Nalmefene to prevent epidural narcotic side effects in pediatric patients: a pharmacokinetic and safety study.

STUDY OBJECTIVE: To determine the pharmacokinetics and preliminary efficacy of nalmefene in children in preventing epidural-induced narcotic side effects. DESIGN: Double-blind, placebo-controlled study. SETTING: University-affiliated children's hospital. PATIENTS: Thirty-four children (aged 2-12 yrs) undergoing cardiothoracic surgery with epidural anesthesia. INTERVENTIONS: Patients were randomized to receive intravenous bolus nalmefene 1 microg/kg or placebo. MEASUREMENTS AND MAIN RESULTS: Six blood samples (one before nalmefene administration and five from 13 randomly designated time points) from each patient were assayed to determine plasma nalmefene concentrations. Patients were assessed for pain, nausea, vomiting, and urinary retention for 24 hours after administration. Concentration-time data were analyzed by a limited sampling strategy with adult pharmacokinetic parameters used as Bayesian priors. A two-compartment, first-order model was fitted to the data using ADAPT II. Pharmacokinetic parameter estimates in these patients were similar to values reported in adults. The initial disposition half-life (t(1/2alpha)) was 0.36+/-0.11 hour, the terminal elimination half-life (t(1/2beta)) 8.7+/-2.3 hours, clearance 0.729+/-0.172 L/kg/hr, and steady-state volume of distribution 7.21+/-2.49 L/kg. Ability to prevent epidural narcotic-induced side effects could not be documented at the 1-microg/kg dose. No statistically significant differences were noted between study and placebo groups with regard to pain, nausea, vomiting, or urinary retention. CONCLUSION: Nalmefene has similar pharmacokinetics in children as in adults. It was administered safely to these patients and did not produce unmanageable pain.

The evolution of Crew Resource Management training in commercial aviation.

In this study, we describe changes in the nature of Crew Resource Management (CRM) training in commercial aviation, including its shift from cockpit to crew resource management. Validation of the impact of CRM is discussed. Limitations of CRM, including lack of cross-cultural generality are considered. An overarching framework that stresses error management to increase acceptance of CRM concepts is presented. The error management approach defines behavioral strategies taught in CRM as error countermeasures that are employed to avoid error, to trap errors committed, and to mitigate the consequences of error.

The effect of age on the pharmacokinetics of the opioid antagonist nalmefene.

1. The disposition of nalmefene was evaluated in young and elderly normal healthy volunteers. Subjects received either a single 1 mg (n = 18 young; n = 11 elderly) or 2 mg (n = 8 young; n = 15 elderly) intravenous bolus dose of nalmefene. 2. Following the administration of nalmefene, the initial plasma concentrations were significantly higher in elderly vs young subjects. The higher concentrations were the result of the 30 to 40% smaller central compartment apparent volume of distribution that was observed in the elderly subjects as compared with the young volunteers (2.8 +/- 1.1 vs 3.9 +/- 1.11 kg-1 for 1 mg dose). The elderly volunteers also had a significantly shorter distributional half-life (t1/2 lambda 1) than young volunteers (0.7 +/- 0.7 vs 1.3 +/- 0.8 h for 1 mg dose). No significant differences between groups were observed for the elimination half-life, clearance or steady-state apparent volume of distribution. 3. Although transiently higher nalmefene plasma concentrations were observed in the elderly immediately following drug administration, there was no association between this observation and adverse events. We conclude that no dosage alteration is warranted in elderly patients.

Disposition of the opioid antagonist, nalmefene, in rat and dog.

1. The disposition of nalmefene in rat and dog was studied using in vitro and in vivo methodology. In vitro metabolite profiles were obtained following incubation of nalmefene with liver microsomes and biological fluids were assayed to profile in vivo metabolites. Characterization of metabolites was accomplished using hplc, co-chromatography with synthetic standards, or LC/MS. 2. In rat, tissue distribution and metabolite plasma concentration-time data were obtained following intravenous bolus dosing of nalmefene. 3. The results indicate that the primary phase I metabolite of nalmefene from liver microsome incubations was the N-dealkylated metabolite, nornalmefene. Quantitative metabolite production was rat >> dog. In vivo, nornalmefene glucuronide was the major metabolite in rat urine, whereas nalmefene glucuronide(s) were predominant in dog urine. 4. More than 90% of the radioactive dose was recovered in the rat excreta and tissues 24 h after an intravenous bolus dose of 14C-nalmefene, with no apparent organ-specific retention of radioactivity. 5. Pharmacokinetic analysis of the rat plasma metabolite data indicated that terminal half-lives for nalmefene and nornalmefene were comparable (approximately 1 h). However, Cmax and AUC of nornalmefene were < or = 7% that of corresponding nalmefene values.

