General inhalational anesthetics - pharmacodynamics, pharmacokinetics and chiral properties.

Since the advent of nitric oxide, diethyl ether, chloroform and cyclopropane, the greatest advancement in the area of general inhalational anesthetics has been achieved by the introduction of fluorinated anesthetics and the relevant chiral techniques. This progress led to marked decrease in mortality rates in anesthesia. In the group of chiral fluorinated compounds, halothane (Fluotan®), isoflurane (Foran®), desflurane (Supran®) and enflurane (Ehran®) are deployed as volatile anesthetics. Chiral anesthetics possess a stereogenic center in their molecules and thus exist as two enantiomers (S)-(+) and (R)-(-). Although these chiral anesthetics are used as racemates, it is crucial to study besides the bioactivities of the racemic compounds also the biological activity and other properties of the particular enantiomers. The present survey discusses the drug category known as inhalational anesthetics in regard to their chiral aspects. These compounds exhibit marked differences between the (R) and (S)-enantiomers in their pharmacodynamics, pharmacokinetics and toxicity. The main analytical technique employed in the enantioseparation of these compounds is gas chromatography (GC). This review lists the individual chiral phases (chiral selectors) used in the enantioseparation as well as in pharmacokinetic studies. The possibilities of preparation of these compounds in their enantiomerically pure form by means of stereoselective synthesis are also mentioned.

[Determination of Sevoflurane, Isoflurane and Enflurane in the air of workplace by gas chromatography].

Objective: To establish a solvent desorption gas chromatographic method for determination of Sevoflurane, Isoflurane and Enflurane in the air of the Workplace. Methods: Sevoflurane, Isoflurane and Enflurane were collected with activated carbon tube and desorbed with dichloromethane, separated with DB-1 capillary columns, and then detected with flame ionization detector. Results: The linearity ranges were 1.9-304.8 µg/ml for Sevoflurane, 2.1-300.4 µg/ml for Isoflurane and 1.7-305.2 µg/ml for Enflurane, The correlation coefficient was both >0.999. Their limits of detection were 0.6 µg/ml, 0.6 µg/ml and 0.5 µg/ml, and Their limits of quatification were 1.9 µg/ml, 2.1 µg/ml and 1.7 µg/ml, and their minimum detectable concentrations were 0.1、0.2 and 0.1 mg/m(3) per 4.5 L of air. Their relative standard deviations (RSD) were 2.5%-3.0%, 2.3%-3.1% and 2.2%-3.0%. The average desorption efficiencies were 101.1%-103.3%, 100.7%-102.7% and 101.0%-102.9%. The sampling efficiency was both 100%. The breakthrough volume of 100 mg actived carbon was 3.7 mg, 3.4 mg and 3.4 mg. Sevoflurane, Isoflurane and Enflurane in activated carbon tube could be kept at least 10 days at room temperature without significant losses. Conclusion: The method shows lower detection limit, high accuracy and precision. It is feasible for determination of Sevoflurane, Isoflurane and Enflurane in the air of workplace.

Programmable Peptide-Cross-Linked Nucleic Acid Nanocapsules as a Modular Platform for Enzyme Specific Cargo Release.

Herein we describe a modular assembly strategy for photo-cross-linking peptides into nucleic acid functionalized nanocapsules. The peptides embedded within the nanocapsules form discrete nanoscale populations capable of gating the release of molecular and nanoscale cargo using enzyme-substrate recognition as a triggered release mechanism. Using photocatalyzed thiol-yne chemistry, different peptide cross-linkers were effectively incorporated into the nanocapsules and screened against different proteases to test for degradation specificity both in vitro and in cell culture. By using a combination of fluorescence assays, confocal and TEM microscopy, the particles were shown to be highly specific for their enzyme targets, even between enzymes of similar protease classes. The rapid and modular nature of the assembly strategy has the potential to be applied to both intracellular and extracellular biosensing and drug delivery applications.

Cardiac Calcium Release Channel (Ryanodine Receptor 2) Regulation by Halogenated Anesthetics.

