blocking agents (NMBA), the potency (EC50) and the rate of equilibration between blood and the effect compartment (k(e0)) have been highlighted. Although these descriptors are intrinsically influenced by the physicochemical characteristics of the drug, the impact of lipid solubility, molecular weight and protein binding on pharmacokinetic-pharmacodynamic (PK-PD) descriptors has not been established for most NMBA. METHODS: The octanol/phosphate buffer distribution coefficients (logD) of various NMBA (vecuronium, rocuronium, mivacurium isomers (cis-cis, cis-trans and trans-trans), doxacurium, cisatracurium, atracurium, succinylcholine) were determined. The free fraction for each drug was measured using an ultrafiltration technique. PK-PD descriptors were obtained from selected clinical studies. Correlations between physicochemical parameters (including molecular weight) and PK-PD descriptors were assessed by linear or multiple linear regression. RESULTS: A wide range of log D (-4.15 for succinylcholine to 0.75 for vecuronium) and free fraction (from 31% for vecuronium to 80% for succinylcholine) is observed for NMBA. Molecular weight combined with either lipid solubility (r2=0.70; P=0.001) or free fraction (r2=0.84; P<0.001) were highly correlated with potency, while for k(e0) a greater degree of correlation was obtained when both lipid solubility and free fraction (r2=0.74; P=0.002) were included. CONCLUSIONS: The basic characteristics of NMBAs, namely, molecular weight, lipid solubility and protein binding, are strongly associated with the kinetics of the drug response.

Simultaneous solid-phase extraction combined with liquid chromatography with ultraviolet absorbance detection for the determination of remifentanil and its metabolite in dog plasma.

To establish pharmacokinetic/pharmacodynamic relationships, a selective and specific high-performance liquid chromatographic method was developed for the quantitation of remifentanil and its metabolite in dog plasma. The assay involves a solid-phase extraction and a reversed-phase chromatographic separation with ultraviolet detection (lambda=210 nm). The calibration curves are linear in the range of 7.89-1500 ng ml(-1). Intra-day assay variability is less than 7% for all standards evaluated. Good recovery, linearity, accuracy, and precision were achieved with the assay that proved readily applicable to pharmacokinetic studies in dogs.

Stereoselective in vitro degradation pattern of mivacurium in human plasma.

BACKGROUND: Mivacurium is a mixture of three isomers, two of which are rapidly broken down in vivo by plasma cholinesterases. This study investigates the stereospecificity of mivacurium in vitro degradation to determine if it accounts for its in vivo behaviour. METHODS: The in vitro rate of degradation of each isomer of mivacurium and the in vitro rate of formation of their primary (monoesters and alcohols) and secondary (alcohols) metabolites were examined using human plasma from six healthy volunteers. The in vitro rate of degradation of the monoester metabolites was also assessed. All these determinations were made using a stereospecific high-performance liquid chromatography assay. RESULTS: The in vitro rate of disappearance of the two active isomers of mivacurium was very rapid, with mean values for the trans trans and cis trans isomers of 0.803 and 0.921 min(-1) respectively. These values are twofold faster than published in vivo data. The in vitro rate of disappearance was much slower for the cis cis isomer, with a mean value of 0.0106 min(-1). The cis trans isomer was converted exclusively to cis monoester and trans alcohol, while only metabolites in the trans and cis configuration were found for the trans trans and cis cis isomers respectively. Mean in vitro rates of disappearance for the trans and cis monoester were 0.00750 and 0.000633 min(-1) respectively. CONCLUSIONS: The in vitro rates of hydrolysis of the active isomers of mivacurium confirm that plasma cholinesterases play a major role in their in vivo degradation, but that in vivo elimination is slowed by extravascular distribution. Mivacurium hydrolysis is stereoselective, the ester group in the trans configuration being more accessible to enzymatic attack. This stereoselective pattern, along with the relatively slow breakdown of the cis cis isomer, sheds light on the in vivo disposition of the cis alcohol metabolite.

Response to mivacurium in a patient compound heterozygous for a novel and a known silent mutation in the butyrylcholinesterase gene: genotyping by sequencing.

