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Biomedical subjects

P L Gambús

Publications and source records attributed to P L Gambús.

7 recordsLinked to original sources
PubMed1998

Pharmacokinetics of intravenous dynorphin A(1-13) in opioid-naive and opioid-treated human volunteers.

BACKGROUND: Dynorphin A(1-13) is a fragment of the endogenous opioid neuropeptide dynorphin A. Previous research suggested that intravenously administered dynorphin A(1-13) has the ability to modulate morphine-induced analgesia. We designed this study to characterize the disposition of intravenous dynorphin immunoreactivity in humans and to determine whether concomitant long-term opioid therapy influenced the pharmacokinetics or side-effects profile of dynorphin A(1-13). METHODS: The study subjects comprised 20 volunteers divided into two groups of 10 each, stratified by dose (low dose, 250 micrograms/kg; high dose, 1000 micrograms/kg). There were four volunteers receiving long-term opioid therapy and six opioid-naive volunteers (nonopioid group) within each dosing group. Dynorphin A(1-13) was infused over 10 minutes, and arterial blood samples were drawn and assayed for dynorphin immunoreactivity. A population modeling approach was used to characterize the pharmacokinetics. Dynorphin effects on heart rate and arterial blood pressure were also studied. RESULTS: The pharmacokinetics of dynorphin immunoreactivity were linear over the dose range studied and were best described by a three-compartment mammillary model whose parameters were volume 1, 5.0 L; volume 2, 0.80 L; volume 3, 12 L; clearance 1, 6.0 L/min; clearance 2, 0.054 L/min; and clearance 3, 0.044 L/min. Concomitant opioid medication did not affect the disposition of dynorphin immunoreactivity. Tachycardia and flushing were commonly observed side effects. The incidence of side effects was dose dependent and was not influenced by long-term opioid use. CONCLUSIONS: Intravenously administered dynorphin A(1-13) is very rapidly metabolized, on the basis of the time course of immunoreactivity in the blood. Long-term opioid therapy did not influence either the pharmacokinetics or incidence of side effects.

Adult↗
PubMed1998

[Characterization of dose profile of remifentanil with computer simulation: comparative study with fentanyl and alfentanyl].

OBJECTIVES: To estimate the optimum dosing regimen and delivery system for remifentanil, a new opioid, using computer simulations based on information from pharmacokinetic and pharmacodynamic models available for fentanyl, alfentanil and remifentanil, as well as from clinical trials of fentanyl and alfentanil. PATIENTS AND METHODS: We estimated the site concentration ranges likely to be needed to blunt response to anesthetic or surgical stimuli and to recover from spontaneous ventilation. Dosing guidelines for remifentanil, fentanyl and alfentanil were estimated for three methods of administration (bolus, bolus + variable continuous infusion or constant continuous infusion). To that end, the time course of opioid concentration was simulated for hypothetical balanced anesthesia lasting 60 min. We then studied the number of boluses, the number of infusion rate steps, time taken to reach the terapeutic threshold, and time from turning off the infusion until reaching a concentration compatible with spontaneous ventilation. RESULTS: The estimated "effect site" concentration ranges for remifentanil were 6 to 10 ng.ml-1 during intubation; 4 to 6 ng.ml-1 during cutaneous incision; 4 to 7 ng.ml-1 for maintenance; and less than 2.5 ng.ml-1 for recovery of spontaneous ventilation. Simulated bolus administration indicated that 21 boluses of remifentanil, 4 boluses of fentanyl and 7 boluses of alfentanil were needed during one hour. The therapeutic threshold was reached within the first minute with remifentanil, within 2 minutes with fentanyl and within 1 min with alfentanil. Time until recovery of spontaneous ventilation was 7 min with remifentanil, 22 min with fentanyl and 14 min with alfentanil. In the simulation of bolus plus variable infusion, the initial bolus of remifentanil was 100 micrograms, the infusion rate for induction and maintenance was 25 micrograms.min-1 and the maintenance rate was 15 micrograms.min-1. The initial bolus of fentanyl was 300 micrograms, the infusion rate for induction and maintenance was 5 micrograms.min-1. The initial bolus of alfentanil was 2,000 micrograms, the infusion rate for induction was 200 micrograms.min-1 and the maintenance rates were 75 and 25 micrograms.min-1. The therapeutic threshold was reached in 1 min with remifentanil, in 2 min with fentanyl and within 1 min with alfentanil. Spontaneous ventilation was recovered 4 min after turning off the infusion of remifentanil, 4 min afterwards with fentanyl and 6 min afterwards with alfentanil. The simulated constant infusion rate for remifentanil of 15 micrograms.min1 (8 micrograms.min-1 for fentanyl and 75 micrograms.min-1 for alfentanil) allowed the therapeutic threshold to be reached in 10 min with remifentanil, in 22 min with fentanyl and in 17 min with alfentanil. Recovery of spontaneous ventilation occurred 5 min after closure of the infusion pump with remifentanil (24 min with fentanyl and 17 min with alfentanil). CONCLUSIONS: Information from pharmacokinetic and pharmacodynamic models allows us to establish the effect site concentration ranges for remifentanil and determine the ideal administration technique for this drug. The simulation also allows us to compare the properties of remifentanil to those of other common opioids such as fentanyl and alfentanil. The results are fairly consistent with clinical evidence, demonstrating the power of pharmacokinetic and pharmacodynamic models for rationally establishing opioid dosing guidelines.

Adult↗
PubMed1995

Validation of the alfentanil canonical univariate parameter as a measure of opioid effect on the electroencephalogram.

BACKGROUND: Several parameters derived from the multivariate electroencephalographic (EEG) signal have been used to characterize the effects of opioids on the central nervous system. These parameters were formulated on an empirical basis. A new statistical method, semilinear canonical correlation, has been used to construct a new EEG parameter (a certain combination of the powers in the EEG power spectrum) that correlates maximally with the concentration of alfentanil at the effect site. To date, this new canonical univariate parameter (CUP) has been tested only in a small sample of subjects receiving alfentanil. METHODS: The CUP was tested on EEG data from prior studies of the effect of five opioids: alfentanil (n = 5), fentanyl (n = 15), sufentanil (n = 11), trefentanil (n = 5), and remifentanil (n = 8). We compared the CUP to the commonly used EEG parameter spectral edge, SE95%. The comparison was based on the signal to noise ratio, obtained by fitting a nonlinear pharmacodynamic model to both parameters. The pharmacodynamic parameter estimates obtained using both measurements were also compared. RESULTS: The values for signal-to-noise ratio were significantly greater for the CUP than for SE95% when considering all the opioids at once. The pharmacodynamic estimates were similar between the two EEG parameters and with previously published results. Semilinear canonical correlation coefficients estimated within each drug group showed patterns similar to each other and to the coefficients in the CUP, but different from coefficients for propofol and midazolam. CONCLUSIONS: Although the CUP was originally designed and tested using alfentanil, we have proven it to be a general measure of opioid effect on the EEG.

Alfentanil↗