Duration of opioid antagonism by nalmefene and naloxone in the dog. A nonparametric pharmacodynamic comparison based on generalized cross-validated spline estimation.

The opioid antagonist nalmefene was compared in its pharmacodynamic properties to the structurally similar antagonist naloxone in a 2 x 2 cross-over study with 8 dogs. Opioid-induced respiratory depression was produced for ca. 7 hours with a constant rate intravenous infusion of 30 micrograms/kg/hr fentanyl and quantified using noninvasive transcutaneous pCO2 recordings. Upon reaching a pseudo-steady state of respiratory depression at 2 hours post fentanyl infusion initiation, the animals then received either nalmefene (12 micrograms/kg/hr) or naloxone (48 micrograms/kg/hr) for 30 minutes. The pharmacodynamic pCO2 responses produced by the combined agonist/antagonist regimen were fitted with a cubic spline function using a generalized cross-validation technique. Various quantities that describe the onset, duration and relative potency of each antagonist were determined directly from the estimated response curves in a model-independent, nonparametric way. The 2 antagonists were compared in terms of these quantities using a statistical model that considers carry-over effects typically arising from a possible development of tolerance. The results indicate that nalmefene: 1. is approximately 4-fold more potent than naloxone, 2. has an onset of reversal as rapid as naloxone, and 3. has a significantly longer (2-fold) pharmacodynamic duration of action than does naloxone. The mean time required for the agonist to regain 30% or 50% of its effect present at the start of the antagonist infusion was 66 and 112 minutes and 37 and 55 minutes for nalmefene and naloxone, respectively. Early, effective pharmacodynamic screening of new drug compounds is a valuable way of accelerating the drug discovery process and reducing escalating drug development costs. This study exemplifies a novel, endpoint oriented pharmacodynamic comparison procedure that can be done expeditiously before starting the time consuming development and validation of a drug level assay, and before engaging in considerably more involved integrated PK/PD studies.

Duration of opioid antagonism by nalmefene and naloxone in the dog: an integrated pharmacokinetic/pharmacodynamic comparison.

A continuous fentanyl infusion was administered to eight adult, male beagle dogs for a duration of approximately 400 min at a rate of 30 micrograms/kg/h. The extent of respiratory depression was quantified by continuous, noninvasive, transcutaneous pCO2 recordings. Upon reaching a pseudosteady-state of respiratory depression at approximately 120 min of fentanyl infusion, the animals then received, in a 2 x 2 crossover fashion separated by approximately 3 weeks, 30-minute equiefficacious infusions of nalmefene (12 micrograms/kg/h) or naloxone (48 micrograms/kg/h). Multiple venous blood samples were taken throughout the dosing regimen, and the resulting fentanyl, nalmefene, or naloxone plasma concentrations were determined. The concentration-time data were analyzed by noncompartmental methods and subsequently linked to the pharmacodynamic effect data by a competitive antagonism link model. Separately, the biophase concentrations were linked to the plasma concentration-time profiles through a single-exponential conduction function. The various pharmacokinetic/pharmacodynamic parameters resulting from this semiparametric analysis were analyzed by ANOVA, using a statistical model that considers carryover effects. The results of these analyses indicate that several pharmacokinetic/pharmacodynamic parameters of the two antagonists were comparable. However, nalmefene had a significantly more protracted terminal disposition and a significantly greater persistency in the biophase evaluated over the experimental time frame from 0 to 450 min.

Captain's and first officers' spheres of influence.

Although the "crew is increasingly the unit of focus for technical and CRM Training, a recent study documented that individual crew members exert influence over the crew in unique ways. The actions of captains and first officers influenced the overall performance of the "crew" both positively and negatively. Captains most often used briefings and leadership behaviors to influence crews. First Officers, on the other hand, influenced crew performance by their use of Inquiry / Assertion / Advocacy, Preparation / Planning / Vigilance activities, and Technical Proficiency.

