Dexmedetomidine decreases cerebral blood flow velocity in humans.

This study was designed to determine the effects of dexmedetomidine on CBF velocity as measured by transcranial Doppler sonography in human volunteers. Dexmedetomidine, a potent alpha-2 adrenergic agonist, was administered by computer-driven infusion pump to six male volunteers. Serial measurements of middle cerebral artery blood flow velocity at four steady-state plasma concentrations of dexmedetomidine were made with a 2-MHz transcranial Doppler transducer via the temporal window. The targeted plasma concentrations were 0.49, 0.65, 0.81, and 0.97 ng/ml. These represent 60, 80, 100, and 120%, respectively, of the mean peak concentration following the intramuscular administration of 2 micrograms/kg of dexmedetomidine. Subjects experienced a significant degree of sedation at the highest infusion rates. Mean CBF velocity decreased with each increase in plasma concentration of dexmedetomidine and then began to return to basal levels after termination of the infusion. A trend toward an increase in the pulsatility index at the higher levels of dexmedetomidine suggests that the observed decrement in CBF velocity was due to an increase in cerebral vascular resistance. Upon initiation of the drug infusion, mean arterial pressure decreased from approximately 95 mm Hg to 78 mm Hg. There were no further decreases in arterial pressure with subsequent increases in plasma concentrations of dexmedetomidine. Arterial carbon dioxide tension increased to a maximum of 45 mm Hg during the drug infusion, but this increase from baseline was not statistically significant. These studies are in agreement with previous animal studies which demonstrate a decrease in CBF after administration of dexmedetomidine.

Pharmacokinetic-pharmacodynamic modeling in drug development: application to the investigational opioid trefentanil.

OBJECTIVE: We determined the possible benefits of a new opioid, trefentanil, relative to fentanyl and alfentanil using high-resolution pharmacokinetic-pharmacodynamic modeling and computer simulations of clinical dosing scenarios. METHODS: First, we determined in nine volunteers the electroencephalographic (EEG) effects and the trefentanil infusion rate that gave maximal EEG changes in 3 to 10 minutes. Then, in a crossover fashion in five volunteers, we compared the pharmacokinetics and EEG pharmacodynamics of trefentanil with fentanyl and alfentanil. Finally, we used computer simulations to predict offset of opioid effects of trefentanil, fentanyl, and alfentanil when given in different dosing schemes. RESULTS: The pharmacokinetic-pharmacodynamic profile of trefentanil was similar to alfentanil, except for a higher elimination clearance. Trefentanil versus alfentanil pharmacokinetic parameters were as follows: Elimination clearance, 0.444 +/- 0.073 versus 0.184 +/- 0.031 L/min; steady-state distribution volume, 37 +/- 7 versus 23 +/- 3 L; and elimination half-life, 127 +/- 24 versus 114 +/- 19 minutes. Trefentanil versus alfentanil pharmacodynamics were as follows: the equilibration half-time between EEG effect and arterial drug concentration, 1.2 +/- 0.5 versus 0.6 +/- 0.4 minutes; and the concentration resulting in 50% of maximal EEG effect, 429 +/- 313 versus 577 +/- 273 ng/ml. The pharmacokinetic-pharmacodynamic profile of fentanyl was significantly different from trefentanil and alfentanil. Simulation of effect compartment concentration decay curves after variable-length infusions predicted more rapid recovery from trefentanil than from alfentanil or fentanyl. CONCLUSION: We suggest that high-resolution pharmacokinetic-pharmacodynamic studies and computer simulations of clinical dosing scenarios may have significant usefulness in appreciating differences between new and established drugs in early phase I studies.

Pharmacokinetics, cortisol release, and hemodynamics after intravenous and subcutaneous injection of human corticotropin-releasing factor in humans.

