Ketamine enantiomers differentially relax isolated coronary artery rings

BACKGROUND AND OBJECTIVE: It has been shown that racemic ketamine increases coronary blood flow and that this effect is at least in part due to a direct vasorelaxing effect of this substance. This study was designed to determine whether ketamine might stereoselectively relax isolated porcine coronary arteries. METHODS: Using the model of isolated vessels we studied the effects of S(+) ketamine, R(-) ketamine, and racemic ketamine (5-500 microg mL(-1)) on artery strips pre-contracted by either potassium chloride (KCl) or prostaglandin F2alpha (PGF2alpha). To elucidate possible mechanisms of action these experiments were repeated in the presence of one of the following compounds: N(omega)-nitro-L-arginine (L-NNA), indomethacin, glibenclamide, and tetraethylammonium (TEA) chloride, an inhibitor of the BK(Ca) K+ channel. RESULTS: Both isoforms and racemic ketamine relaxed isolated coronary arteries in a concentration-dependent manner in concentrations beyond those used in clinical practice. S(+) ketamine exerted the strongest vasorelaxing effect, followed by racemic ketamine and R(-) ketamine. Pretreatment with L-NNA, indomethacin, or glibenclamide did not alter the vasodilating properties of ketamine, whereas TEA chloride significantly attenuated the vasorelaxing effects of all the three forms of ketamine. CONCLUSIONS: Ketamine dilates coronary arteries in vitro when administered in high concentrations. There is a stereoselective difference with a stronger vasorelaxing effect of S(+) ketamine compared to racemic and R(-) ketamine. The impact of TEA chloride suggests that the activation of the BK(Ca) channel may contribute to the vasodilating effect of ketamine.     

Metabolism of ketamine stereoisomers by human liver microsomes.

Ketamine is used clinically as a racemic mixture of optical isomers that differ in their analgesic properties and psychomimetic effects. Administered individually, or together as the racemate, ketamine enantiomers differ in their hepatic clearance and duration of anesthetic effect. S(+) ketamine exhibits a greater clearance and faster anesthetic recovery compared to the racemate and a greater clearance compared to R(-) ketamine. Ketamine undergoes extensive hepatic metabolism, primarily via N-demethylation to norketamine, yet little is known about the human metabolism of ketamine enantiomers. The purpose of this investigation therefore was to characterize ketamine racemate and enantiomer metabolism by human liver and to test the hypothesis that differences in hepatic ketamine enantiomer metabolism can account for observed differences in ketamine enantiomer pharmacokinetics. Ketamine N-demethylation by microsomes from three human livers was measured by gas chromatography-mass spectrometry. At ketamine concentrations typically achieved during anesthesia (5 microM), the rate of S(+) ketamine demethylation was 20% greater than that of R(-) ketamine and 10% greater than that of the racemate (P < .05). At all ketamine concentrations, the rate of racemate demethylation was less than the sum of the rates for the individual enantiomers, reflecting a metabolic enantiomeric interactin whereby one ketamine enantiomer inhibits the metabolism of the other enantiomer. N-demethylation of racemic ketamine and each enantiomer was catalyzed by two apparent enzymes, a high affinity-low capacity enzyme (Km1 30-50 microM, Vmax1 2-6 nmoles.min-1 x nmole-1) and a low affinity-high capacity enzyme (Km2 600-800 microM, Vmax2 9-15 nmoles.min-1 x nmole-1).(ABSTRACT TRUNCATED AT 250 WORDS)     

The Effects of Ketamine and Its Enantiomers on the Morphine- or Dexmedetomidine-induced Antinociception after Intrathecal Administration in Rats

Background: The spinal administration of some N-methyl-d-aspartate receptor antagonists results in antinociception and potentiates the effects of opioids and [alpha]2-adrenoceptor agonists, but ketamine and its enantiomers have not been examined. The present study investigated the interactions of racemic ketamine, R (-)-ketamine and S (+)-ketamine with morphine and with dexmedetomidine.

Methods: Intrathecal catheters were implanted into male Wistar rats. Three days later, the acute nociceptive sensitivity was assessed using the tail-flick test. Analgesic latencies were converted to the percentage maximum possible effect. The dose that yielded 50% of the maximum possible effect (ED50) and dose-response and time-course curves were determined for the ketamines (30-300 [mu]g), morphine (0.1-3.0 [mu]g), dexmedetomidine (0.3-10.0 [mu]g), and mixtures of two doses of ketamines (30 or 100 [mu]g) with different doses of morphine or dexmedetomidine for fixed-dose analysis.

