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M Maze

Publications and source records attributed to M Maze.

At least 55 records · Page 3Linked to original sources
PubMed1996

Antinociceptive response to nitrous oxide is mediated by supraspinal opiate and spinal alpha 2 adrenergic receptors in the rat.

BACKGROUND: Despite nearly 150 years of clinical use, the mechanism(s) of action of nitrous oxide (N2O) remains in doubt. In some but not all studies the analgesic properties of N2O can be attenuated by opiate receptor antagonists. The purported mechanism for the opiate antagonistic effect relates to the finding that N2O increases supraspinal levels of endogenous opiates, although this finding has been disputed. Based on the observations that (1) N2O promotes the release of catecholamines, including the endogenous alpha 2 adrenergic agonist norepinephrine, and (2) that descending noradrenergic inhibitory pathways are activated by opioid analgesics, this study sought to determine whether alpha 2 adrenergic receptors are involved in the antinociceptive action of nitrous oxide. METHODS: Institutional approval was obtained for the study. Rats breathed 70% N2O and 30% O2 in an enclosed chamber. After a 30-min exposure, significant antinociception was indicated by an increase in the latency response to a noxious stimulus (tail-flick latency). The tail-flick latency was tested in rats exposed to 70% N2O after either systemic or regional (intrathecal or intracerebroventricular) injections with either competitive (atipamezole; yohimbine) or noncompetitive (N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline) alpha 2 adrenoceptor antagonists, or the opiate receptor antagonist naloxone. RESULTS: When administered systemically, both the opiate (naloxone) and alpha 2 adrenoceptor antagonists (atipamezole, yohimbine, and N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline) blocked the enhanced tail-flick latency response to N2O-Naloxone administered intracerebroventricularly, but not intrathecally, blocked the enhanced tail-flick latency response to N2O. Conversely, atipamezole administered intrathecally, but not intracerebroventricularly, blocked the enhanced tail-flick latency response to N2O. CONCLUSIONS: These data suggest that both supraspinal opiate and spinal alpha 2 adrenoceptors play a mediating role in the antinociceptive response to N2O in rats. A possible mechanism may involve a descending inhibitory noradrenergic pathway that may be activated by opiate receptors in the periaqueductal gray region of the brain stem in the rat after exposure to N2O.

Adrenergic alpha-Antagonists↗
PubMed1996

Dexmedetomidine does not attenuate increases in excitatory amino acids after transient global ischemia in the rabbit.

This study was designed to evaluate the ability of dexmedetomidine, an alpha 2-adrenergic agonist, to attenuate increases in the hippocampal concentration of extracellular glutamate and glycine that result from episodes of transient global cerebral ischemia. After the induction of anesthesia with halothane and oxygen, microdialysis catheters were stereotactically inserted into the hippocampi of 16 New Zealand white rabbits. After the collection of baseline samples of dialysate, animals were randomly assigned to receive an intravenous infusion of either saline (n = 8) or dexmedetomidine (n = 8). Transient global cerebral ischemia was produced by the inflation of a neck tourniquet and induction of deliberate hypotension for 10 min. Dialysates were collected during the ischemic period and for the ensuing 60 min of reperfusion. During ischemia, the concentrations of glutamate and glycine increased from the preischemic baseline in both groups. Glutamate concentrations rapidly returned to baseline after reperfusion, whereas glycine concentrations remained elevated throughout the reperfusion period. There were no significant differences between the control and dexmedetomidine-treated groups. These results suggest that the mechanism of the putative neuroprotective effects of dexmedetomidine is not related to decreased concentrations of glutamate or glycine.

Adrenergic alpha-Agonists↗
PubMed1995

Desensitization to the behavioral effects of alpha 2-adrenergic agonists in rats.