OBJECTIVE: Two clinical trials investigated the pharmacokinetics of human corticotropin-releasing factor (hCRF), resulting cortisol release, and associated hemodynamic changes. METHODS: In a 3 x 3 Latin square design, subjects were randomized to receive a single dose of 5 microg x kg(-1) hCRF as a 10-minute intravenous infusion, a 180-minute infusion, and a subcutaneous injection in separate study sessions 7 days apart. Twelve additional subjects obtained a subcutaneous dose of either 300, 600, or 1200 microg hCRF on 3 consecutive days. Noncompartmental and compartmental pharmacokinetic analysis was performed. Hemodynamic response was characterized with use of pharmacodynamic models. RESULTS: The volume of distribution at steady state was 9.81 +/- 3.0 and 15.61 +/- 2.9, and the clearance was 256 +/- 40 mL x min(-1) and 345 +/- 90 mL x min(-1) for the 10-minute and 180-minute intravenous infusion, respectively (P < .05). Corresponding elimination half-life was 45 +/- 7 minutes and 37 +/- 10 minutes. Two-compartment and 1-compartment models adequately described the 10-minute and 180-minute infusions, respectively. The bioavailability of hCRF after subcutaneous administration was 67% +/- 17%. Apparent clearance remained unchanged for different subcutaneous doses. Peak plasma cortisol concentrations were similar after subcutaneous and intravenous administration of hCRF. Repetitive administration of hCRF did not result in accumulation but produced a reduced plasma cortisol response. A sigmoidal model related plasma hCRF concentrations to increase in heart rate (maximum, 39 beats x min(-1)). The relationship between the modest decrease in diastolic blood pressure and plasma hCRF concentrations was linear. CONCLUSION: The pharmacokinetics of intravenously administered hCRF were nonlinear, but apparent clearance was constant for various subcutaneous doses. An excellent bioavailability and preserved bioactivity make the subcutaneous route an attractive choice. Repetitive administration of hCRF probably caused tolerance of the cortisol response.

The pharmacokinetics of lignocaine in humans during a computer-controlled infusion.

Several types of chronic pain syndromes are effectively treated with sodium channel blockers such as lignocaine. Further investigation of this therapeutic modality would be facilitated by refinement of the parameters describing lignocaine distribution and elimination. This would allow precise lignocaine infusion by a computer-controlled infusion to attain and maintain stable target lignocaine concentrations. Arterial blood samples were obtained at frequent intervals during a computer-controlled infusion of lignocaine in 12 adult human volunteers. Plasma lignocaine concentrations of 1, 2, 3, 4 and 5 microg/ml were targeted for 15 min at each concentration. A three-compartment mammillary pharmacokinetic model best described the resulting concentration vs time profile. A population pharmacokinetic analysis was performed using three different techniques; the two-stage, pooled and mixed effects modelling. There was marked overshoot of the plasma concentration above the target prior to refinement of the pharmacokinetic parameters. The best parameters of a three-compartment mammillary model fit to the measured concentration using the pooled data approach were: V(1) = 7.44, V(2) =11.5 and V(3) = 97.71; Cl(1) = 0.585, Cl(2) = 2.23 and Cl(3) =1.64 l/min. Similarly calculated parameters using NONMEM were V(1) = 6.99, V(2) =12.2 and V(3) =1341; Cl(1) = 0.703, Cl(2) =1.24 and Cl(3) =1.49 l/min. The addition of age as a covariate of the pharmacokinetic parameters improved the model in both cases. Height, lean body mass and body surface area as covariates of the pharmacokinetic parameters did not improve the predicted value of the model. Prospective testing of the pharmacokinetic parameters will be required to define whether they function well. The refinement of pharmacokinetic parameters for the computer-controlled intravenous infusion of lignocaine will facilitate further research in pain therapy. Published lignocaine pharmacokinetic values have a relatively large central volume of distribution, and hence, when implemented as a computer-controlled infusion, result in dramatic overshoot shortly after targeting a higher plasma concentration. In light of the long-lasting pain relief provided by sodium channel blockade in neuropathic pain states, overshoot of plasma concentrations must be avoided if the concentration vs effect relationship is to be defined.

Nitrous oxide produces a biphasic effect on opiate-induced muscle rigidity in the rat.

Muscle rigidity is a side effect of potent opiate agonists like alfentanil. Older clinical studies suggested that nitrous oxide (N2O) augments opiate rigidity, but this has never been rigorously examined in an animal model. Sixty-two Wistar rats were placed in a Plexiglas box through which fresh gas flowed at 4 l/min. Muscle rigidity was assessed using gastrocnemius electromyographic (EMG) activity. Rats were exposed to either 60% N2O in O2 or 100% O2, EMG was measured for 10 min, alfentanil (0, 50, 175, or 350 micrograms/kg) was administered intravenously, and data were collected for 45 min. Alfentanil produced a dose-dependent increase in EMG activity in both O2 and N2O groups (p < 0.001). At 1 min postalfentanil, N2O caused significantly more rigidity than 100% O2 (p < 0.001). However, beginning at 5 min, N2O attenuated both the magnitude and the duration of rigidity. Study of a separate group of animals breathing 30% O2 demonstrated that N2O's attenuating effect on alfentanil rigidity was not due to reduced inspired oxygen concentration. These results are described by a theoretical model of the pharmacodynamic interactions of alfentanil and nitrous oxide.