Results: Neither racemic ketamine nor its enantiomers alone had a significant effect on the tail-flick test, with the exception of the highest dose of racemic ketamine, which caused motor impairment. Morphine and dexmedetomidine each produced dose-dependent antinociception, with ED50 of 1.7 [mu]g (95% confidence interval: 1.04-2.32) and 4.85 [mu]g (3.96-5.79), respectively. A low dose (30 [mu]g) of racemic ketamine or its enantiomers did not influence the ED50 of morphine significantly. Coadministration of 100 [mu]g racemic ketamine or S (+)-ketamine, but not R (-)-ketamine, significantly enhanced and prolonged the antinociceptive effect of morphine. Both doses of racemic ketamine or its isomers significantly decreased the ED50 value for dexmedetomidine, although the higher dose of racemic or S (+)-ketamine had the highest potency. One-hundred micrograms of racemic ketamine or S (+)-ketamine also prolonged the effects of dexmedetomidine.     

S(+)-ketamine up-regulates neuronal regeneration associated proteins following glutamate injury in cultured rat hippocampal neurons

In previous studies, racemic ketamine improved neurological outcome after experimental brain injury and S(+)-ketamine demonstrated neuroprotective effects in neurons after damage in vitro. We compared the expression of regeneration-associated proteins in rat hippocampal neurons after glutamate injury and treatment with S(+)-ketamine versus racemic ketamine. Following an 8 minute exposure to 100 microM glutamate, neurons were maintained untreated or in the presence of S(+)-ketamine or racemic ketamine (10(-4) M, 10(-5) M, 10(-6) M) for one week. Growth-associated protein-43 (GAP-43) and synaptosomal-associated protein-25 (SNAP-25) was analyzed by Western Blotting, the mitochondrial transmembrane potential (MTP) by fluorescence imaging, and [3H]2-deoxy-D-glucose ([3H]2-DG) uptake by scintillation spectrometry. Seven days after exposure, GAP-43 decreased to 15% and SNAP-25 to 30% in the glutamate-injured, untreated neurons. The MTP declined to 50% and [3H]2-DG to 30%. Both S(+)-ketamine and racemic ketamine at 10(-4) M and 10(-5) M minimized the decline in MTP, almost maintaining it at control value. Additionally, S(+)-ketamine and racemic ketamine decreased the reduction in [3H]2-DG. S(+)-ketamine at 10(-4) M and 10(-5) M and racemic ketamine at 10(-4) M reduced the decline in SNAP-25 to 60% of controls (P < .05). However, S(+)-ketamine at 10(-4) M and 10(-5) M only reversed the decrease in GAP-43 to 50% and 40% of controls, respectively (P < .05). We conclude that the synthesis of a growth-associated protein related to plasticity and repair in the adult nervous system is increased by S(+)-ketamine but is not increased by racemic ketamine.     

Ketamine stereoselectively affects vasorelaxation mediated by ATP-sensitive K(+) channels in the rat aorta

BACKGROUND: The effect of ketamine on vasodilation mediated by adenosine triphosphate (ATP)-sensitive K(+) channels has not been studied. The present study was designed to determine whether ketamine might stereoselectively affect vasorelaxation induced by an ATP-sensitive K(+) channel opener in the isolated rat aorta. METHODS: Rings of the rat aorta with or without endothelium were suspended for isometric force recording. During contraction to phenylephrine (3 x 10(-7) M), vasorelaxation in response to an ATP-sensitive K(+) channel opener levcromakalim (10(-8) to 10(-5) M) or a nitric oxide donor sodium nitroprusside (10(-10) to 10(-5) M) was obtained. Glibenclamide (10(-5) M), S(+) ketamine (10(-4) M), or ketamine racemate (10(-5) to 10(-4) M) was applied 15 min before addition of phenylephrine. RESULTS: Vasorelaxation induced by levcromakalim was completely abolished by an ATP-sensitive K(+) channel antagonist glibenclamide (10(-5) M) in the aorta with or without endothelium. Ketamine racemate (3 x 10(-5) to 10(-4) M) significantly inhibited this vasorelaxation in a concentration-dependent fashion, whereas S(+) ketamine did not affect the relaxation. However, the highest concentration of ketamine racemate and S(+) ketamine used in the present study did not alter vasorelaxation in response to sodium nitroprusside in the aorta without endothelium. CONCLUSION: In the isolated rat aorta, clinically relevant concentrations of ketamine racemate can inhibit relaxation induced by an ATP-sensitive K(+) channel opener, whereas S(+) ketamine did not produce any inhibitory effect on this vasorelaxation. These results suggest that ketamine stereoselectively alters vasodilation ATP-sensitive K(+) channels in the conduit artery.     

S (+)-Ketamine Increases Muscle Sympathetic Activity and Maintains the Neural Response to Hypotensive Challenges in Humans

Background: S (+)-Ketamine is reported to exert twofold greater analgesic and hypnotic effects but a shorter recovery time in comparison with racemic ketamine, indicating possible differential effects of stereoisomers. However, cardiovascular regulation during S (+)-ketamine anesthesia has not been studied. Muscle sympathetic activity (MSA) may be an indicator of the underlying alterations of sympathetic outflow. Whether S (+)-ketamine decreases MSA in a similar manner as the racemate is not known. Thus, the authors tested the hypothesis that S (+)-ketamine changes MSA and the muscle sympathetic response to a hypotensive challenge.

