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Ketamine is a widely used drug for its anesthetic and analgesic properties; it is also considered as a drug of abuse, as many cases of ketamine illegal consumption were reported. Ketamine is N-demethylated by liver microsomal cytochrome P450 into norketamine. The identification of the enzymes responsible for ketamine metabolism is of great importance in clinical practice. In the present study, we investigated the metabolism of ketamine in human liver microsomes at clinically relevant concentrations. Liver to plasma concentration ratio of ketamine was taken into consideration. Pooled human liver microsomes and human lymphoblast-expressed P450 isoforms were used. N-demethylation of ketamine was correlated with nifedipine oxidase activity (CYP3A4-specific marker reaction), and it was also correlated with S-mephenytoin N-demethylase activity (CYP2B6-specific marker reaction). Orphenadrine, a specific inhibitor to CYP2B6, and ketoconazole, a specific inhibitor to CYP3A4, inhibited the N-demethylation of ketamine in human liver microsomes. In human lymphoblast-expressed P450, the activities of CYP2B6 were higher than those of CYP3A4 and CYP2C9 at three concentrations of ketamine, 0.005, 0.05, and 0.5 mM. When these results were extrapolated using the average relative content of these P450 isoforms in human liver, CYP3A4 was the major enzyme involved in ketamine N-demethylation. The present study demonstrates that CYP3A4 is the principal enzyme responsible for ketamine N-demethylation in human liver microsomes and that CYP2B6 and CYP2C9 have a minor contribution to ketamine N-demethylation at therapeutic concentrations of the drug.

Advances in chiral chromatographic separations have given pharmacologists and toxicologists the tools to examine unexpected clinical results involving chiral drugs. The ability to unravel complex phenomena associated with drug transport and drug metabolism is presented in this manuscript. The relation between the chirality of the drug mefloquine and the intracellular concentrations of the drug cyclosporine is illustrated by examining the effect of the enantiomers of mefloquine on the transport activity of P-glycoprotein (Pgp). These studies were conducted using a liquid chromatographic column containing immobilized Pgp. The results demonstrated that (+)-mefloquine competitively displaced the Pgp substrate cyclosporine whereas (-)-mefloquine had no effect on cyclosporine-Pgp binding. The data suggest that cyclosporine cellular and CNS concentrations can be increased through the concomitant administration of (+)-mefloquine. The use of chirality in clinical and forensic situations is also illustrated by the metabolism of the enantiomers of ketamine (KET). The plasma concentrations of (+)-KET and (-)-KET and the norketamine metabolites (+)-NK and (-)-NK were measured in rat plasma using enantioselective gas chromatography. The separations were accomplished using a gas chromatography chiral stationary phase based on beta-cyclodextrin. The pharmacokinetic profiles of (+)-, (-)-KET and (+)-, (-)-NK were determined in control and protein-calorie malnourished (PCM) rats to determine the effect of PCM on ketamine metabolism and clearance. The results indicate that PCM produced a significant and stereoselective decrease in KET and NK metabolism. The data suggest that the effects of environmental factors (smoking, alcohol use, diet) and drug interactions (coadministered agents) can be measured using the changes in stereochemical metabolic and pharmacokinetic patterns of KET and similar drugs.

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.

Since the three-dimensional structure of the NMDA receptor has not been determined experimentally, indirect computer-assisted molecular modeling techniques appear to be of great usefulness in the characterization of the common pharmacophore of all NMDA receptor noncompetitive antagonists, despite their structural differences. Indeed, the conformational analysis of three different chemical families (MK801, PCP, dexoxadrol and their analogues), has allowed us to visualize the different conformations and configurations of each molecule. Superimposition with configurations 1 and 2 of the MK801 molecule has allowed us to propose active conformations and thereafter a geometrical characterization of the pharmacophore, especially the determination of the orientation of the nitrogen lone pair (NLP) related to the phenyl. On the other hand, electrostatic studies, combined with geometrical features, have allowed us to schematize the interaction mode of an active conformation to the binding site. Finally, studies of the molecular lipophilic potential (MLP) have provided us information on the position of lipophilic and hydrophilic zones of the pharmacophore.