A comparison of propranolol and diazepam for preoperative anxiolysis.

The effectiveness of propranolol, a nonsedating anxiolytic premedication, was studied by monitoring preoperative anxiety and postoperative recovery of cognitive function in 92 healthy ASA physical status I females aged 15-42 yr undergoing outpatient dilatation and curettage (D&C) for therapeutic abortion. In a randomized double-blind design, patients received one of the following oral medications 1-1.5 hr preoperatively: (1) diazepam 10 mg (n = 31); (2) propranolol 80 mg (n = 31); (3) placebo (n = 30). Anxiety throughout the hospital stay was monitored using the State-Trait Anxiety Inventory (STAI). Postoperative cognitive recovery was assessed using the digit span and Trieger tests. STAI anxiety levels were recorded on admission to hospital, immediately before entering the operating room, and two hours postoperatively. There was no difference among the anxiolytic properties of the three medications and all three patient groups showed a significant decrease in anxiety levels after administration of the medication. Tests of cognitive function after anaesthesia showed the fastest return to baseline status in patients receiving propranolol, possibly because beta adrenergic blockade blunted the autonomic signs of light anaesthesia and less anaesthetic was administered. None of the study premedications was demonstrated to have an anxiolytic advantage, but propranolol did offer a faster return of cognitive function in the postoperative period.

The relationship between the visual analog pain intensity and pain relief scale changes during analgesic drug studies in chronic pain patients.

BACKGROUND: Most analgesic drug studies in humans quantify drug action based on verbal reports of pain intensity and pain relief. Although measures of pain intensity and pain relief show a good overall correlation, it is not known if they relate to each other consistently over time Such consistency is necessary if both measures are used to depict analgesic drug action versus time. This study examined in chronic pain patients if the relationship between visual analog pain intensity and pain relief scores was consistent during two analgesic drug studies. METHODS: Data from two independently performed analgesic drug studies were analyzed using linear regression. Data were split into pain intensity and pain relief scores recorded before and after patients' experience of maximum analgesia (>90% of maximum pain relief). The slopes of the linear regression line depicting pain intensity versus pain relief scores before and after maximum analgesia were statistically compared. RESULTS: The slope of the linear regression line before and after maximum analgesia was significantly different in both drug studies (nonoverlapping 95% confidence intervals), -2.16+/-0.57 versus -1.05+/-0.10 and -1.47+/-0.26 versus -1.09+/-0.07, respectively. These results are compatible with the observation that patients indicating the same pain intensity before and after maximum analgesia reported a different magnitude of pain relief. CONCLUSIONS: The relationship between visual analog pain intensity and pain relief scores changed systematically during both analgesic drug studies. The authors hypothesize that patients' interpretation of the pain relief scale had changed during the studies and therefore suggest using the pain intensity scale to quantify analgesic drug action over time.

The dose of propofol required to prevent children from moving during magnetic resonance imaging.