BACKGROUND: Halogenated anesthetics activate cardiac ryanodine receptor 2-mediated sarcoplasmic reticulum Ca release, leading to sarcoplasmic reticulum Ca depletion, reduced cardiac function, and providing cell protection against ischemia-reperfusion injury. Anesthetic activation of ryanodine receptor 2 is poorly defined, leaving aspects of the protective mechanism uncertain. METHODS: Ryanodine receptor 2 from the sheep heart was incorporated into artificial lipid bilayers, and their gating properties were measured in response to five halogenated anesthetics. RESULTS: Each anesthetic rapidly and reversibly activated ryanodine receptor 2, but only from the cytoplasmic side. Relative activation levels were as follows: halothane (approximately 4-fold; n = 8), desflurane and enflurane (approximately 3-fold,n = 9), and isoflurane and sevoflurane (approximately 1.5-fold, n = 7, 10). Half-activating concentrations (Ka) were in the range 1.3 to 2.1 mM (1.4 to 2.6 minimum alveolar concentration [MAC]) with the exception of isoflurane (5.3 mM, 6.6 minimum alveolar concentration). Dantrolene (10 µM with 100 nM calmodulin) inhibited ryanodine receptor 2 by 40% but did not alter the Ka for halothane activation. Halothane potentiated luminal and cytoplasmic Ca activation of ryanodine receptor 2 but had no effect on Mg inhibition. Halothane activated ryanodine receptor 2 in the absence and presence (2 mM) of adenosine triphosphate (ATP). Adenosine, a competitive antagonist to ATP activation of ryanodine receptor 2, did not antagonize halothane activation in the absence of ATP. CONCLUSIONS: At clinical concentrations (1 MAC), halothane desflurane and enflurane activated ryanodine receptor 2, whereas isoflurane and sevoflurane were ineffective. Dantrolene inhibition of ryanodine receptor 2 substantially negated the activating effects of anesthetics. Halothane acted independently of the adenine nucleotide-binding site on ryanodine receptor 2. The previously observed adenosine antagonism of halothane activation of sarcoplasmic reticulum Ca release was due to competition between adenosine and ATP, rather than between halothane and ATP.

Conformational Exploration of Enflurane in Solution and in a Biological Environment.

Enflurane is a fluorinated volatile anesthetic, whose bioactive conformation is not known. Actually, a few studies have reported on the conformations of enflurane in nonpolar solution and gas phase. The present computational and spectroscopic (infrared and NMR) work shows that three pairs of isoenergetic conformers take place in the gas phase, neat liquid, polar, and nonpolar solutions. According to docking studies, a single conformation is largely preferred over its isoenergetic isomers to complex with the active site of Integrin LFA-1 enzyme (PDB code: 3F78 ), where the widely used anesthetic isoflurane (a constitutional isomer of enflurane) is known to bind. Weak hydrogen bonding from an electrostatic interaction between the CHF2 hydrogen and the central CF2 fluorines was not found to rule the conformational isomerism of enflurane. Moreover, intramolecular interactions based on steric, electrostatic, and hyperconjugative effects usually invoked to describe the anomeric effect are not responsible for the possible bioactive conformation of enflurane, which is rather governed by the enzyme induced fit.

Inhalation anesthesia is preferable for recording rat cardiac function using an electrocardiogram.

The effects of inhalation anesthesia (2% isoflurane, sevoflurane, or enflurane) and intraperitoneal anesthesia with pentobarbital (65 mg/kg) were compared in rats using an electrocardiogram (ECG) and determination of blood oxygen saturation (SPO2) levels. Following inhalation anesthesia, heart rate (HR) and SPO2 were acceptable while pentobarbital anesthesia decreased HR and SPO2 significantly. This indicates that inhalation anesthesia is more preferable than pentobarbital anesthesia when evaluating cardiovascular factors. Additionally, pentobarbital significantly increased HR variability (HRV), suggesting a regulatory effect of pentobarbital on the autonomic nervous system, and resulted in a decreased response of the baro-reflex system. Propranolol or atropine had limited effects on ECG recording following pentobarbital anesthesia. Taken together, these data suggest that inhalation anesthesia is suitable for conducting hemodynamic analyses in the rat.

Up-regulation of Alzheimer's disease-associated proteins may cause enflurane anesthesia induced cognitive decline in aged rats.

Isoflurane anesthesia can cause post-operative cognitive dysfunction in elderly patients. As an isomer of isoflurane, enflurane may also account for cognitive dysfunction. However, the mechanism of enflurane-induced cognitive dysfunction remains obscure. In this study, we investigated the effects of enflurane anesthesia on cognitive function and the possible roles of ß-amyloid protein and phosphorylated tau protein in response to enflurane anesthesia in aged rats. After intraperitoneal injection of enflurane, the Morris water maze and the step-down passive avoidance tests were conducted to test the cognitive ability and memory. The enflurane group showed prolonged escape latency, extended space exploration time and increased number of errors at early stage after enflurane anesthesia, suggesting that enflurane should be responsible for the impairment of cognition in aged rats. In addition, we analyzed the expression level of ß-amyloid and phosphorylation level of tau in the hippocampus by immunoblotting. Interestingly, the levels of ß-amyloid and phosphorylated tau in the hippocampus increased significantly at early stage and then restored to pre-anesthetic levels. Taken together, our results suggest that increasing of ß-amyloid and phosphorylation of tau are important to cause cognitive decline in aged rats during initial stage after enflurane anesthesia.