Ketamine, used clinically as an intravenous analgetic and dissociative anaesthetic agent, is a racemate with both pharmacokinetic and pharmacodynamic enantioselectivity. S-ketamine has been found have a higher clearance and greater potency than R-ketamine as well as a greater therapeutic index. We performed a study in rats with two complementary paradigms: (i) constant rate "washin" infusion until fatal, (ii) brief infusion then "washout". These, respectively, allowed examination of ketamine and norketamine serial plasma enantiomer concentrations and tissue distribution at maximal and minimal drug effects. Both paradigms found plasma concentrations of R-ketamine>S-ketamine; however, tissue distribution coefficients for S-ketamine>R-ketamine. For paradigm (i), plasma concentrations of R-norketamine>S-norketamine; for paradigm (ii), R-norketamine>>S-norketamine initially, but S-norketamine>>R-norketamine later. Comparison of distribution coefficients of ketamine and norketamine enantiomers for the two paradigms provided indirect evidence for metabolic inversion. During washin, when circulating concentrations of ketamine enantiomers were high, uptake and metabolism occurred predominantly in the kidney and to a lesser extent in liver, lung and gut, with formation of R-norketamine by a (presumed) first-order process predominating. However, following washout, when circulating concentrations of ketamine enantiomers were low, uptake and metabolism was dominated by the kidney and gut. Under these conditions inversion of R- to S-ketamine appeared to predominate with subsequent metabolism to S-norketamine by (presumed) zero-order processes. In summary, different profiles for the uptake and metabolism of ketamine enantiomers were apparent following constant rate washin, and brief infusion washout, paradigms with i.v. rac-ketamine. Uptake into most tissues, and metabolism in some tissues, was enantioselective.

Ketamine (2-o-chlorophenenyl-2-methylaminocyclohexanone hydrochloride) is a dissociative general anaesthetic with neuroprotective properties. Since ketamine is optically active, we compared the neuroprotective efficacy of the (+)- or (-)-enantiomers in global cerebral ischaemia. Rat corticostriatal slices superfused with, or incubated in, artificial CSF at 34 degrees C were subjected to a brief ischaemic insult. Dopamine efflux was measured using fast cyclic voltammetry. Tissue metabolism was determined with 2,3,5-triphenyltetrazolium chloride staining, a marker of mitochondrial enzyme activity. In control slices, ischaemia caused rapid striatal dopamine release (to 122 microM over 18 s) after an initial delay of 149s. Racemic ketamine (100 micromol/l) significantly delayed (by 24%, P<0.05), slowed (by 63%, P<0.01) and reduced (by 27%, P<0.05) ischaemia-induced dopamine release. Ischaemia (10 min) also caused significant decreases in striatal (25%, P<0.01) and cortical (31%, P<0.001) metabolic activity, manifested as a drop in mean TTC staining intensity. Racemic ketamine and its (+)- and (-)-enantiomers (each 100 microM) attenuated the loss of metabolic activity in the striatum. However, in the cortex, only (+)-ketamine (100 microM) was significantly neuroprotective. We conclude that neuroprotection by ketamine in cerebral ischaemia is both region- and isomer-dependent.

A stereoselective high-performance liquid chromatographic method for the determination of the enantiomers of ketamine and its active metabolite, norketamine, in human plasma is described. The compounds were extracted from plasma by liquid-liquid extraction three times in a combination of cyclohexane with 2.5 M NaOH, 1 mM HCl and 1 M carbonate buffer. Stereoselective separation was achieved on a Chiralcel OD column with a mobile phase of n-hexane-2-propanol (98:2, v/v). The detection wavelength was 215 nm. The lower limits of the determination of the method were 5 ng/ml for ketamine and 10 ng/ml for norketamine. The intra- and inter-day coefficients of variation ranged from 2.9 to 9.8% and from 3.4 to 10.7% for all compounds, respectively. The method was sensitive and sufficiently reproducible for stereoselective monitoring of ketamine and norketamine in human plasma during pharmacokinetic studies after the administration of ketamine for analgesia.