BACKGROUND: Intravenous propofol offers several advantages as an anesthetic for children undergoing magnetic resonance imaging. However, the dose of propofol required to prevent movement during magnetic resonance imaging is likely to be less than that required for surgical anesthesia. METHODS: Thirty children between the ages of 1 and 10 years, undergoing elective magnetic resonance imaging as outpatients were randomly assigned to receive a propofol infusion at a rate of 50, 75, or 100 micrograms.kg-1.min-1 during the imaging procedure. Anesthesia was induced with inhalation of halothane, nitrous oxide, and oxygen, and a 2 mg.kg-1 loading dose of propofol. Immediately after insertion of an intravenous catheter, inhaled anesthetics were discontinued and the propofol infusion started. The children then were observed for movement during the scan. RESULTS: There were no significant differences among the three groups with respects to mean age (4.4 +/- 2.0 yr), weight (17.6 +/- 5.1 kg), induction time (11 +/- 3 min), scan duration (55 +/- 26 min), or recovery time (30 +/- 8 min). Five of ten patients who received 50 micrograms.kg-1 x min-1 moved during the scan, three of ten patients who received 75 micrograms.kg-1 x min-1 moved, and none of the children who received 100 micrograms.kg-1 x min-1 moved. Two patients experienced a decrease of arterial oxygen saturation to less than 95% after receiving the initial bolus of propofol. The arterial oxygen saturation returned to normal within 15 s without specific treatment other than continued supplemental oxygen. There were no episodes of hypoxemia during image acquisition. None of the children experienced nausea or vomiting. CONCLUSIONS: Following induction of anesthesia with halothane, nitrous oxide, and a 2 mg.kg-1 loading dose of propofol, infusion of propofol at a rate of 100 micrograms.kg-1 x min-1 effectively prevents children from moving during elective magnetic resonance imaging. A transient decrease in arterial oxygen saturation can occur after the initial bolus of propofol. Recovery from anesthesia is rapid and without nausea or vomiting.

The pharmacokinetics and hemodynamic effects of intravenous and intramuscular dexmedetomidine hydrochloride in adult human volunteers.

BACKGROUND: Dexmedetomidine is an alpha 2 agonist with potential utility in clinical anesthesia for both its sedative and sympatholytic properties. METHODS: The pharmacokinetics and hemodynamic changes that occurred in ten healthy male volunteers were determined after administration of dexmedetomidine 2 micrograms/kg by intravenous or intramuscular route in separate study sessions. RESULTS: The intramuscular absorption profile of dexmedetomidine, as determined by deconvolution of the observed concentrations against the unit disposition function derived from the intravenous data, was biphasic. The percentage bioavailability of dexmedetomidine administered intramuscularly compared with the same dose administered intravenously was 73 +/- 11% (mean +/- SD). After intramuscular administration, the mean time to peak concentration was 12 min (range 2-60 min) and the mean peak concentration was 0.81 +/- 0.27 ng/ml. After intravenous administration of dexmedetomidine, there were biphasic changes in blood pressure. During the 5-min intravenous infusion of 2 micrograms/kg dexmedetomidine, the mean arterial pressure (MAP) increased by 22% and heart rate (HR) declined by 27% from baseline values. Over the 4 h after the infusion, MAP declined by 20% from baseline and HR rose to 5% below baseline values. The hemodynamic profile did not show acute alterations after intramuscular administration. During the 4 h after intramuscular administration, MAP declined by 20% and HR declined by 10%. CONCLUSIONS: The intramuscular administration of dexmedetomidine avoids the acute hemodynamic changes seen with intravenous administration, but results in similar hemodynamic alterations within 4 h.

Comparative absorption kinetics of intramuscular midazolam and diazepam.

PURPOSE: This study investigates the rate and extent of absorption following intramuscular injection of midazolam and diazepam. METHODS: Four healthy male volunteers were recruited in this randomized three-way cross-over study. On one occasion each subject received simultaneous im injections of 5 mg midazolam and 10 mg diazepam in separate deltoid muscles. On two other separate occasions each subject received an iv infusion of 7.5 mg midazolam and 30 mg diazepam over five minutes. Frequent arterial blood samples were collected for up to two hours and venous blood samples were collected for up to 24 hours for midazolam and ten days for diazepam. A gas chromatography assay was used to determine the plasma concentrations of midazolam and diazepam. The im absorption profiles were estimated using constrained least-squares deconvolution. RESULTS: There were substantial intersubject variabilities in the estimated pharmacokinetic parameters (volume and clearances) of intravenous midazolam and diazepam. The mean (+/-sd) time to peak plasma concentration (Cmax) was shorter for im midazolam (17.5 +/- 6.5 min) relative to diazepam (33.8 +/- 7.5 min). The mean (+sd) time to peak absorption rate was also shorter for midazolam (9 +/- 2 vs 13.8 +/- 7.5 min). The peak rate of absorption was identical (0.18 mg. min-1) and bioavailability was 1.0 for both drugs. CONCLUSIONS: We conclude that midazolam has more rapid absorption than diazepam following im administration.

Computer-controlled infusion of intravenous dexmedetomidine hydrochloride in adult human volunteers.