Ventilation/perfusion ratios measured by multiple inert gas elimination during experimental cardiopulmonary resuscitation.

BACKGROUND: During cardiopulmonary resuscitation (CPR) the ventilation/perfusion distribution (VA /Q) within the lung is difficult to assess. This experimental study examines the capability of multiple inert gas elimination (MIGET) to determine VA /Q under CPR conditions in a pig model. METHODS: Twenty-one anaesthetised pigs were randomised to three fractions of inspired oxygen (1.0, 0.7 or 0.21). VA/ Q by micropore membrane inlet mass spectrometry-derived MIGET was determined at baseline and during CPR following induction of ventricular fibrillation. Haemodynamics, blood gases, ventilation distribution by electrical impedance tomography and return of spontaneous circulation were assessed. Intergroup differences were analysed by non-parametric testing. RESULTS: MIGET measurements were feasible in all animals with an excellent correlation of measured and predicted arterial oxygen partial pressure (R(2) = 0.96, n = 21 for baseline; R(2) = 0.82, n = 21 for CPR). CPR induces a significant shift from normal VA /Q ratios to the high VA /Q range. Electrical impedance tomography indicates a dorsal to ventral shift of the ventilation distribution. Diverging pulmonary shunt fractions induced by the three inspired oxygen levels considerably increased during CPR and were traceable by MIGET, while 100% oxygen most negatively influenced the VA /Q. Return of spontaneous circulation were achieved in 52% of the animals. CONCLUSIONS: VA /Q assessment by MIGET is feasible during CPR and provides a novel tool for experimental purposes. Changes in VA /Q caused by different oxygen fractions are traceable during CPR. Beyond pulmonary perfusion deficits, these data imply an influence of the inspired oxygen level on VA /Q. Higher oxygen levels significantly increase shunt fractions and impair the normal VA /Q ratio.

Salient features of enantioselective gas chromatography: the enantiomeric differentiation of chiral inhalation anesthetics as a representative methodological case in point.

The enantiomeric differentiation of the volatile chiral inhalation anesthetics enflurane, isoflurane, and desflurane by analytical and preparative gas chromatography on various modified cyclodextrins is described. Very large enantioseparation factors α are obtained on the chiral selector octakis(3-O-butanoyl-2,6-di-O-pentyl)-γ-cyclodextrin (Lipodex E). The gas-chromatographically observed enantioselectivities are corroborated by NMR-spectroscopy using Lipodex E as chiral solvating agent and by various sensor devices using Lipodex E as sensitive chiral coating layer. The assignment of the absolute configuration of desflurane is clarified. Methods are described for the determination of the enantiomeric distribution of chiral inhalation anesthetics during narcosis in clinical trials. The quantitation of enantiomers in a sample by the method of enantiomeric labeling is outlined. Reliable thermodynamic parameters of enantioselectivity are determined by using the retention-increment R' approach for the enantiomeric differentiation of various chiral halocarbon selectands on diluted cyclodextrin selectors.

Exposure to halogenated ethers causes neurodegeneration and behavioural changes in young healthy experimental animals: a systematic review and meta analyses.

The FDA issued a warning that repeated and prolonged use of inhalational anaesthetics in children younger than 3 years may increase the risk of neurological damage. Robust clinical evidence supporting this warning is however lacking. A systematic review of all preclinical evidence concerning isoflurane, sevoflurane, desflurane and enflurane exposure in young experimental animals on neurodegeneration and behaviour may elucidate how severe this risk actually is PubMed and Embase were comprehensively searched on November 23, 2022. Based on predefined selection criteria the obtained references were screened by two independent reviewers. Data regarding study design and outcome data (Caspase-3 and TUNEL for neurodegeneration, Morris water maze (MWM), Elevated plus maze (EPM), Open field (OF) and Fear conditioning (FC)) were extracted, and individual effect sizes were calculated and subsequently pooled using the random effects model. Subgroup analyses were predefined and conducted for species, sex, age at anesthesia, repeated or single exposure and on time of outcome measurement. Out of the 19.796 references screened 324 could be included in the review. For enflurane there were too few studies to conduct meta-analysis (n = 1). Exposure to sevoflurane, isoflurane and desflurane significantly increases Caspase-3 levels and TUNEL levels. Further, sevoflurane and isoflurane also cause learning and memory impairment, and increase anxiety. Desflurane showed little effect on learning and memory, and no effect on anxiety. Long term effects of sevoflurane and isoflurane on neurodegeneration could not be analysed due to too few studies. For behavioural outcomes, however, this was possible and revealed that sevoflurane caused impaired learning and memory in all three related outcomes and increased anxiety in the elevated plus maze. For isoflurane, impaired learning and memory was observed as well, but only sufficient data was available for two of the learning and memory related outcomes. Further, single exposure to either sevoflurane or isoflurane increased neurodegeneration and impaired learning and memory. In summary, we show evidence that exposure to halogenated ethers causes neurodegeneration and behavioural changes. These effects are most pronounced for sevoflurane and isoflurane and already present after single exposure. To date there are not sufficient studies to estimate the presence of long term neurodegenerative effects. Nevertheless, we provide evidence in this review of behavioral changes later in life, suggesting some permanent neurodegenerative changes. Altogether, In contrast to the warning issued by the FDA we show that already single exposure to isoflurane and sevoflurane negatively affects brain development. Based on the results of this review use of sevoflurane and isoflurane should be restrained as much as possible in this young vulnerable group, until more research on the long term permanent effects have been conducted.