Unlabelled: The effects of S(+)- and R(-)-ketamine on heteromeric N-methyl-D-aspartate receptor channels were investigated on the epsilon1/zeta1, epsilon2/zeta1, epsilon3/zeta1, and epsilon4/zeta1 channels expressed in Xenopus oocytes. S(+)-ketamine inhibited all four epsilon/zeta channels more effectively than R(-)-ketamine. The inhibitor concentrations for half-control response for S(+)-ketamine were quite similar among the four channels with 0.44-0.56 microM. However, the inhibitor concentrations for half-control response for R(-)-ketamine varied slightly among the four channels with 1.0 microM for epsilon2/zeta1 and epsilon3/zeta1 channels and 1.9-2.0 microM for epsilon1/zeta1 and epsilon4/zeta1 channels. Thus, the potency ratio of S(+)- and R(-)-ketamine for heteromeric channels was only slightly different among the epsilon/zeta channels., Implications: The potency order and ratio of ketamine isomers for inhibition of N-methyl-D-aspartate receptor channels may not be so different between the brain region and the developmental stage.

Unlabelled: Cytokine production, neutrophil adhesion to endothelial cells, and release of reactive oxygen species are thought to be critical events in sepsis or ischemia/reperfusion. Modulation of leukocyte responses by anesthetics may have an important role in limiting tissue injury under these conditions. Therefore, we investigated the effect of ketamine on the expression of CD18, CD62L, and oxygen radical production of human neutrophils in vitro and on interleukin-6 production in endotoxin-stimulated human whole blood. Ketamine inhibited both the N-formyl-methionyl-leucyl-phenylalanine- and phorbol 12-myristate 13-acetate-induced up-regulation of CD18 and shedding of CD62L, determined by flow cytometry, in a concentration-dependent manner. Ketamine also caused a significant suppression of oxygen radical generation of isolated human neutrophils. In addition, there was a significant decrease in endotoxin-stimulated interleukin-6 production in human whole blood. The inhibitory effects were similar for racemic ketamine and its isomers S(+)-ketamine and R(-)-ketamine, suggesting that the inhibition of stimulated neutrophil function is most likely not mediated through specific receptor interactions., Implications: Modulation of leukocyte responses by anesthetics may have an important role in limiting tissue injury in sepsis or ischemia/reperfusion. Therefore, we examined the effect of ketamine on stimulated neutrophil functions in vitro. These neutrophil functions were significantly inhibited by ketamine, independent of whether the racemic mixture or isomers were tested.

The management of the uncooperative pediatric patient undergoing minor surgical procedures has always been a great challenge. Several sedative techniques are available that will effectively alleviate anxiety, but short of general anesthesia, no sedative regimen is available that will enable treatment of the uncooperative child. Ketamine produces a unique anesthetic state, dissociative anesthesia, which safely and effectively enables treatment of these children. The pharmacology, proposed mechanisms of action, and clinical use of ketamine (alone and in combination with other agents) are reviewed and evaluated.

Background: Differences in the pharmacokinetics of the enantiomers of ketamine have been reported. The authors sought to determine whether these differences extend to pulmonary uptake and peripheral tissue distribution and to test the hypothesis that tissue distribution of the stereoisomers differs because of carrier-mediated drug transport., Methods: The dispositions of markers of intravascular space and blood flow (indocyanine green, ICG) and total body water and tissue perfusion (antipyrine) were determined along with S-(+)- and R-(-)-ketamine in five mongrel dogs. The dogs were studied while anesthetized with 2.0% halothane. Marker and drug dispositions were described by recirculatory pharmacokinetic models based on frequent early and less-frequent later arterial blood samples. These models characterize pulmonary uptake and the distribution of cardiac output into parallel peripheral circuits., Results: Plasma elimination clearance of the S-(+)-ketamine enantiomer, 29.9 ml x min(-1) x kg(-1), was higher than that of the R-(-)-enantiomer, 22.2 ml x min(-1) x kg(-1). The apparent pulmonary tissue volumes of the ketamine S-(+) and R-(-)-enantiomers (0.31 l) did not differ and was approximately twice that of antipyrine (0.16 l). The peripheral tissue distribution volumes and clearances and the total volume of distribution (2.1 l/kg) were the same for both stereoisomers when elimination clearances were modeled from the rapidly equilibrating peripheral compartment., Conclusions: Although the elimination clearance of S-(+)-ketamine is 35% greater than that of the R-(-)-enantiomer, there is no difference in the apparent pulmonary tissue volume or peripheral tissue distribution between the stereoisomers, suggesting that physicochemical properties of ketamine other than stereoisomerism determine its perfusion-limited tissue distribution.