BACKGROUND: This investigation extended the pharmacokinetic analysis of our previous study, of intravenous dexmedetomidine in 10 healthy male volunteers, and prospectively tested the resulting compartmental pharmacokinetics in an additional six subjects using a computer-controlled infusion pump (CCIP) to target four different plasma concentrations of dexmedetomidine for 30 min at each concentration. METHODS: A three-compartment mamillary pharmacokinetic model best described the intravenous dexmedetomidine concentration versus time profile following the 5 min intravenous infusion of 2 micrograms/kg in our previous study. Nonlinear regression was performed using both two-stage and pooled data techniques to determine the population pharmacokinetics. The pooled technique allowed covariates, such as weight, age, and height of the subjects, to be incorporated into the nonlinear regression to test the hypothesis that these additional covariates would reduce the residual error between the measured concentrations and the predicted values. RESULTS: The addition of age, weight, lean body mass, and body surface area as covariates of the pharmacokinetic parameters did not improve the predictive value of the model. However, the model was improved when subject height was a covariate of the volume in the central compartment. The residual error in the pharmacokinetic model was markedly lower with the pooled versus the two-stage approach. The following pharmacokinetic values were obtained from the pooled analysis of the zero-order dexmedetomidine infusion: V1 = 8.05, V2 = 12.4, V3 = 175 (L), Cl1 = (0.0101*height [cm]) -1.33, Cl2 = 2.05, and Cl3 = 2.0 (L/min). Prospective evaluation of the pooled pharmacokinetic parameters using a computer-controlled infusion in six healthy volunteers showed the precision (average [(absolute error)/measured concentration]) of the CCIP to be 31.5% and the bias (average [error/measured concentration]) to be -22.4%. A pooled regression of the combined CCIP and zero-order data confirmed that the covariate, height (cm), was related in linear fashion to Cl1. A striking nonlinearity of dexmedetomidine pharmacokinetics related to concentration was observed during the CCIP infusion. The final pharmacokinetic values for the entire data set were: V1 = 7.99, V2 = 13.8, V3 = 187 (L), Cl1 = (0.00791*height [cm]) -0.927, Cl2 = 2.26, and Cl3 = 1.99 (L/min). CONCLUSIONS: Pharmacokinetics of dexmedetomidine are best described by a three-compartment model. Addition of age, weight, lean body mass, and body surface area do not improve the predictive value of the model. Additional improvement in CCIP accuracy for dexmedetomidine infusions would require magnification modification of the model based on the targeted concentration.

Dose-ranging study in younger adult and elderly patients of ORG 9487, a new, rapid-onset, short-duration muscle relaxant.

The purpose of this multicenter, randomized, assessorblind placebo-controlled study was to determine which of five doses of the new, rapid-onset neuromuscular relaxant, ORG 9487, provided both good to excellent tracheal intubating conditions 60 s after administration and a clinical duration of action < 20 min in 120 younger (aged 18-64 yr) and 61 elderly (aged 65-85 yr) adult patients. Anesthesia was induced with fentanyl (2-5 micrograms/kg) and thiopental (3-6 mg/kg) and maintained with N2O/O2 and a propofol infusion (50-300 micrograms.kg-1.min-1). Neuromuscular train-of-four (TOF) monitoring by electromyography (Datex Relaxograph) commenced immediately after anesthetic induction and was followed, within 30 s, by one of five doses of ORG 9487 (0.5, 1.0, 1.5, 2.0, 2.5 mg/kg) or a placebo. Tracheal intubation was attempted at 60 s and again, in the case of failure, at 90 s. Conditions were assessed with a 4-point scale. Maximum block, clinical duration (time to 25% T1 recovery), and recovery (TOF > or = 0.7) were measured. Dose-dependent changes were observed in tracheal intubating conditions and neuromuscular block. Good to excellent intubating conditions at 60 s were present in most younger adult (52 of 60) and elderly (26 of 31) patients administered doses > or = 1.5 mg/kg. Mean clinical durations < 20 min were observed in adult patients at doses up to 2.0 mg/kg and in geriatric patients up to 1.5 mg/kg. Thus, doses of 1.5-2.0 mg/kg ORG 9487 enabled both rapid tracheal intubation and a short clinical duration of action in adult and elderly patients.