Determination of mirfentanil hydrochloride (A-3508.HCl) in human plasma by liquid chromatography-mass spectrometry.

A method for the quantitation of mirfentanil hydrochloride (A-3508.HCl) in human plasma is presented for the first time, using LC-MS with single ion monitoring. The drug is extracted with a C-18 solid-phase cartridge and the extract is analysed using a 3 cm C-18 column connected to the ion source of a mass spectrometer via a thermospray interface. The intense ion produced by the protonated molecular ion at m/z 377 is detected by the mass spectrometer in positive-ion mode. The range of quantitation is 0.4-100 ng ml-1 from a 0.5 ml plasma sample. Results of assay validation are given. The method was used to analyse samples from a human pharmacokinetic study following intravenous administration of mirfentanil hydrochloride.

Simultaneous determination of phenolphthalein and phenolphthalein glucuronide from dog serum, urine and bile by high-performance liquid chromatography.

A procedure is described to simultaneously quantitate phenolphthalein and its glucuronide metabolite from dog serum, urine and bile using high-performance liquid chromatography. The major advantages of this over pre-existing methods include direct analysis of the parent compound and glucuronide metabolite without enzymatic hydrolysis, increased sensitivity and the potential for automation of a large number of samples. Analytes were extracted from serum and urine using a combination of liquid- and solid-phase extraction methodology. Bile samples were analyzed directly after a twenty-fold dilution with mobile phase. The components plus internal standard were separated by reversed-phase high-performance liquid chromatography using step gradient elution and quantitated by the absorbance of ultraviolet light at 230 nm. Limits of detection from 1 ml of serum, 0.1 ml of urine and 0.05 ml of bile were 0.1, 0.5 and 10 microgram/ml for phenolphthalein and 0.1, 10 and 50 microgram/ml for phenolphthalein glucuronide, respectively.

Determination of [3H]brifentanil, a potent narcotic analgesic, from rat serum by high-performance liquid chromatography with on-line radioactive detection.

A method for rapid analysis of [3H]brifentanil extracted from rat serum is described that has the advantages of sensitivity, speed and specificity. The method is based on extraction from serum via solid-phase extraction followed by chromatographic separation on a reversed-phase high-performance liquid chromatographic column. Detection of [3H]brifentanil is accomplished with an on-line radioactive detector, thus the laborious step of peak collection and subsequent liquid scintillation counting is eliminated. The developed method is sensitive to 0.1 ng/ml and has been successfully applied to pharmacokinetic studies in rats. In vivo metabolites retaining the radiolabel have been detected with the method and were more polar than the parent compound as based upon the elution order on the reversed-phase system.

Outcomes of crew resource management training.

Participants' self-reports and measures of attitudes regarding flightdeck management indicate that crew resource management training is favorably received and causes highly significant, positive changes in attitudes regarding crew coordination and personal capabilities. However, a subset of participants reacted negatively to the training and showed boomerangs (negative change) in attitudes. Explorations into the causes of this effect pinpoint personality factors and group dynamics as critical determinants of reactions to training and of the magnitude and direction of attitude change. Implications of these findings for organizations desiring to enhance crew effectiveness are discussed, and areas of needed additional research are described.

The structure of cockpit management attitudes.

A revised version of the Cockpit Management Attitudes Questionnaire (CMAQ) is introduced. Factor analyses of responses from 3 different samples reveal comparable factor structure (previous attempts to factor analyze this measure had produced equivocal results). Implications for the measurement of attitudes and the assessment of attitude change are discussed. It is argued that the CMAQ will benefit both special training programs and efforts to explore attitude-performance linkages in air-transport operations.

Sensitive method for the determination of pentamorphone in serum by liquid chromatography-mass spectrometry with thermospray interface.