BACKGROUND: Patients who are homozygous for the atypical mutation, compound heterozygous for atypical and silent mutations, or homozygous for silent mutations (SS) respond to mivacurium with extensively prolonged neuromuscular block. Although important, exact phenotyping of these patients is difficult. This article presents the pharmacodynamics and pharmacokinetics of a normal dose of mivacurium in a patient with phenotype SS, including a pedigree analysis and delineation of the molecular genetic method used to identify the genotype. METHODS: The neuromuscular block following administration of mivacurium, at a dose of 0.14 mg/kg, was monitored in a 30-yr-old healthy man with use of a mechanosensor and mechanomyography, and times to different levels of recovery were measured. Venous samples for determination of the mivacurium isomers were collected during the interval 134-494 min after administration of mivacurium, and the terminal half-lives were calculated. Butyrylcholinesterase activity, phenotype, and genotype were determined for both the patient and the family. Complete nucleotide sequencing was used to identify the genotype. RESULTS: A train-of-four ratio of 0.75 was reached 469 min after the injection of mivacurium. The terminal elimination half-lives of the mivacurium isomers, cis-trans and trans-trans, were 90 min. Complete nucleotide sequencing revealed two point mutations, the known silent variant S7 and a previously undescribed mutation of amino acid residue 170 introducing a stop codon. CONCLUSIONS: The patient was compound heterozygous for silent mutations in the butyrylcholinesterase gene. The response to mivacurium was an extensively prolonged duration of action. Identification of the rare silent mutations presupposes access to modern molecular genetic methods such as complete nucleotide sequencing.

Concentration-effect relationship of cisatracurium at three different dose levels in the anesthetized patient.

BACKGROUND: The linearity of cisatracurium elimination and its concentration-effect relation were determined as part of a traditional rich data study with three dose levels in patients receiving balanced anesthesia. METHODS: Forty-eight adults with American Society of Anesthesiologists status I-II were randomized to receive an intravenous bolus dose of 0.075, 0.15, or 0.30 mg/kg cisatracurium. Anesthesia was induced and maintained with nitrous oxide-oxygen, propofol, and fentanyl. The mechanical response of the adductor pollicis muscle was recorded. Arterial blood samples were collected over 8 h. Cisatracurium, laudanosine, and the monoquaternary alcohol concentrations were measured by high-performance liquid chromatography. To assess the relative contribution of the input function, a parametric (assuming elimination from both the central and peripheral compartments) and a nonparametric pharmacokinetic-pharmacodynamic model were both applied to data. RESULTS: Dose proportionality of the body disposition of cisatracurium and its two major metabolites at doses up to 0.30 mg/kg was confirmed. With the parametric approach, the effect compartment concentration at 50% block (EC50) significantly increased with the dose (136 vs. 157 vs. 209 ng/ml), whereas the effect compartment equilibration rate constant decreased (0.0675 vs. 0.0568 vs. 0.0478 min(-1)). A similar dose-dependent effect of the pharmacokinetic-pharmacodynamic relation was observed with the nonparametric approach, but the trend was 50% less pronounced. CONCLUSION: A dose-related change in pharmacokinetic-pharmacodynamic parameters was identified with both modeling approaches. A pharmacokinetic origin was ruled out, although no definite explanation of the underlying mechanism could be provided. These findings suggest that doses relevant to the anesthetic practice be used for estimation of EC50.

Measurement of succinylcholine concentration in human plasma by electrospray tandem mass spectrometry.

An electrospray mass spectrometric method for the quantification of the depolarizing neuromuscular blocking agent succinylcholine (SUX) is described. An extraction method compatible with direct infusion inlet was developed and leads to an analysis cycle time of 7--8 min instead of 25 min that would be required for HPLC inlet. SUX was extracted from human plasma on C1 solid-phase cartridges and was analyzed using positive ion electrospray tandem mass spectrometry (ESI-MS/MS). SUX plasma concentrations were determined by a stable isotope dilution assay using hexadeuterosuccinylcholine diiodide (SUXd6) as the internal standard. The calibration curve was prepared using the ratio of intensities of the major product ions in the collision-induced dissociation spectrum for known concentration ratios of SUX and SUXd6 in plasma. Calibration curves for the quantification were linear from 25 to 4000 ng/ml. For intraday precision, CV were < or =6% and accuracy ranged from 98 to 103%. For the interday precision, CV were < or =10% and accuracy ranged from 90 to 102%. This method is specific, sensitive, reproducible, and practical in a clinical setting.

Peripheral link model as an alternative for pharmacokinetic-pharmacodynamic modeling of drugs having a very short elimination half-life.

Attempts to obtain estimates of pharmacokinetic-pharmacodynamic (PK-PD) parameters for mivacurium with traditional central link models were unsuccessful in many patients. We hypothesized that a link model with the peripheral compartment would be more appropriate for mivacurium in view of its extremely rapid plasma clearance and its potential elimination by tissue pseudocholinesterases. For validation purposes, the peripheral link model was applied to other neuromuscular blocking agents (NMBA), i.e., atracurium and doxacurium which have respectively an intermediate and a long elimination half-life. Assuming peripheral elimination in PK-PD modeling was investigated but found to have no impact on the estimation of PK-PD parameters. Our results indicate that, for drugs having intermediate and long elimination half-lives, EC50 values are similar with either the central or peripheral link model. For mivacurium, a peripheral link model enables PK-PD modeling in all subjects, with more precision in the PK-PD parameter estimates and a better fitting of the effect data when compared to the central link model. For these reasons, a peripheral link model should be preferred for mivacurium.