BACKGROUND: The analgesic and sedative-hypnotic utility of the alpha 2 agonists clonidine and dexmedetomidine are currently being investigated. Both compounds exert their behavioral responses by activating central alpha 2 adrenoceptors, albeit with different selectivities and efficacies. Furthermore, the analgesic and hypnotic behavioral responses are produced at different sites and may be affected independently of one another. A series of studies was conducted in rats to determine (1) whether tolerance and cross-tolerance develop to the analgesic actions of clonidine or dexmedetomidine; (2) how the number of available alpha 2 adrenoceptors affects the analgesic response to dexmedetomidine and clonidine; and (3) how the number of available alpha 2 adrenoceptor affects the hypnotic response to dexmedetomidine. METHODS: Rats were administered equianalgesic doses of dexmedetomidine or clonidine continuously, subcutaneously by osmotic minipumps. After 7 days the analgesic response to acutely administered dexmedetomidine or clonidine at median effective analgesic doses was assessed by the tail-flick latency response. The number of alpha 2 adrenoceptors in the spinal cord was diminished in a dose-dependent manner by covalent modification with a noncompetitive receptor blocker, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). Recovery of the tail-flick latency response to clonidine and dexmedetomidine was determined and correlated to the recovery of receptor density as assessed by radiolabeled-ligand binding studies. The alpha 2 adrenoceptor population in the locus ceruleus of rats was depleted with EEDQ, and recovery of the hypnotic response (as assessed by the loss of righting reflex) to dexmedetomidine was determined and correlated to the recovery of receptor density. RESULTS: After 7 days of chronic treatment with dexmedetomidine, analgesic responses to dexmedetomidine and clonidine remained unaltered. However, chronic treatment with clonidine significantly decreased the analgesic effect of clonidine, whereas the analgesic effect to dexmedetomidine was unaffected. In the EEDQ experiments, the analgesic response to dexmedetomidine was restored to normal when 44% of the alpha 2 adrenoceptors in the spinal cord were available for agonist binding; comparatively more alpha 2 adrenoceptors (77%) were required for the analgesic response to clonidine to be restored. The recovery of the hypnotic response to dexmedetomidine after EEDQ treatment was retarded when compared with the recovery of the analgesic response to that compound. Greater than 77% of alpha 2 adrenoceptors in the locus ceruleus must be available for the hypnotic response to alpha 2 agonists to be expressed. CONCLUSIONS: Fewer alpha 2 adrenoceptors need to be available for analgesia to be produced by dexmedetomidine compared with the number required for analgesia by clonidine. This difference should result in less tolerance in the analgesic response to dexmedetomidine than to clonidine with chronic use. Dexmedetomidine requires fewer alpha 2 adrenoceptors to elicit an analgesic response than it does to elicit a hypnotic response. Thus the analgesic properties of alpha 2-adrenergic agonists persist after the hypnotic response has been attenuated after chronic alpha 2 agonist administration.

Adrenergic alpha-Agonists↗
PubMed1995

Role of pertussis toxin-sensitive G-proteins in the analgesic and anesthetic actions of alpha 2-adrenergic agonists in the rat.

BACKGROUND: alpha 2 Adrenoceptors are coupled to G-proteins sensitive to pertussis toxin (PTX) in the locus coeruleus. At this site, the hypnotic response to dexmedetomidine, an alpha 2 agonist, can be blocked by pretreatment with PTX. G-proteins sensitive to PTX may also be involved in the transduction of anesthetic and analgesic responses to alpha 2 agonists at supraspinal or spinal sites. To address this question the effects of pretreatment with PTX administered intracerebroventricularly, intrathecally, or a combination of the two were examined on the MAC for halothane, and the anesthetic-sparing and analgesic effects of a systemically administered alpha 2 agonist, dexmedetomidine. METHODS: Rats were cannulated intracerebroventricularly, intrathecally, and with a combination of intracerebroventricular/intrathecal and treated with PTX (0 and 2.5 micrograms intracerebroventricularly; 0 or 0.5 microgram intrathecally; 0 + 0 or 2.5 + 0.5 intracerebroventricular-intrathecal)). After 7 days, either the analgesic (tail-flick latency) or the MAC-sparing effects of a calculated 50% effective dose of dexmedetomidine were measured. To confirm that intracerebroventricularly administered PTX was effective, ribosylation of G-proteins was assessed in periventricular brain tissue. RESULTS: The analgesic action of dexmedetomidine was blocked by PTX intrathecally but not by PTX via the intracerebroventricular route. The MAC-sparing action of dexmedetomidine was not blocked by PTX via the intrathecal or intracerebroventricular routes alone or in combination. Yet, intracerebroventricularly administered PTX effectively ribosylated the G-proteins. CONCLUSIONS: Taken together with the authors' previous report, these data suggest that the hypnotic and the analgesic responses to dexmedetomidine are transduced via PTX-sensitive G-protein-coupled alpha 2 adrenoceptors but at separate sites (analgesic-spinal; hypnotic-locus coeruleus). Further studies are needed to localize the precise site(s) for the MAC-sparing effect of dexmedetomidine and to establish whether PTX-sensitive G-proteins are involved in this response.