Methods: Muscle sympathetic activity was recorded by microneurography in the peroneal nerve of six healthy participants before and during anesthesia with S (+)-ketamine (670 [mu]g/kg intravenously followed by 15 [mu]g [middle dot] kg-1 [middle dot] min-1). Catecholamine and ketamine plasma concentrations, heart rate, and arterial blood pressure were also determined. MSA responses to a hypotensive challenge were assessed by injection of sodium nitroprusside (2-10 [mu]g/kg) before and during S (+)-ketamine anesthesia. In the final step, increased arterial pressure observed during anesthesia with S (+)-ketamine was adjusted to preanesthetic values by sodium nitroprusside infusion (1-6 [mu]g [middle dot] kg-1 [middle dot] min-1).

Results: Anesthesia with S (+)-ketamine (ketamine plasma concentration 713 +/- 295 [mu]g/l) significantly increased MSA burst frequency (mean +/- SD; 18 +/- 6 to 35 +/- 11 bursts/min) and burst incidence (32 +/- 10 to 48 +/- 15 bursts/100 heartbeats) and was associated with a doubling of norepinephrine plasma concentration (from 159 +/- 52 to 373 +/- 136 pg/ml) parallel to the increase in MSA. Heart rate and arterial blood pressure also significantly increased. When increased arterial pressure during S (+)-ketamine was decreased to awake values with sodium nitroprusside, MSA increased further (to 53 +/- 24 bursts/min and 60 +/- 20 bursts/100 heartbeats, respectively). The MSA increase in response to the hypotensive challenge was fully maintained during anesthesia with S (+)-ketamine.     

Effects of anesthesia and recovery from ketamine racemate and enantiomers on regional cerebral glucose metabolism in rats

BACKGROUND: Unlike most anesthetics, ketamine racemate (S, R (+/-)-ketamine) induces heterogenous changes in cerebral metabolism. S, R (+/-)-ketamine is an equimolar mixture of two enantiomers, S (+)-ketamine and R (-)-ketamine, which differ in affinity for neuroreceptors and pharmacologic activities. This study investigated comparatively the effects of ketamine racemate and enantiomers on cerebral metabolism. METHODS: Regional cerebral metabolic rates for glucose (rCMRglc) were determined with the quantitative, autoradiographic [C]2-deoxy-d-glucose technique in 40 brain regions of Fischer-344 rats. rCMRglc were measured in three groups of rats during equimolar anesthesia, 10 min after intraperitoneal injection of 170 mg/kg S, R (+/-)-ketamine, S (+)-ketamine, or R (-)-ketamine; in three groups of rats during recovery from equivalent anesthesia, 20 min after intravenous injection of 20, 12.5, and 30 mg/kg S, R (+/-)-ketamine, S (+)-ketamine, or R (-)-ketamine; and in two groups of saline-injected control rats. RESULTS: S, R (+/-)-ketamine and S (+)-ketamine induced a sustained anesthesia; deep rCMRglc decreases in 22 and 14 cortical, thalamic, cerebellar, and brainstem regions; and rCMRglc increases in two limbic regions (average decreases, 23 and 15%). R (-)-ketamine determined a shorter anesthesia, lesser rCMRglc decreases in 11 brain areas, and marked rCMRglc increases in 14 basal ganglia and limbic regions (average decrease, 4%). S, R (+/-)-ketamine, S (+)-ketamine, and R (-)-ketamine all produced postanesthetic behavioral activation; widespread rCMRglc increases in 28, 16, and 20 cortical, thalamic, basal ganglia, limbic, and brainstem regions; and rCMRglc decreases in few auditory and limbic regions (average increases, 35, 13, and 20%). CONCLUSIONS: S, R (+/-)-ketamine and S (+)-ketamine anesthesia but not R (-)-ketamine anesthesia induced widespread rCMRglc reductions that were unreported but are typical of gaseous and intravenous general anesthetics. Postanesthetic recovery led to divergent, sharp behavioral and rCMRglc activations. The relation to dose of behavioral and rCMRglc effects differs from those of aminergic agents and resembles those of N-methyl-d-aspartate receptor antagonists, suggesting that ketamine racemate and enantiomers may preferentially interact with this receptor type.     

Effects of Anesthesia and Recovery from Ketamine Racemate and Enantiomers on Regional Cerebral Glucose Metabolism in Rats

Background: Unlike most anesthetics, ketamine racemate (S, R (+/-)-ketamine) induces heterogenous changes in cerebral metabolism. S, R (+/-)-ketamine is an equimolar mixture of two enantiomers, S (+)-ketamine and R (-)-ketamine, which differ in affinity for neuroreceptors and pharmacologic activities. This study investigated comparatively the effects of ketamine racemate and enantiomers on cerebral metabolism.