Pharmacokinetic studies of neuromuscular blocking agents: good clinical research practice (GCRP).

In September 1997, an international consensus conference on standardization of studies of neuromuscular blocking agents was held in Copenhagen, Denmark. Based on the conference, a set of guidelines for good clinical research practice (GCRP) in pharmacokinetic studies of neuromuscular blocking agents is presented. Guidelines include: design of the study; relevant patient groups to investigate; test drug administration, sampling and analysis; pharmacokinetic analysis; pharmacokinetic/pharmacodynamic modeling; population pharmacokinetics; statistics; and presentation of pharmacokinetic data. The guidelines are intended to aid those working in this research area; it is hoped that they will assist researchers, editors of scientific papers, and pharmaceutical companies in improving the quality of pharmacokinetic studies.

Oral absorption of clarithromycin in acute illness and during convalescence in patients with community-acquired pneumonia.

STUDY OBJECTIVE: To compare the extent of oral clarithromycin absorption in patients during an illness and in health. DESIGN: Sequential two-phase prospective study including an acutely ill pneumonia phase (PP) and a subsequent convalescent phase (CP). STUDY POPULATION: Patients >/= 18 years old with radiographically confirmed community-acquired pneumonia (CAP) who were admitted to the hospital. METHODS: During both study phases, patients received one single 500-mg dose of oral clarithromycin. Serial blood samples were drawn over a 24-h period in order to characterize the plasma concentration-time curves. Area under the curve from zero to 24 h (AUC(0-24)), maximum plasma concentration (Cmax), and time to maximum concentration (Tmax) were determined for both clarithromycin and its metabolite, 14-hydroxyclarithromycin, and compared between the two phases. RESULTS: Twelve patients completed both phases of the study. For clarithromycin, there was a significant increase AUC(0-24) (47.37 +/- 8.51 microg/h/mL vs 36.22 +/- 6.09 microg/h/mL) in favor of the PP. There were no significant differences detected with respect to Cmax (4.32 +/- 0.63 microg/mL vs 3.57 +/- 0.46 microg/mL), or Tmax (3.50 +/- 0.50 h vs 2.83 +/- 0.59 h) between PP and CP. For 14-hydroxyclarithromycin, the AUC(0-24) and Cmax were significantly higher (5.84 +/- 1.08 microg/h/mL vs 8.84 +/- 1.92 microg/h/mL; 0.42 +/- 0.08 microg/mL vs 0.76 +/- 0.23 microg/mL) in the CP as compared to the PP. Tmax remained unchanged. CONCLUSION: The extent of absorption of oral clarithromycin was not diminished during an acute illness with CAP.

Vecuronium pharmacokinetics and pharmacodynamics during hypothermic cardiopulmonary bypass in infants and children.

PURPOSE: To determine the effect of moderate and deep hypothermic cardiopulmonary bypass (CPB) on the pharmacokinetic and pharmacodynamic behaviour of vecuronium in infants and children. METHODS: We studied 12 patients undergoing surgery for congenital heart disease under narcotic-nitrous oxide anesthesia. Neuromuscular blockade was maintained constant (TI 4-10% by Datex electromyograph) by adjusting a vecuronium infusion. Plasma vecuronium concentrations (Cpss) were analysed by HPLC to describe a pseudosteady-state during each of the pre-CPB, CPB and post-CPB phases. Paired arterial blood samples were taken 20 min apart after at least 20 min of constant infusion. RESULTS: Nine cases were analysed, mean age 20 mo, mean weight 9 kg. Three patients had deep and six moderate hypothermia. In the pre-CPB phase Cpss fell into two groups (mean +/- SD: 330 +/- 42 ng x ml(-1); 127 +/- 27 ng x ml(-1); P < 0.001); similarly the clearances showed a bimodal distribution (mean +/- SD: 5.08 +/- 0.94; 11.51 +/- 0.2 ml x min(-1) x kg(-1) P < 0.001), although in different patients. During CPB this bimodal distribution disappeared. Vecuronium infusion rate (VIR) decreased by 84% and 92% from pre-CPB to CPB phase in deep and moderate hypothermia groups respectively (P < 0.05), paralleled by decreases in Cpss of 36% (P > 0.05) and 52% (P < 0.05). CONCLUSION: Changes in vecuronium requirements and plasma concentrations during CPB demonstrate that vecuronium pharmacokinetics and pharmacodynamics are both affected by hypothermic CPB in infants. The finding of bimodal distributions for plasma vecuronium and vecuronium clearance highlights the need for individual monitoring of neuromuscular blockade in this age group.