Adrenergic alpha-2 Receptor Agonists↗
PubMed1995

Alpha-2 adrenergic modulation of sleep: time-of-day-dependent pharmacodynamic profiles of dexmedetomidine and clonidine in the rat.

Alpha adrenergic agonists such as clonidine are widely used for their antihypertensor effects, but they also cause sedation. The mechanisms underlying soporific effects of such compounds are poorly understood, but appear to involve the alpha-2 adrenergic receptor sub-type. To further investigate the role of this receptor in sleep-wake regulation, rats received injections i.p. either during their peak of activity (circadian time CT-18: 6 hr after lights out) or near the mid-point of their sleep-dominated phase (CT-5: 5 hr after lights on) with either the highly selective alpha-2 agonist dexmedetomidine (dMED) 0.02 to 0.04 mg/kg or the less selective alpha-2 agonist, clonidine 0.04 to 0.08 mg/kg, or vehicle. Clonidine and dMED showed remarkable overall similarities in their soporific profiles. Except for the lower dose of clonidine, both CT-5 and CT-18 treatments increased the percent of time spent in non-REM (NREM) sleep. The increase in NREM was followed by a reduction of NREM sleep that was accompanied by locomotor activity and body temperature above control levels. After CT-5 treatments, this period of reduced NREM sleep was followed by a secondary increase in NREM 7 to 10 hr posttreatment. REM sleep was markedly reduced for 9 to 10 hr after all treatments at both times of day, with elevated REM levels 18 to 30 hr posttreatment. Pre-treatment with the selective alpha-2 antagonist atipamezole (0.5 mg/kg) reversed the effects of CT-18 dMED 0.04 mg/kg except REM sleep suppression, which was only partially reversed. The NREM-inducing potency of dMED 0.02 mg/kg was greater when administered at CT-18 than at CT-5. Taken together with other evidence, these findings suggest that the profound NREM-inducing effects of dMED may be mediated by postsynaptic alpha-2 adrenoceptors. Furthermore, the pharmacodynamic action of alpha-2 adrenergic agonists, like many other sedative hypnotics (e.g., benzodiazepines), produce a hysteresis in sleep-wake regulation characterized by "rebound" waking after drug-induced sleep.

Adrenergic alpha-Agonists↗
PubMed1994

Chronic administration of an alpha 2 adrenergic agonist desensitizes rats to the anesthetic effects of dexmedetomidine.

alpha 2 adrenergic agonists are being administered perioperatively to facilitate the anesthetic management of the surgical patient. In some clinical settings, use of alpha 2 adrenergic agonists has been extended into the postoperative period to prolong the patients' sedative and stress-free state. We studied whether the administration of alpha 2 adrenergic agonists over an extended period of time would result in "desensitization" to the central actions of alpha 2 adrenergic agonists. Male Sprague-Dawley rats were administered dexmedetomidine, a highly selective alpha 2 adrenergic agonist, at rates varying between 1 and 10 micrograms.kg-1.h-1 via a chronically implanted SC osmotic pump. Spontaneous locomotor activity, tested in an open-field box, was significantly lower in both 3- and 10-micrograms.kg-1.h-1 treatment groups but returned to normal by the second or sixth day, respectively. The hypnotic response to dexmedetomidine IP was decreased in the 10-micrograms.kg-1.h-1 dose group from the second day, and by the fourth day in the 3-micrograms.kg-1.h-1 group. Recovery from the desensitized state was rapid and occurred on the third day after pump removal in the 3-micrograms.kg-1.h-1 group and by the fifth day after pump removal in the 10-micrograms.kg-1.h-1 dose group. By using a higher dose of dexmedetomidine IP (250 micrograms.kg in lieu of 100 micrograms/kg) at day 7 in "tolerant" rats, the hypnotic response could partially be "restored" towards normal. An attenuated hypnotic response could still be demonstrated even when dexmedetomidine was administered directly into the locus coeruleus (LC) in rats pretreated chronically with dexmedetomidine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗
PubMed1994

Perturbation of ion channel conductance alters the hypnotic response to the alpha 2-adrenergic agonist dexmedetomidine in the locus coeruleus of the rat.