Methods: Regional cerebral metabolic rates for glucose (rCMRglc) were determined with the quantitative, autoradiographic [14C]2-deoxy-d-glucose technique in 40 brain regions of Fischer-344 rats. rCMRglc were measured in three groups of rats during equimolar anesthesia, 10 min after intraperitoneal injection of 170 mg/kg S, R (+/-)-ketamine, S (+)-ketamine, or R (-)-ketamine; in three groups of rats during recovery from equivalent anesthesia, 20 min after intravenous injection of 20, 12.5, and 30 mg/kg S, R (+/-)-ketamine, S (+)-ketamine, or R (-)-ketamine; and in two groups of saline-injected control rats.

Results: S, R (+/-)-ketamine and S (+)-ketamine induced a sustained anesthesia; deep rCMRglc decreases in 22 and 14 cortical, thalamic, cerebellar, and brainstem regions; and rCMRglc increases in two limbic regions (average decreases, 23 and 15%). R (-)-ketamine determined a shorter anesthesia, lesser rCMRglc decreases in 11 brain areas, and marked rCMRglc increases in 14 basal ganglia and limbic regions (average decrease, 4%). S, R (+/-)-ketamine, S (+)-ketamine, and R (-)-ketamine all produced postanesthetic behavioral activation; widespread rCMRglc increases in 28, 16, and 20 cortical, thalamic, basal ganglia, limbic, and brainstem regions; and rCMRglc decreases in few auditory and limbic regions (average increases, 35, 13, and 20%).     

Cognitive impairment after small-dose ketamine isomers in comparison to equianalgesic racemic ketamine in human volunteers

BACKGROUND: Ketamine is increasingly used in pain therapy but may impair brain functions. Mood and cognitive capacities were compared after equianalgesic small-dose S(+)-, R(-)-, and racemic ketamine in healthy volunteers. METHODS: Twenty-four subjects received intravenous 0.5 mg/kg racemic, 0.25 mg/kg S(+)-, and 1.0 mg/kg R(-)-ketamine in a prospective, randomized, double-blind, crossover study. Hemodynamic variables, mood, and cognitive capacities were assessed for 60 min. RESULTS: Transient increases in blood pressure, heart rate, and catecholamines were similar after administration of all drugs. At 20 min after injection, subjects felt less decline in concentration and were more brave after S(+)- than racemic ketamine. They reported being less lethargic but more out-of-control after R(-)- than racemic ketamine. Ketamine isomers induced less drowsiness, less lethargy, and less impairment in clustered subjective cognitive capacity than racemic ketamine for the 60-min study. Objective concentration capacity [test time, S(+): 25.4 +/- 15.2 s, R(-): 34.8 +/- 18.4 s, racemic ketamine: 40.8 +/- 20.8 s, mean +/- SD] and retention in primary memory [test time, S(+): 4.6 +/- 1.2 s, R(-): 4.2 +/- 1.4 s, racemic ketamine: 4.0 +/- 1.4 s, mean +/- SD] declined less after S(+)- than either R(-)- or racemic ketamine at 1 min. At 5 min, immediate recall, anterograde amnesia, retention in primary memory, short-term storage capacity, and intelligence quotient were less reduced after the isomers than racemic ketamine. Speed reading and central information flow decreased less after S(+)- than racemic ketamine. CONCLUSIONS: Early after injection, ketamine isomers induce less tiredness and cognitive impairment than equianalgesic small-dose racemic ketamine. In addition, S(+)-ketamine causes less decline in concentration capacity and primary memory. The differences in drug effects cannot be explained by stereoselective action on one given receptor.     

Cognitive Impairment after Small-dose Ketamine Isomers in Comparison to Equianalgesic Racemic Ketamine in Human Volunteers

Background: Ketamine is increasingly used in pain therapy but may impair brain functions. Mood and cognitive capacities were compared after equianalgesic small-dose S (+)-, R (-)-, and racemic ketamine in healthy volunteers.

Methods: Twenty-four subjects received intravenous 0.5 mg/kg racemic, 0.25 mg/kg S (+)-, and 1.0 mg/kg R (-)-ketamine in a prospective, randomized, double-blind, crossover study. Hemodynamic variables, mood, and cognitive capacities were assessed for 60 min.

Results: Transient increases in blood pressure, heart rate, and catecholamines were similar after administration of all drugs. At 20 min after injection, subjects felt less decline in concentration and were more brave after S (+)- than racemic ketamine. They reported being less lethargic but more out-of-control after R (-)- than racemic ketamine. Ketamine isomers induced less drowsiness, less lethargy, and less impairment in clustered subjective cognitive capacity than racemic ketamine for the 60-min study. Objective concentration capacity [test time, S (+): 25.4 +/- 15.2 s, R (-): 34.8 +/- 18.4 s, racemic ketamine: 40.8 +/- 20.8 s, mean +/- SD] and retention in primary memory [test time, S (+): 4.6 +/- 1.2 s, R (-): 4.2 +/- 1.4 s, racemic ketamine: 4.0 +/- 1.4 s, mean +/- SD] declined less after S (+)- than either R (-)- or racemic ketamine at 1 min. At 5 min, immediate recall, anterograde amnesia, retention in primary memory, short-term storage capacity, and intelligence quotient were less reduced after the isomers than racemic ketamine. Speed reading and central information flow decreased less after S (+)- than racemic ketamine.     