Ketamine is usually administered as a racemate, which is composed of the two isomers, S(+)-and R(-)-ketamine. Recently, we have shown that racemic ketamine at clinical relevant concentrations specifically inhibits the transporter proteins for norepinephrine, dopamine and serotonin heterologously expressed in HEK-293 cells (Nishimura, M., Sato, K., Okada, T., Yoshiya, I., Schloss, P., Shimada, S. and Tohyama, M., Ketamine inhibits monoamine transporters expressed in human embryonic kidney 293 cells. Anesthesiology, 88 (1998) 768-774). Since ketamine interacts stereoselectively with most of its targets, we now investigated whether ketamine also exhibits stereoselectivity on the monoamine transporters. Only the dopamine transporter was found to be stereoselectively inhibited with S(+)-ketamine being almost eight times more potent than R(-)-ketamine (Ki = 46.9 microM for S(+)-ketamine, 390 microM for R(-)-ketamine). In contrast, ketamine exhibited no stereoselectivity for norepinephrine and serotonin transporters.

Ketamine is an intravenous drug with special properties that make it the only agent that presently serves as anesthetic, sedative, amnesiac and analgesic. Although it is sometimes forgotten, ketamine is still considered a viable drug. Water soluble, stable and non-irritant when administered intravenously, ketamine has rapid onset after intravenous injection and provides acceptable anesthesia when administered in continuous infusion. There properties make ketamine useful for total intravenous anesthesia. Both propofol and midazolam are effective in reducing ketamine's adverse side effects. Administered in children by oral, nasal, rectal and intramuscular routes, ketamine allows for gentle anesthetic induction. It can also serve as an adjuvant in regional anesthesia to supplement analgesia. In adults ketamine is most often used for major surgery, particularly in the elderly or in high risk patients who are in shock, severely dehydrated or hemodynamically unstable, or in obstetric patients with hypovolemia or hemorrhage. It is probably the anesthetic of choice for patients with hyperreactive airways. Ketamine's strong analgesic effect at subanesthetic doses allows it to be used as an analgesic during postoperative intensive care or as an analgesic-plus-sedative for patients receiving mechanical ventilation. Interest in using ketamine at low doses for cancer and non-cancer patients with chronic pain has grown recently.

Recognizing that the stereochemical structure of NMDA receptor antagonist ketamine provides valuable data about the relationship between its conformation and absolute configuration by CD-UV analysis, a method for the identification of ketamine enantiomers is proposed which avoids the need for authentic samples of the enantiomers. The ketamine enantiomers were separated by HPLC using Chiralcel OJ stationary phase. The in situ registration of CD and UV spectra, together with the application of the octant rule for cyclohexanone derivatives, makes possible the direct assignment of the eluted ketamine enantiomers., (Copyright 1999 Wiley-Liss, Inc.)

Purpose: To determine whether neurochemical activation of the N-methyl-D-aspartate (NMDA) receptor-gated ion channel shows quantitative changes, measured as binding of 11C-labeled (S)-[N-methyl]ketamine, in patients with medial temporal lobe epilepsy (MTLE)., Methods: Eight patients with MTLE who were evaluated regarding epilepsy surgery underwent positron emission tomography (PET) with (S)-[N-methyl-11C]ketamine. The presurgical investigations included magnetic resonance imaging (MRI), PET with 18F-fluoro-deoxyglucose (18FDG), and seizure monitoring by using video-EEG. The uptake of (S)-[N-methyl-11C]ketamine in the temporal lobe of ictal onset was compared with the contralateral side and correlated to changes in regional glucose metabolism measured by PET with 18FDG., Results: (S)-[N-methyl-11C]ketamine rapidly reached the brain, and high radioactivities were measured in the striatum, thalamic nuclei, and cortical regions. Overall the brain uptake and regional binding potentials of (S)-[N-methyl-11C]ketamine were similar to measurements observed previously in healthy controls. However, 20 min after administration, when blood flow influence was negligible, a side-to-side comparison revealed a 9-34% reduction of tracer radioactivity in the temporal lobes of ictal onset. At earlier times, the differences in binding potentials were less pronounced, 9-21%. The magnitude and distribution of the reduction were similar to the metabolic pattern seen on PET scans with 18FDG., Conclusions: Radioactivity uptake of intravenously administered (S)-[N-methyl-11C]ketamine was reduced in temporal lobes of ictal in patients with TLE. This may reflect reduced NMDA-receptor density, reduced perfusion, focal atrophy, or other factors.