Determination of neostigmine in human plasma and cerebrospinal fluid by high-performance liquid chromatography with ultraviolet detection.

A high-performance liquid chromatographic assay coupled with ultraviolet detection has been developed for the determination of neostigmine in human plasma and cerebrospinal fluid. A novel solid-phase extraction procedure was first used for this analyte and allowed good recovery (89+/-4.5%) together with ease and speed of execution. The method was sensitive, reproducible (C.V.<4.5%) and accurate (100+/-6.6%) over the range 2.6-167.0 ng/ml neostigmine concentrations in plasma or cerebrospinal fluid, and was applied successfully to study the pharmacokinetics of neostigmine in patients suffering from chronic postoperative abdominal pain.

Assuming peripheral elimination: its impact on the estimation of pharmacokinetic parameters of muscle relaxants.

For anesthetic drugs undergoing nonorgan-based elimination, there is a definite trend towards using pharmacokinetic (PK) models in which elimination can occur from both central (k10) and peripheral compartments (k20). As the latter cannot be assessed directly, assumptions have to be made regarding its value. The primary purpose of this paper is to evaluate the impact of assuming various degrees of peripheral elimination on the estimation of PK parameters. For doing so, an explanatory model is presented where previously published data from our laboratory on three muscle relaxants, i.e., atracurium, doxacurium, and mivacurium, are used for simulations. The mathematical aspects for this explanatory model as well as for two specific applications are detailed. Our simulations show that muscle relaxants having a short elimination half-life are more affected by the presence of peripheral elimination as their distribution phase occupies the major proportion of their total area under the curve. Changes in the exit site dependent PK parameters (Vdss) are also mostly significant when k20 is smaller than k10. Although the physiological processes that determine drug distribution and those affecting peripheral elimination are independent, the two are mathematically tied together in the two-compartment model with both central and peripheral elimination. It follows that, as greater importance is given to k20, the rate of transfer from the central compartment (k12) increases. However, as a result of a proportional increase in the volume of the peripheral compartment, peripheral concentrations remain unchanged whether or not peripheral elimination is assumed. These findings point out the limitations of compartmental analysis when peripheral elimination cannot be measured directly.

Determination of succinylcholine in human plasma by high-performance liquid chromatography with electrochemical detection.

An alternative HPLC method for the quantification of the depolarizing neuromuscular blocking agent succinylcholine in human plasma is described. Drug spiked plasma and patient plasma samples were extracted using a C1 solid-phase cartridge. Succinylcholine was separated on a Cyano column and quantitated using electrochemical detection at a potential of 450 mV and 750 mV. Mobile phase consisted of a mixture of phosphoric acid-acetonitrile-methanol (45:35:25) adjusted to an apparent pH of 5. Standard curves for the quantitation were linear in the range of 250-8000 ng/ml. Between-day and within-day relative standard deviations were 5.1% and 1.7%, respectively. Mean drug recovery and accuracy was 68% and 104%, respectively.

Pharmacokinetics and pharmacodynamics of cisatracurium after a short infusion in patients under propofol anesthesia.

UNLABELLED: Fourteen patients, ASA physical status I or II, were recruited to assess the pharmacokinetic-pharmacodynamic relationship of cisatracurium under nitrous oxide/sufentanil/propofol anesthesia. The electromyographic response of the abductor digiti minimi muscle was recorded on train-of-four stimulation of the ulnar nerve. A 0.1-mg/kg dose of cisatracurium was given as an infusion over 5 min. Arterial plasma concentrations of cisatracurium and its major metabolites were measured by using high-performance liquid chromatography. A nontraditional two-compartment pharmacokinetic model with elimination from central and peripheral compartments was used. The elimination rate constant from the peripheral compartment was fixed to the in vitro rate of degradation of cisatracurium in human plasma (0.0237 min(-1)). The mean terminal half-life of cisatracurium was 23.9+/-3.3 min, and its total clearance averaged 3.7+/-0.8 mL x min(-1) x kg(-1). Using this model, the volume of distribution at steady state was significantly increased compared with that obtained when central elimination only was assumed (0.118+/-0.027 vs 0.089+/-0.017 L/kg). The effect-plasma equilibration rate constant was 0.054+/-0.013 min(-1). The 50% effective concentration (153+/-33 ng/mL) was 56% higher than that reported in patients anesthetized with volatile anesthetics, which suggests that, compared with inhaled anesthetics, a cisatracurium neuromuscular block is less enhanced by propofol. IMPLICATIONS: The drug concentration-effect relationship of the muscle relaxant cisatracurium has been characterized under balanced and isoflurane anesthesia. Because propofol is now widely used as an IV anesthetic, it is important to characterize the biological fate and the concentration-effect relationship of cisatracurium under propofol anesthesia as well.