The effects of ketamine and its enantiomers on the morphine- or dexmedetomidine-induced antinociception after intrathecal administration in rats

BACKGROUND: The spinal administration of some N-methyl-d-aspartate receptor antagonists results in antinociception and potentiates the effects of opioids and alpha2-adrenoceptor agonists, but ketamine and its enantiomers have not been examined. The present study investigated the interactions of racemic ketamine, R(-)-ketamine and S(+)-ketamine with morphine and with dexmedetomidine. METHODS: Intrathecal catheters were implanted into male Wistar rats. Three days later, the acute nociceptive sensitivity was assessed using the tail-flick test. Analgesic latencies were converted to the percentage maximum possible effect. The dose that yielded 50% of the maximum possible effect (ED50) and dose-response and time-course curves were determined for the ketamines (30-300 microg), morphine (0.1-3.0 microg), dexmedetomidine (0.3-10.0 microg), and mixtures of two doses of ketamines (30 or 100 microg) with different doses of morphine or dexmedetomidine for fixed-dose analysis. RESULTS: Neither racemic ketamine nor its enantiomers alone had a significant effect on the tail-flick test, with the exception of the highest dose of racemic ketamine, which caused motor impairment. Morphine and dexmedetomidine each produced dose-dependent antinociception, with ED50 of 1.7 microg (95% confidence interval: 1.04-2.32) and 4. 85 microg (3.96-5.79), respectively. A low dose (30 microg) of racemic ketamine or its enantiomers did not influence the ED50 of morphine significantly. Coadministration of 100 microg racemic ketamine or S(+)-ketamine, but not R(-)-ketamine, significantly enhanced and prolonged the antinociceptive effect of morphine. Both doses of racemic ketamine or its isomers significantly decreased the ED50 value for dexmedetomidine, although the higher dose of racemic or S(+)-ketamine had the highest potency. One-hundred micrograms of racemic ketamine or S(+)-ketamine also prolonged the effects of dexmedetomidine. CONCLUSIONS: These data indicate that racemic ketamine and S(+)-ketamine, but not R(-)-ketamine, exhibit similar effectiveness in potentiating the antinociceptive effects of both morphine and dexmedetomidine.     

Synergistic Inhibition of Muscarinic Signaling by Ketamine Stereoisomers and the Preservative Benzethonium Chloride

Background: Ketamine (Ketalar; Parke-Davis, Morris Plains, NJ) has been shown to inhibit muscarinic signaling with a median inhibitory concentration (IC50) of 5.7 micro Meter. Whereas Ketalar is a racemic mixture, recent interest has focused on clinical use of the S(+) ketamine isomer, which is three times as potent an analgesic as the R(-) isomer yet seems to be associated with fewer psychoactive side effects. Therefore, the authors studied the effects of S(+) and R(-) ketamine and the preservative benzethonium chloride on muscarinic signaling.

Methods: Rat m1 muscarinic acetylcholine receptors were expressed recombinantly in Xenopus laevis oocytes. Ca2+ -activated Cl sup - currents in response to 10 sup -7 M acetyl-beta-methylcholine were determined by two-electrode voltage clamping in the presence of various concentrations of ketamine and benzethonium. Concentration-inhibition curves were constructed and used for algebraic and isobolographic analysis.

Results: The IC50 was 125 +/- 33 micro Meter for S(+) ketamine, and 91 +/- 19 micro Meter for R(-) ketamine. This difference was not statistically significant, indicating that muscarinic inhibition by ketamine is not stereoselective. The R(-)/S(+) mixture had an IC50 of 48 +/- 1 micro Meter, and thus the stereoisomers interact synergistically. When appropriate concentrations of benzethonium were added, an IC50 of 15 +/- 2 micro Meter resulted.     

Ketamine Stereoselectively Affects Vasorelaxation Mediated by ATP-sensitive K+ Channels in the Rat Aorta

Background: The effect of ketamine on vasodilation mediated by adenosine triphosphate (ATP)-sensitive K+ channels has not been studied. The present study was designed to determine whether ketamine might stereoselectively affect vasorelaxation induced by an ATP-sensitive K+ channel opener in the isolated rat aorta.

Methods: Rings of the rat aorta with or without endothelium were suspended for isometric force recording. During contraction to phenylephrine (3 x 10-7 m), vasorelaxation in response to an ATP-sensitive K+ channel opener levcromakalim (10-8 to 10-5 m) or a nitric oxide donor sodium nitroprusside (10-10 to 10-5 m) was obtained. Glibenclamide (10-5 m), S(+) ketamine (10-4 m), or ketamine racemate (10-5 to 10-4 m) was applied 15 min before addition of phenylephrine.