On-line capillary electrophoresis-electrospray ionization mass spectrometry (CE-ESI-MS) has been employed for the determination of racemic mixtures of the chiral drugs, terbutaline, ketamine, and propranolol. Separation of the different chiral forms has been achieved by introducing cyclodextrins (CDs), which act as chiral selectors, into the CE operating electrolytes. Cyclodextrins function as chiral selectors in CE because of their ability to form host-guest complexes (inclusion complexes) of varying stability with an array of chiral drugs and other compounds. Derivatized forms of beta-CD (i.e., dimethyl-beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin) were used in this study due to their higher solubilities in the aqueous methanolic operating electrolyte than native beta-CD. Addition of minor quantities of methanol to the aqueous-based CE operating electrolytes improved the stability of electrospray ionization conditions and further enhanced CE resolution of the enantiomeric pairs relative to purely aqueous systems. Introduction of the CDs into the CE operating electrolytes caused suppression of analyte signals in ESI-MS, and the dependence of analyte signal intensities on the solution concentrations of the derivatized beta-CDs was examined. Under optimized conditions, the different enantiomeric forms of the compounds under investigation were successfully separated and detected by CE-ESI-MS.

The enantiomers of five racemic anaesthetic drugs were resolved with cyclodextrins using capillary zone electrophoresis. Parameters which affected the chiral resolution, such as type and concentration of cyclodextrin, temperature, and addition of organic modifier were investigated. The results show that the enantiomeric discrimination of the solutes is influenced by the structural shape of the solute molecules, separation temperature, and type of cyclodextrin. It was found that alpha-cyclodextrin was the best enantioselector for resolution of prilocaine and ketamine, while the enantiomers of mepivacaine, ropivacaine, and bupivacaine were resolved with beta-cyclodextrin and/or modified beta-cyclodextrins, i.e., methyl- and 2-hydroxypropyl-beta-cyclodextrin, as chiral selectors. The length of the alkyl chain on the amino group of the drug molecule had a strong effect on the enantioresolution of mepivacaine, ropivacaine, and bupivacaine. Baseline separation of racemic ketamine was achieved with alpha- and methyl-beta-cyclodextrin at 15 degrees C. Addition of 5 M urea to the running buffer containing beta-cyclodextrin at high concentrations resulted in the enantioseparation of prilocaine, mepivacaine, and ketamine. Enantioresolution was improved upon the addition of 10% methanol to the buffer containing urea and beta-cyclodextrin. Generally, the complex formed between the S-enantiomers and modified beta-cyclodextrins was stronger than the corresponding R-forms. An exception was prilocaine where the R-form gave a more stable complex both with alpha- and beta-cyclodextrin.

The compatibility of ketamine and morphine mixture was studied. In addition, pH adjustment to minimise local tissue irritation led to no change in stability of the mixture up to pH 5.9. It appears that ketamine and morphine mixtures are stable over a 24 h period.

Background: S(+) ketamine, because of its higher anesthetic potency and lower risk of psychotomimetic reactions, has been suggested to be superior to presently available racemic ketamine. The racemate is a direct vasodilator in vivo, and thus the authors investigated the vasorelaxing effects of ketamine enantiomers on rat aorta., Methods: Rat isolated aortic rings with and without endothelium were contracted with 3 x 10(-7) M norepinephrine. Then 10(-5) to 3 x 10(-3) M S(+), R(-), or racemic ketamine were added cumulatively. Vascular responses to ketamine were further studied in rings pretreated with the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine (NNLA), the adenosine triphosphate-sensitive K+ channel antagonist glibenclamide, and the L-type calcium channel blocking agent D888., Results: Ketamine enantiomers and the racemate produced concentration-dependent vasorelaxation. The relaxing effect of S(+) ketamine was significantly weaker compared with R(-) ketamine and the racemate reflected by the half-maximum effective concentration (EC50) values of 11.6 x 10(-4), 4.8 x 10(-4), and 6 x 10(-4) M, respectively. Removal of the endothelium and NNLA or glibenclamide pretreatment did not significantly alter the vasorelaxing effect of ketamine. In contrast, D888 pretreatment significantly shifted the concentration-effect curves of both S(+) and R(-) ketamine rightward (EC50 values of 18.9 x 10(-4) and 8.5 x 10(-4) M, respectively), whereas the difference between the isomers was not affected., Conclusions: Vasorelaxation by ketamine enantiomers is quantitatively stereoselective: The effect of S(+)ketamine is significantly weaker compared with that of the racemate and R(-) ketamine. This stereoselective difference is not due to nitric oxide release, activation of adenosine triphosphate-sensitive potassium channels, or differential inhibition of L-type calcium channels.