A liquid chromatographic-mass spectrometric method for the determination of 14-beta-n-pentylaminomorphinone (pentamorphone) and 14-beta-n-pentylaminocodeinone (PAC) as internal standard is developed. Concentration levels in serum were calculated by the ratio of the peak areas of pentamorphone to PAC versus the concentration of pentamorphone. Peak areas were measured using selected-ion-recording of the pseudo-molecular ions of pentamorphone and PAC (m/z 369 and m/z 383, respectively). Aliquots (50 microliters) of sample were injected on a C18 mu Bondapak column following solid-phase extraction. The lowest limit of quantitation observed was 43 pg/ml. The sensitivity, accuracy and reproducibility of the method were demonstrated to be satisfactory for application in pharmacokinetic study of pentamorphone.

Preliminary results from the evaluation of cockpit resource management training: performance ratings of flightcrews.

The first data from the NASA/University of Texas Crew Performance project on the behavior of flightcrews with and without formal training in Cockpit Resource Management (CRM) is reported. Expert observers made detailed ratings of 15 components of crew behavior in both line operations and in full mission simulations. The results indicate that such training in crew coordination concepts increases the percentage of crews rated as above average in performance and decreases the percentage rated as below average. The data also show high and unexpected degrees of variations in rated performance among crews flying different aircraft within the same organization. It was also found that the specific behaviors that triggered observer ratings of above or below average performance differed markedly between organizations. Characteristics of experts' ratings and future research needs are also discussed.

How effective is cockpit resource management training? Exploring issues in evaluating the impact of programs to enhance crew coordination.

The question "Is cockpit resource management effective?" has been asked frequently in the years since 1979 when a National Aeronautics and Space Administration (NASA)/Industry workshop addressed the concepts of crew coordination and effective utilization of all available resources in flight operations (Cooper, White, & Lauber, 1980). If one looks at the proliferation of cockpit resource management (CRM) training programs in domestic and foreign, civil and military aviation, and the enormous investment in time and money that they entail, it would appear that the question has been answered in the affirmative. It is our position, however, that the question remains open and that empirical evidence is just beginning to accumulate.

Abnormal humoral immune response to Staphylococcus aureus in patients with Staphylococcus aureus hyper IgE syndrome.

Patients with the S. aureus hyper IgE syndrome (SAHIGES) have an abnormal IgE response to cell wall and surface antigens of S. aureus. In this paper we describe the detection of IgE antibodies to soluble antigens of staphylococci (S. aureus and S. epidermidis) and qualitative abnormalities of the IgG response to soluble S. aureus antigens in patients with SAHIGES. These findings may be of pathogenetic importance and help to delineate SAHIGES from other diseases.

[Persistent generalized lymphadenopathies in homosexuals and drug addicts: changes in humoral and cellular immunity]. / Lymphadénopathies persistantes généralisées chez les homosexuels et les toxicomanes: altérations de l'immunité humorale et cellulaire.

In two groups of subjects at risk for acquired immune deficiency syndrome (AIDS), homosexual males and intravenous drug users with persistent generalized lymphadenopathy, humoral and cell-mediated immunity were compared. A small group of patients with definite AIDS were also studied. It was found that levels of immunoglobulins, serological markers for virus and other infections, cell-mediated immunity and histology of lymph nodes were similar in homosexuals and drug users, whereas the lymphocyte sub-populations differed completely. The number of T4+ lymphocytes was markedly decreased in homosexuals but normal in drug users; the number of T8+ lymphocytes was much higher in drug users than in homosexuals. This discrepancy may explain the extremely low prevalence of AIDS cases observed among Swiss drug users as compared with the high frequency noted among homosexuals.

Staphylococcus aureus skin colonization in atopic dermatitis patients.

A study was conducted to compare the Staphylococcus aureus skin colonization of 21 patients with atopic dermatitis (AD) and 22 healthy controls. It was found that the total aerobe count (total CFU/cm2), the S. aureus fraction thereof and the S. aureus carrier frequency were significantly higher in apparently normal skin of AD patients than in healthy individuals. In addition, compared to normal skin of patients S. aureus density was 100 to 1,000 times higher in the 3 different kinds of lesional skin (dermatitic, lichenified and impetiginized sites). 190 S. aureus strains isolated from the skin of AD patients were tested for sensitivity to 5 topically used antibiotics and the results reported. Besides the biological consequences for the person affected by AD this severe colonization with S. aureus is of epidemiological importance. Several outbreaks of S. aureus infections by dispersal from dermatitic skin have been described. Therefore some preventive and therapeutic aspects are discussed.