Results: Vasorelaxation induced by levcromakalim was completely abolished by an ATP-sensitive K+ channel antagonist glibenclamide (10-5 m) in the aorta with or without endothelium. Ketamine racemate (3 x 10-5 to 10-4 m) significantly inhibited this vasorelaxation in a concentration-dependent fashion, whereas S(+) ketamine did not affect the relaxation. However, the highest concentration of ketamine racemate and S(+) ketamine used in the present study did not alter vasorelaxation in response to sodium nitroprusside in the aorta without endothelium.     

A Comparison of Remifentanil and Morphine Sulfate for Acute Postoperative Analgesia after Total Intravenous Anesthesia with Remifentanil and Propofol

Background: The transition from remifentanil intraoperative anesthesia to postoperative analgesia must be planned carefully due to the short duration of action (3-10 min) of remifentanil hydrochloride, a potent, esterase-metabolized micro-opioid agonist. This study compared the efficacy and safety of transition regimens using remifentanil or morphine sulfate for immediate postoperative pain relief in patients who had surgery under general anesthesia with remifentanil/propofol.

Methods: One hundred fifty patients who had received open-label remifentanil and propofol for intraoperative anesthesia participated in this multicenter, double-blind, double-dummy study and were randomly assigned to either the remifentanil (R) group or the morphine sulfate (M) group. Twenty minutes before the anticipated end of surgery, the propofol infusion was decreased by 50%, and patients received either a placebo bolus (R group) or a bolus of 0.15 mg/kg morphine (M group). At the end of surgery, the propofol and remifentanil maintenance infusions were discontinued and the analgesic infusion was started: either 0.1 micro gram [center dot] kg sup -1 [center dot] min sup -1 remifentanil (R group) or placebo analgesic infusion (M group). During the 25 min after tracheal extubation, remifentanil titrations in increments of 0.025 micro gram [center dot] kg sup -1 [center dot] min sup -1 and placebo boluses (R group), or 2 mg intravenous morphine boluses and placebo rate increases (M group) were administered as necessary at 5-min intervals to control pain. Patients received the 0.075 mg/kg intravenous morphine bolus (R group) or placebo (M group) at 25 and 30 min after extubation, and the analgesic infusion was discontinued at 35 min. From 35 to 65 minutes after extubation, both groups received 2-6 mg open-label morphine analgesia every 5 min as needed.

Results: Successful analgesia, defined as no or mild pain with adequate respiration (respiratory rate [RR] >or= to 8 breaths/min and pulse oximetry >or= to 90%), was achieved in more patients in the R group than in the M group (58% vs. 33%, respectively) at 25 min after extubation (P < 0.05). The median remifentanil rate for successful analgesia was 0.125 micro gram [center dot] kg sup -1 [center dot] min sup -1 (range, 0.05-0.23 micro gram [center dot] kg sup -1 [center dot] min sup -1), and the median number of 2-mg morphine boluses used was 2 (range, 0-5 boluses). At 35 min after extubation, >or= to 74% of patients in both groups experienced moderate to severe pain. Median recovery times from the end of surgery were similar between groups. Transient respiratory depression, apnea, or both were the most frequent adverse events (14% for the R group vs. 6% for the M group; P > 0.05).     

Pharmacokinetics of Prilocaine after Intravenous Administration in Volunteers: Enantioselectivity

Background: Prilocaine exists in two stereoisomeric configurations, the enantiomers s(+)- and R(-)-prilocaine. The drug is clinically used as the racemate. This study examined the pharmacokinetics of the enantiomers after intravenous administration of the racemate.

Methods: Ten healthy male volunteers received 200 mg racemic prilocaine as a 10-min intravenous infusion. Blood samples were collected for 8 h after the start of the infusion. Plasma concentrations were measured by stereoselective high-performance liquid chromatography (HPLC). Unbound fractions of the enantiomers in blank blood samples, spiked with racemic prilocaine, were determined using equilibrium dialysis.

Results: The unbound fraction of R(-)-prilocaine (mean +/- SD, 70% +/- 8%) was smaller (P < 0.05) than that of S(+)-prilocaine (73% +/- 5%). The total plasma clearance of R(-)-prilocaine (2.57 +/- 0.46 l/min) was larger (P < 0.0001) than that of S(+)-prilocaine (1.91 +/- 0.30 l/min). The steady-state volume of distribution of R(-)-prilocaine (279 +/- 94 l) did not differ from that of S(+)-prilocaine (291 +/- 93 l). The terminal half-life of R(-)-prilocaine (87 +/- 27 min) was shorter (P < 0.05) than that of S(+)-prilocaine (124 +/- 64 min), as was the mean residence time of R(-)-prilocaine (108 +/- 30 min) compared with S(+)-prilocaine (155 +/- 59 min; P < 0.005).     