Unlabelled: The anaesthetic potency of the (S)-ketamine isomer is approximately double that of racemic ketamine. The aim of this study was to compare the recovery of cerebral function after a bolus of 1.3 mg/kg racemic ketamine or 0.65 mg/kg (S)-ketamine followed by continuous application of 4 or 2 mg/kg x h over 15 minutes., Methods: With their informed consent and approval of the local ethics committee 12 healthy volunteers were enrolled in a double-blind, cross-over study. All drugs were dissolved in identical volumes. On three dates with an interval of one week at least ketamine/NaCl, (S)-ketamine/physostigmine or (S)-ketamine/NaCl was administered (table 1). The sequence was randomized. In addition, the unspecific antagonistic potential of the centrally acting, cholinergic agonist physostigmine (0.012 mg/kg) after (S)-ketamine was tested against saline-placebo. Neuropsychological tests (tests 3-5 of the syndrome-short-test [Erzigkeit, see references]) were used to quantify cerebral function before and at 45, 75, 105, 135, 165 and 195 min after anaesthesia. All data are mean values and standard deviation. Comparisons over time and between drugs were carried out using two-dimensional analysis of variance (ANOVA). Wilcoxon-tests were used post-hoc. p < 0.05 was considered significant., Results: After (S)-ketamine the subjects were able to carry out the tasks more rapidly than after racemic ketamine (p < 0.05). Mean time to reach preoperative test performance +10% was 117.5 min for (S)-ketamine/physostigmine, 121.3 min for (S)-ketamine/NaCl and 141.6 min for racemic ketamine (p < 0.05 between (S)-ketamine and racemic ketamine). No differences were found between physostigmine and placebo. The incidence of side effects (mainly nausea, vomiting) was not different., Discussion: (S)-ketamine offers a shorter recovery time after short anaesthesia compared to racemic ketamine. The investigated dose of physostigmine was probably too low to produce antagonism of (S)-ketamine. An increased dosage of physostigmine has yet to be studied, but is likely to cause a higher rate of side effects such as nausea, vomiting, bradycardia and possibly even tonic-clonic seizures.