BACKGROUND: The alpha 2-adrenergic agonists are members of a novel class of hypnotic-anesthetic agents that selectively bind to alpha 2 adrenoceptors in the locus coeruleus (LC) to initiate their pharmacologic action. The postreceptor molecular mechanism of the hypnotic action of alpha 2-adrenergic agonists remains unknown. In this study we addressed the role of conductance through a variety of calcium and potassium ion channels in the hypnotic action of dexmedetomidine in the LC of the rat. METHODS: Cannulas were inserted stereotactically into the LC of halothane-anesthetized rats (n = 318). After at least 48 h, rats were tested for loss of righting reflex in response to administration of the alpha 2-adrenergic agonist dexmedetomidine at a hypnotic (7.0 micrograms LC) or subhypnotic (3.5 micrograms LC) dose. To establish the mediating role of various species of calcium and potassium ion channels in the hypnotic response, rats were pretreated with the following drugs before the administration of dexmedetomidine LC:S(+)202791 (L-type calcium-channel activator), nifedipine and R(-)202791 (L-type calcium-channel blocker), SNX 111 (N-type calcium-channel blocker), SNX 230 (P-type calcium-channel blocker), quinine (calcium-activated and voltage-gated potassium-channel blocker), charybdotoxin (calcium-activated potassium-channel blocker), dendrotoxin (voltage-gated potassium-channel blocker), or glybenclamide (adenosine triphosphate-sensitive potassium-channel blocker). The drugs were used in doses not causing behavioral effects that could have confounded the interpretation of loss of righting reflex. RESULTS: SNX 230 and the dihydropyridines nifedipine and R(-)202791 produced loss of righting reflex in the presence of a subhypnotic dose of dexmedetomidine. The hypnotic-enhancing effects of the dihydropyridines could be blocked with S(+)202791, which also diminished loss of righting reflex in response to dexmedetomidine 7.0 micrograms LC. Quinine, dendrotoxin, and charybdotoxin each attenuated the hypnotic response to dexmedetomidine 7.0 micrograms LC. The hypnotic response to dexmedetomidine was not significantly altered by SNX 111 or glybenclamide. CONCLUSIONS: Inhibition of ion conductance through L- or P-type calcium channels and facilitation of conductance through voltage-gated or calcium-activated potassium channels may be involved in the mechanism of hypnotic action of alpha 2-adrenergic agonists. These changes in ion conductance were capable of producing membrane hyperpolarization and decreasing neuronal excitability. There was no evidence for the involvement of adenosine triphosphate-sensitive potassium channels or N-type calcium channels in the hypnotic response to dexmedetomidine.

Adrenergic alpha-Agonists↗
PubMed1993

The alpha 2 adrenergic agonist, dexmedetomidine, selectively attenuates ischemia-induced increases in striatal norepinephrine concentrations.

This study was designed to evaluate the ability of a selective alpha 2 adrenergic agonist (dexmedetomidine) to attenuate ischemia-induced increases in striatal norepinephrine, 3 methoxy-4-hydroxyphenethyleneglycol (MHPG), dopamine, and 5-hydroxyindoleacetic acid (5-HIAA). Following the induction of anesthesia with halothane and oxygen, microdialysis catheters were stereotactically inserted into the striatum of 9 New Zealand white rabbits. Monitored variables included epidural temperature, arterial blood gases and pH, mean arterial pressure, blood glucose concentrations and the electroencephalogram. Following collection of baseline samples of dialysate, animals were randomized to receive a continuous infusion of saline (n = 4) or dexmedetomidine (n = 5). Cerebral ischemia was produced by the inflation of a neck tourniquet and induction of deliberate hypotension. Dialysate collection continued during the ischemic period and for the ensuing 140 min of reperfusion. All dialysate was frozen at -80 degrees C prior to its analysis by liquid chromatography for catecholamine content. There were no significant differences between the two groups for temperature, arterial blood gases, or mean arterial pressure. Blood glucose concentrations increased in the dexmedetomidine group. The electroencephalogram became isoelectric within 30 s of tourniquet inflation in all animals. Analysis of the norepinephrine and MHPG levels revealed significantly lower values for the dexmedetomidine-treated group during and following the ischemic period. There were no differences between groups for extracellular dopamine or 5-HIAA concentrations. These results suggest that the alpha 2 agonist dexmedetomidine can selectively attenuate ischemia-induced increases in striatal norepinephrine concentrations.

Adrenergic alpha-Agonists↗
PubMed1993

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.

Adrenergic alpha-Agonists↗
PubMed1993

Role of imidazoline-preferring receptors in the genesis of epinephrine-induced arrhythmias in halothane-anesthetized dogs.