Cerebral physiological responses to bolus injection of racemic, S(+)- or R(-)-ketamine in the pig

BACKGROUND: Little is known about the influence of ketamine and its enantiomers on cerebral haemodynamics, and there are no direct comparison reports. This study was designed to evaluate cerebrovascular responses to bolus injections of racemic, S(+)- and R(-)-ketamine in an established experimental model. METHODS: Anaesthesia was induced with propofol in 14 pigs and maintained with fentanyl and vecuronium. The intra-arterial xenon clearance technique was used to calculate the cerebral blood flow (CBF). Eight pigs (part I) were given three consecutive 60-s intravenous (i.v.) bolus injections of 10 mg/kg of racemic ketamine (Ketalar, Pfizer), and cerebral and systemic physiological responses were studied for 30 min after each injection. Following the determination of equipotent doses of the racemate and its enantiomers by recumbency tests, bolus injections of racemic ketamine (10 mg/kg), S-ketamine (5 mg/kg) and R-ketamine (20 mg/kg) were given in randomized sequence to another six pigs (part II) and evaluated at 1, 5, 10, 15, 25 and 40 min. RESULTS: No statistically significant acute tolerance in the CBF response to racemic ketamine was found in part I of the study. In part II, the decreases in the mean arterial pressure (MAP) and CBF by S-ketamine were significantly smaller than those by racemic and R-ketamine (both P < 0.001). No study drug had any significant effect on the cerebral arteriovenous oxygen content difference (C(av)O(2)) over time, but S-ketamine was associated with lower C(av)O(2) than racemic ketamine (P = 0.008) and R-ketamine (P = 0.016). CONCLUSIONS: Bolus injection of S-ketamine was associated with less cerebral and systemic haemodynamic depression than racemic or R-ketamine in equipotent doses in this experimental model. These findings indicate possible advantages of S-ketamine over racemic ketamine.     

Pharmacokinetics of prilocaine after intravenous administration in volunteers: enantioselectivity

BACKGROUND: Prilocaine exists in two stereoisomeric configurations, the enantiomers S(+)- and R(-)-prilocaine. The drug is clinically used as the racemate. This study examined the pharmacokinetics of the enantiomers after intravenous administration of the racemate. METHODS: Ten healthy male volunteers received 200 mg racemic prilocaine as a 10-min intravenous infusion. Blood samples were collected for 8 h after the start of the infusion. Plasma concentrations were measured by stereoselective high-performance liquid chromatography (HPLC). Unbound fractions of the enantiomers in blank blood samples, spiked with racemic prilocaine, were determined using equilibrium dialysis. RESULTS: The unbound fraction of R(-)-prilocaine (mean +/- SD, 70%+/-8%) was smaller (P < 0.05) than that of S(+)-prilocaine (73%+/-5%). The total plasma clearance of R(-)-prilocaine (2.57+/-0.46 l/min) was larger (P < 0.0001) than that of S(+)-prilocaine (1.91+/-0.30 l/min). The steady-state volume of distribution of R(-)-prilocaine (279+/-94 l) did not differ from that of S(+)-prilocaine (291+/-93 l). The terminal half-life of R(-)-prilocaine (87+/-27 min) was shorter (P < 0.05) than that of S(+)-prilocaine (124+/-64 min), as was the mean residence time of R(-)-prilocaine (108+/-30 min) compared with S(+)-prilocaine (155+/-59 min; P < 0.005). CONCLUSIONS: The pharmacokinetics of prilocaine are enantioselective. The difference in clearance is most likely a result of a difference in intrinsic metabolic clearance. The difference in the pharmacokinetics of the enantiomers of prilocaine does not seem to be clinically relevant.     

Stereoselectivity of Bupivacaine in Local Anesthetic-sensitive Ion Channels of Peripheral Nerve

Background: The local anesthetic bupivacaine exists in two stereoisomeric forms, R(+)- and S(-)-bupivacaine. Because of its lower cardiac and central nervous system toxicity, attempts were made recently to introduce S(-)-bupivacaine into clinical anesthesia. We investigated stereoselective actions of R(+)- and S(-)-bupivacaine toward two local anesthetic-sensitive ion channels in peripheral nerve, the Na+ and the flicker K+ channel.

Methods: In patch-clamp experiments on enzymatically demyelinated peripheral amphibian nerve fibers, Na+ and flicker K+ channels were investigated in outside-out patches. Half-maximum inhibiting concentrations (IC50) were determined. For the flicker K+ channel, simultaneous block by R(+)-bupivacaine and S(-)-bupivacaine was analyzed for competition and association (k1) and dissociation rate constants (k-1) were determined.

Results: Both channels were reversibly blocked by R(+)- and S(-)-bupivacaine. The IC50 values (+/-SEM) for tonic Na+ channel block were 29 +/- 3 [mu]M and 44 +/- 3 [mu]M, respectively. IC50 values for flicker K+ channel block were 0.15 +/- 0.02 [mu]M and 11 +/- 1 [mu]M, respectively, resulting in a high stereopotency ratio (+/-) of 73. Simultaneously applied enantiomers competed for a single binding site. Rate constants k1 and k-1 were 0.83 +/- 0.13 x 106 M-1 [middle dot] s-1 and 0.13 +/- 0.03 s-1, respectively, for R(+)-bupivacaine and 1.90 +/- 0.20 x 106 M-1 [middle dot] s-1 and 8.3 +/- 1.0 s-1, respectively, for S(-)-bupivacaine.     