The pharmacological profile of ketamine: Until recently, clinically available ketamine was a racemic mixture containing equal amounts of two enantiomers, (S)- and (R)-ketamine. The pharmacological profile of racemic ketamine is characterized by the so called dissociative anesthetic state and profound sympathomimetic properties. Among the different sites of action, N-methyl-D-aspartate (NMDA)-receptor antagonism is considered to be the most important neuropharmacological mechanism of ketamine. Effects on opiate receptors, monoaminergic and cholinergic transmitters, and local anesthetic effects are obvious as well. Following intravenous administration, a rapid onset of action is seen within 1 min, lasting for about 10 min. The anaesthetic state is terminated due to redistribution, followed by hepatic and renal elimination with a half-life period of 2-3 h. For alternative administration, the intramuscular and oral route is also appropriate. The most important adverse effects are hallucinations and excessive increases in blood pressure and heart rate. These reactions can be attenuated or avoided by combining of ketamine with sedative or hypnotic drugs like midazolam and/or propofol. During controlled ventilation, increases in intracranial pressure are unlikely to occur. The special pharmacological profile of (S)-ketamine: In general, the pharmacological properties of (S)-ketamine are comparable to the racemic compound. On the different sites of action, qualitatively comparable effects were found, but significant quantitative differences also became obvious. When compared with (R)-ketamine and the racmic mixture, the analgesic and anesthetic potency of (S)-ketamine is threefold or twofold higher. Thus, a 50% reduction of dosage is possible to achieve comparable clinical results. Because of the faster elimination of (S)-ketamine, better control of anesthesia will be provided. In summary, the pharmacokinetic improvements of (S)-ketamine are characterized by a reduced drug load, along with more rapid recovery. The clinical use of (S)-ketamine: The clinical use of (S)-ketamine depends on its analgesic and sympathomimetic properties, whereas the anaesthetic potency remains in the background. In clinical anesthesiology, (S)-ketamine, especially in combination with midazolam and/or propofol, can be used for short procedures with preserved spontaneous ventilation, for induction of anesthesia in patients with shock or asthmatic disorders, and for induction and maintenance of anesthesia in caesarean sections. Additional indications are repeated anesthesia, for example, in burn patients, analgesia during delivery and diagnostic procedures and intramuscular administration in uncooperative patients. The value of (S)-ketamine as an analgesic component for total intravenous anesthesia has not been defined yet. In comparison with opioides, the advantages are related to improved hemodynamic stability and reduced postoperative respiratory depression. When (S)-ketamine, especially in combination with midazolam, is used for analgosedation in intensive care medicine, a reduction of exogenous catecholamine demand can be expected. Moreover, the effects on intestinal motility are superior to opioids. In combination with midazolam and propofol, excellent control of analgosedation was found, making both combinations suitable for situations in which repeated neurological assessment of patients is necessary. In emergency and disaster medicine, (S)-ketamine is of outstanding importance because of its minimal logistic requirements, the chance for intramuscular administration and the broad range of use for analgesia, anaesthesia and analgosedation as well. Further perspectives of (S)-ketamine may be the treatment of chronic pain and the assumed neuroprotective action of the substance.

Unlabelled: Clinically used ketamine is a racemic mixture of two isomers, (S)- and (R)-ketamine, in equal amounts. Previous investigations showed the anaesthetic potency of (S)-ketamine to be three times higher than that of (R)-ketamine. The aim of this study was to compare the effects of (S)-ketamine/midazolam and racemic ketamine/midazolam on endocrine and cardiovascular parameters, recovery, and side effects in unpremedicated patients during knee surgery., Methods: 41 patients scheduled for elective knee surgery were investigated in a prospective, double-blind, and randomised design. For induction of intravenous anesthesia, patients received 0.1 mg/kg midazolam, 0.003 mg/kg atropine, 1 mg/kg (S)-ketamine or 2 mg/kg racemic ketamine, respectively. For tracheal intubation, 1 mg vecuronium and 1.5 mg/kg suxamethonium were injected. After intubation and relaxation with a total dose of 0.1 mg/kg vecuronium, a continuous infusion of 0.5 mg/kg/h (S)- or 1 mg/kg/h racemic ketamine was administered throughout the surgery. In addition, 0.05 mg/kg/h midazolam was infused continuously in both groups throughout surgery. Ventilation was performed with N2O/O2 (FiO2 0.3). Blood samples were taken using a central venous line five times before induction as well as during and after surgery for analysis of adrenaline, noradrenaline (by high-pressure liquid chromatography with electrochemical detection), anti-diuretic hormone (ADH), adrenocorticotropic hormone (ACTH), and cortisol (by radioimmunoassay). In addition, systolic and diastolic arterial pressure (SAP, DAP), heart rate (HR), and arterial oxygen saturation were measured. The time intervals between the end of ketamine and midazolam infusion and the return of consciousness and orientation were recorded. The incidence and quality of dreams and other side effects were reported by the patients., Results: Biometric data of the groups were comparable. Plasma adrenaline and noradrenaline did not change significantly during anaesthesia. ADH increased significantly (p < 0.05) after skin incision in both groups.

The effects of the commercially available ketamine preparation (Ketanest), the ketamine racemate and of the two enantiomers, the R(-)-racemate and the S(+)-racemate, as well as its drug-free solvent were examined by N-formyl-methionyl-leucyl-phenylalanine-(FMLP)- and zymosan-induced oxygen radical production of polymorphonuclear cells (PMN). The racemate and the two enantiomers of ketamine suppressed FMLP- and zymosan-induced chemiluminescence of PMN in a dose-dependent fashion to the same extent. Therefore suppression of chemiluminescence of PMN by ketamine does not result from a specific receptor interaction.