BACKGROUND: Drugs with a central alpha 2-adrenergic action can increase the threshold for halothane-epinephrine-induced arrhythmias. Recently, imidazoline-preferring receptors were shown to play a significant role in the hypotensive effect of alpha 2-adrenergic agonists containing an imidazole ring in their structure. To address the question of whether the antiarrhythmic property of the alpha 2-adrenergic agonists was caused by activation of alpha 2-adrenoceptors or imidazoline-preferring receptors in the central nervous system, the effect of an imidazoline (atipamezole) and a nonimidazoline (L-659,066 and yohimbine) alpha 2-adrenergic antagonist were examined as etiologic factors in the genesis of halothane-epinephrine-induced arrhythmias in dogs. METHODS: Adult mongrel dogs were anesthetized with halothane (1.3%) and monitored continuously for systemic arterial pressure and for premature ventricular contractions. The arrhythmogenic dose (AD) of epinephrine, defined as the smallest dose producing four or more premature ventricular contractions within a 15-s period, was determined in the presence of atipamezole (an imidazoline compound that acrosses the blood-brain barrier), L-659,066 (a nonimidazoline compound that does not penetrate the blood-brain barrier), and yohimbine (a nonimidazoline compound that passes the blood-brain barrier). These drugs were administered either intravenously or into the cisterna magna to assess the site of action for changes in responsiveness. RESULTS: Intravenous atipamezole decreased the AD of epinephrine in the dose-dependent fashion. However, neither L-659,066 nor yohimbine, administered peripherally, decreased the AD of epinephrine. Central administration of atipamezole also decreased the AD of epinephrine, while L-659,066, even if administered centrally, did not affect the AD of epinephrine in the presence of halothane. CONCLUSIONS: Because the imidazoline ring-containing alpha 2-adrenergic antagonist (atipamezole) potentiated the halothane-epinephrine-induced arrhythmias and the nonimidazole alpha 2-adrenergic antagonist (L-659,066 and yohimbine) did not, it is possible that the imidazoline-preferring, rather than the alpha 2-adrenergic, receptor is responsible for the antiarrhythmic property of alpha 2-adrenergic agonists.

Adrenergic alpha-Antagonists↗
PubMed1993

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.

Adrenergic alpha-Agonists↗
PubMed1993

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.

Adrenergic alpha-Agonists↗
PubMed1993

Neuroprotection by the alpha 2-adrenoreceptor agonist dexmedetomidine in a focal model of cerebral ischemia.

BACKGROUND: Dexmedetomidine, a highly selective alpha 2-adrenoreceptor agonist, decreases central sympathetic activity and reduces the anesthetic requirement of halothane. Preliminary studies show that dexmedetomidine improves the outcome from ischemic injury and, therefore, may have potential therapeutic value. METHODS: The authors studied 14 rabbits that underwent a 2-h occlusion of the left internal carotid, anterior cerebral, and middle cerebral arteries, followed by 4 h of reperfusion. Ten minutes after occlusion, the animals were treated with either normal saline (n = 7) or dexmedetomidine (n = 7) using a computer-controlled infusion rate calculated to maintain a steady state plasma concentration. Halothane concentration was reduced by 50% for dexmedetomidine-treated animals to maintain a comparable level of anesthesia. Somatosensory evoked potentials were used to confirm adequate ischemia, and injury was assessed by histopathology. RESULTS: There were significant differences in the area of ischemic neuronal damage between the groups in the cortex (halothane alone, 38.2 +/- 6.0% SEM vs. halothane plus dexmedetomidine, 20.0 +/- 2.7% SEM, P = 0.018), but not in the striatum (halothane alone, 68.7 +/- 12.6% SEM vs. halothane plus dexmedetomidine, 43.5 +/- 15.9% SEM, P = 0.24), nor in physiologic parameters. Dexmedetomidine plasma levels obtained every 90 min showed a mean of 4.0 +/- 0.15 ng/ml. CONCLUSIONS: Results from this study indicate that postischemic administration of dexmedetomidine, in a dose that reduces the anesthetic requirements by 50%, has a neuroprotective effect in this model of focal cerebral ischemia.

Adrenergic alpha-Agonists↗
PubMed1993

Implementation of a radioreceptor assay for dexmedetomidine.