S(+)-ketamine, but not R(-)-ketamine, reduces postischemic adherence of neutrophils in the coronary system of isolated guinea pig hearts.

Polymorphonuclear neutrophils (PMN) play a crucial role in the initiation of reperfusion injury. In a previous study, we found that ketamine reduced the postischemic adherence of PMN to the intact coronary system of isolated guinea pig hearts. Because ketamine is a racemic mixture (1:1) of two optical enantiomers, we looked for possible differences in action between the stereoisomers. Seventy-six guinea pig hearts were perfused in the "Langendorff" mode under conditions of constant flow (5 mL/min) using modified Krebs-Henseleit buffer. After 15 min of global warm ischemia, freshly isolated human PMN (10(6)) were infused as a bolus into the coronary system during the second minute of reperfusion. PMN adhesion was expressed as the numeric difference between PMN recovered in the effluent and those applied. Series A hearts received 5 microM S(+), 5 microM R(-), or 10 microM racemic ketamine starting 20 min before ischemia and during reperfusion. In Series B hearts, 10 microM nitro-L-arginine, an inhibitor of NO synthase, was added to the perfusate. In Series C, PMN were preincubated for 15 min with 5 microM S(+)- or R(-)-ketamine. Coronary vascular leak was assessed by measuring the rate of formation of transudate on the epicardial surface. Ischemia/reperfusion without anesthetics increased coronary PMN adherence from 25.5% +/-2.3% (basal) to 35.3%+/-1.5% of the number applied. S(+)-ketamine reduced postischemic adherence in each series (A, 25.5%+/-5.1%; B, 22.5%+/-1.7%; C, 25.3%+/-7.7%), as did racemate (A, 26.4%+/-3.7%). Although 5 microM R(-)-ketamine had no effect on adhesion (A, 30.5%+/-6.7%; B, 34.3%+/-5.1%; C, 34.3%+/-4.3%), it significantly increased vascular leak in the presence of NOLAG. These findings indicate stereoselective differences in biological action between the two ketamine isomers: S(+)-ketamine inhibited PMN adherence, R(-)-ketamine worsened coronary vascular leak in reperfused isolated hearts. IMPLICATIONS: In this study, we demonstrated stereoselective differences in the biologic action of the two ketamine isomers in an animal model of myocardial ischemia. Polymorphonuclear neutrophil adherence to the coronary vasculature after ischemia was inhibited by S(+)-ketamine, whereas R(-)-ketamine increased coronary vascular fluid leak.     

Influence of Acidosis on Cardiotonic Effects of Milrinone

Background: The present study was designed to determine whether augmentation of cardiac performance by milrinone is affected by acidosis in in vivo canine and in vitro guinea pig preparations, and to elucidate a mechanism in relation to the cyclic adenosine monophosphate (cAMP) formation.

Methods: Halothane-anesthetized, ventilated dogs were randomly assigned to a control group (arterial pH [pHa] [nearly =] 7.4, base excess [BE] > -2 mM; n = 7), mild acidosis group (pHa [nearly =] 7.2, BE < -9 mM; n = 7), or severe acidosis group (pHa < 7, BE < -20 mM; n = 6). Arterial blood pressure, left ventricular pressure (including maximum rate of increase, LV dP/dtmax), and pulmonary blood flow (PBF) were measured. Acidosis was induced by transient hypoxia and maintained with hydrogen chloride infusion. Hemodynamic responses to milrinone infusions at 2 and 5 micro gram [center dot] kg sup -1 [center dot] min were then studied. In addition, left atria and right ventricular strips were dissected from guinea pig hearts and suspended in HEPES-Tyrode solution, with pH values adjusted to 7.4, 7, or 6.6. The concentration-response relation of isometric contractions for milrinone (10 sup -7 to 10 sup -4 M) and 8-bromo-cAP (10 sup -4 to 10 sup -3 M) were determined.

Results: In the control group of dogs, significant increases in LN dP/dtmax (2,674 +/- 822 to 3,999 +/- 1,016 mmHg/s [means +/- SD]) and PBF (2.04 +/- 0.98 to 2.44 +/- 0.96 l/min [means +/- SD]) were seen with a milrinone infusion of 5 micro gram [center dot] kg sup -1 [center dot] min sup -1. In the mild acidosis group, 5 micro gram [center dot] kg sup -1 min sup -1 milrinone also increased LV dP/dtmax and PBF. However, neither LV dP/dtmax nor PBF changed in the severe acidosis group. In in vitro experiments, milrinone exerted a positive inotropic effect in a concentration-dependent manner on the right ventricular preparations at pH 7.4, but not at pH 7 and 6.6, whereas no significant difference was observed in inotropic responses to 8-bromo-cAMP at pH values of 6.6, 7, and 7.4 on the right ventricular strips. In the right ventricular in vitro preparation, 10 sup -4 M milrinone was accompanied by a significant increase in intracellular cAMP content at a pH of 7.4 but not 7.