Fentanyl (1-[2-phenethyl]-4-N-[N-propionylanilino]piperidine) is a potent synthetic opiate commonly used for surgical analgesia and sedation. Reports of abuse of this highly addictive drug among health care personnel have prompted the need to verify the concentration in the unused portion of single-dose ampules returned to the pharmacy. We describe a simple quantitative method for the analysis of fentanyl citrate (Sublimaze) in syringes returned to the pharmacy following surgery. Fentanyl citrate (0.1 mL) and 2H5-fentanyl (internal standard, 0.05 mL, 100 mg/L) were extracted with Toxi-A tubes (Toxi-Lab, Irvine, CA) and analyzed by gas chromatography-mass spectrometry. Calibration was linear from 1 to 60 mg/L (correlation coefficient of 0.997, n = 13) and had a limit of detection of 0.4 mg/L. Mean recovery at concentrations from 5 to 50 mg/L was 89% (range, 69-104%). No interferences were found with morphine, ketamine, midazolam, sufentanil, or alfentanil. These drugs were not selected for their potential chromatographic interference but for their availability in surgical syringes. This assay is useful in verifying that any unused fentanyl is discarded according to narcotic regulations, thereby avoiding the possibility of diversion for illicit consumption.

Isomers are two or more different substances with the same molecular formula (i.e., the same number of different types of atoms). There are two main types of isomerism: 1) structural isomerism, and 2) steroisomerism. Structural isomers (e.g., enflurane and isoflurane) have different molecular structures, and usually behave like different drugs. Occasionally, structural isomers are interconvertible (i.e., they are tautomers or dynamic isomers); this occurs with the barbiturates and midazolam. Steroisomers have identical structures, but a different configuration or spatial arrangement. Stereiosomerism in drugs is often due to chirality or "handedness"; i.e., the presence of right-handed (R)- and left-handed (S)- forms of drugs which are nonsuperimposable mirror images ("enantiomers"). Approximately 60% of anaesthetic agents are chiral drugs; some of these are administered as single enantiomers. However, many synthetic chiral drugs are equal mixtures of (R)- and (S)-isomers, and there are often important differences in their activity and pharmacokinetics. Halothane, enflurane, and isoflurane are chiral drugs with different anaesthetic potencies. Similar differences occur with intravenous anaesthetics; thus, (S) (+)-ketamine causes fewer psychotic emergence reactions, less agitated behaviour, and better intraoperative amnesia and analgesia than its enantiomer. Some local anaesthetics are administered as chiral mixtures; the (S)-isomers have a longer action because of enhanced vasoconstriction. (S)-prilocaine is more slowly metabolized than its enantiomer, while (S)-bupivacaine may produce less cardiotoxicity than (R)-bupivacaine. These differences suggest that some anaesthetic drugs (particularly ketamine and chiral local anaesthetics) should be administered as single enantiomers. In recent years, their synthesis has been greatly simplified, and almost all new drugs may soon be introduced in this form.(ABSTRACT TRUNCATED AT 250 WORDS)

In a randomized, double-blind study, we have examined the stereoselective disposition and pharmacodynamic characteristics of ketamine in surgical patients after i.v. administration of S(+)-ketamine 1 mg/kg body weight (25 patients) or racemic ketamine 2 mg/kg body weight (25 patients). S(+)-Ketamine was not inverted to R(-)-ketamine. After racemate administration we observed statistically significant (P < 0.01) smaller clearance and volume of distribution for R(-)-ketamine compared with S(+)-ketamine. In contrast, the pharmacokinetic variables of S(+)-ketamine were not significantly different between treatment groups. Systolic and diastolic arterial pressure and heart rate increased significantly (P < 0.005) in both groups. At 1, 3 and 15 min after S(+)-ketamine administration, significantly greater increase in systolic and diastolic pressures were observed compared with the racemate group. There was no correlation between the changes in haemodynamic variables and plasma catecholamine concentrations, which remained unaffected after administration of the medications.