We have implemented a radioreceptor assay for dexmedetomidine, a novel alpha 2-adrenoceptor agonist. Receptor-bearing membranes were prepared from rat cerebral cortex and 3H-clonidine, 4 nM, was used as the labeled ligand. Dexmedetomidine displaced 3H-clonidine in a linear fashion over a concentration of 2 x 10(-10) to 2 x 10(-8)M. The detection limit of dexmedetomidine (i.e. 10% of radiolabeled ligand displaced) in this assay was 50 pg.ml-1 which is comparable to that seen with the reference method which utilizes gas chromotography with mass spectrometer (GC/MS) in series (Vuorilehto et al. 1989). Endogenous catecholamines, which can displace the radiolabeled ligand from its binding site, could easily be eliminated with a one-step extraction procedure. A comparison was made with the reference method (GC/MS) in 47 human plasma samples; the correlation coefficient (r2) was 0.61 (P < 0.001). The radioreceptor assay was also successfully applied for determining dexmedetomidine concentration in rabbit samples. These data indicate that the radioreceptor assay can be utilized for characterizing the pharmacokinetics of novel alpha 2 agonists which are now being introduced into the clinical practice of anaesthesia.

Adrenergic alpha-Agonists↗
PubMed1993

Cardiopulmonary and behavioral responses to computer-driven infusion of detomidine in standing horses.

Cardiopulmonary and behavioral responses to detomidine, a potent alpha 2-adrenergic agonist, were determined at 4 plasma concentrations in standing horses. After instrumentation and baseline measurements in 7 horses (mean +/- SD for age and body weight, 6 +/- 2 years, and 531 +/- 48.5 kg, respectively), detomidine was infused to maintain 4 plasma concentrations: 2.1 +/- 0.5 (infusion 1), 7.2 +/- 3.5 (infusion 2), 19.1 +/- 5.1. (infusion 3), and 42.9 +/- 10 (infusion 4) ng/ml, by use of a computer-controlled infusion system. Detomidine caused concentration-dependent sedation and somnolence. These effects were profound during infusions 3 and 4, in which marked head ptosis developed and all horses leaned heavily on the bars of the restraining stocks. Heart rate and cardiac index decreased from baseline measurements (42 +/- 7 beats/min, 65 +/- 11 ml.kg of body weight-1.min-1) in linear relationship with the logarithm of plasma detomidine concentration (ie, heart rate = -4.7 [loge detomidine concentration] + 44.3, P < 0.01; cardiac index = -10.5 [loge detomidine concentration] + 73.6, P < 0.01). Second-degree atrioventricular block developed in 5 of 7 horses during infusion 3, and in 6 of 7 horses during infusion 4. Mean arterial blood pressure increased significantly from 118 +/- 11 mm of Hg at baseline to 146 +/- 27 mm of Hg at infusion 4. Similar responses were observed for mean pulmonary artery and right atrial pressures. Systemic vascular resistance (baseline, 182 +/- 28 mm of Hg.ml-1.min-1.kg-1) increased significantly during infusions 3 and 4 (to 294 +/- 79 and 380 +/- 58, respectively). (ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗
PubMed1992

Dexmedetomidine synergism with midazolam in the elevated plus-maze test in rats.

The anxiolytic profile of dexmedetomidine, a novel, highly-selective alpha 2-adrenergic agonist, was examined in rats in the elevated plus-maze test when administered either alone or in combination with the benzodiazepine agonist midazolam. Dexmedetomidine, 0.1-10 micrograms/kg, was inactive in modifying the rats' behavioral response in this test. Midazolam, 0.1-10 mg/kg, dose-dependently produced an anxiolytic-like profile characterized by an increased time spent in the open arms of the elevated plus-maze. A combination of dexmedetomidine 0.5 micrograms/kg and midazolam 0.5 mg/kg produced a synergistic interaction. This heterergic interaction of dexmedetomidine on midazolam's anxiolytic-like profile was dose-dependently blocked by pretreatment with an alpha 2-adrenergic antagonist, atipamezole, 10-50 micrograms/kg, and a benzodiazepine antagonist flumazenil, 1.0 and 10 mg/kg, but not by the alpha 1-adrenergic antagonist, prazosin, 0.1-10 mg/kg. While the transmembrane signal transduction pathways for benzodiazepine- and alpha 2-agonist responses do not share any molecular component, there does appear to be "crosstalk" between these two systems. These may involve GABA or noradrenergic "downstream" effects of either dexmedetomidine or midazolam, respectively.

Adrenergic alpha-Antagonists↗