[Health hazards resulting from occupational exposure to enfluran - overview of tests and analysis of admissible concentration values]. / Zagrozenia zdrowotne wynikajace z narazenia zawodowego na enfluran ­ przeglad badan i próba analizy wartosci dopuszczalnych stezen.

The aim of this work is to analyze the health hazards of enflurane exposure and to analyze the occupational exposure limits (OEL). The method of obtaining evidence based on a review of online databases of scientific journals was used. Enflurane is an inhalation anesthetic. Malignant hyperthermia, seizures, arrhythmias, respiratory depression and hypotension have been observed in patients. Occupational exposure to enflurane may occur in healthcare professionals. The target organ for enflurane is the central nervous system with a critical consequence of deterioration in psychomotor performance. In studies on volunteers recruited from the medical staff of operating rooms exposed to enflurane, a significant deterioration in the results of the Simple Reaction Time Test was shown. World experts' groups assume that the LOAEC (lowest observed adverse effect concentration) value for the deterioration of psychomotor test results is 5-10% of the MAC value (minimal anesthetic concentration), i.e., 6342-12 684 mg/m3. Assessment of the nephrotoxic potential of enflurane has shown that it is unlikely to occur because biotransformation of enflurane in humans results in a low peak serum fluoride concentration of 15 µmol/l. Early reports about liver damage in patients were not be supported. Occupational exposure epidemiological studies have raised concerns about the effects of anesthetic gas mixtures on the abortion rate or on fetal development and birth defects in children, but none of these studies specifically determined the type and concentration of anesthetic gases used. The carcinogenicity and mutagenicity studies were negative. Occupational exposure to enflurane is not monitored in Poland, as no standard value has been established for it in the air of the working environment. It is necessary to quickly introduce this anesthetic along with the applicable limit value to the OEL list. Med Pr. 2022;73(1):51-69.

Halogen bonded complexes between volatile anaesthetics (chloroform, halothane, enflurane, isoflurane) and formaldehyde: a theoretical study.

The structures and intermolecular interactions in the halogen bonded complexes of anaesthetics (chloroform, halothane, enflurane and isoflurane) with formaldehyde were studied by ab initio MP2 and CCSD(T) methods. The CCSD(T)/CBS calculated binding energies of these complexes are between -2.83 and -4.21 kcal mol(-1). The largest stabilization energy has been found for the C-Br···O bonded halothane···OCH(2) complex. In all complexes the C-X bond length (where X = Cl, Br) is slightly shortened, in comparison to a free compound, and an increase of the C-X stretching frequency is observed. The electrostatic interaction was excluded as being responsible for the C-X bond contraction. It is suggested that contraction of the C-X bond length can be explained in terms of the Pauli repulsion (the exchange overlap) between the electron pairs of oxygen and halogen atoms in the investigated complexes. This is supported by the DFT-SAPT results, which indicate that the repulsive exchange energy overcompensates the electrostatic one. Moreover, the dispersion and electrostatic contributions cover about 95% of the total attraction forces, in these complexes.

Blue shifts and unusual intensity changes in the infrared spectra of the enflurane···acetone complexes: spectroscopic and theoretical studies.

Blue-shifting C-H···O hydrogen-bonded complexes between enflurane (CHFCl-CF(2)-O-CHF(2)) and deuterated acetone have been identified in CCl(4) solution by FT-IR spectroscopy. For the two ν(C-H) stretching vibrations of enflurane the observed blue shifts are +17 and +11 cm(-1). The corresponding two infrared ν(C-H) bands show the opposite changes of their intensity, one is decreasing, and the other is significantly increasing, upon formation of the hydrogen bonding. The structures, binding energies, and theoretical infrared spectra of the enflurane-acetone complexes were calculated by MP2 and B3LYP methods using the 6-311++G(d,p) basis set. The interaction energies were evaluated by the complete basis set limit (CBS) calculations at the HF, MP2, and CCSD(T) levels of theory. Although the MP2 method slightly overestimates the blue shifts, the MP2 predicted frequency difference and the relative IR intensities of two ν(C-H) stretching bands for the enflurane-acetone complexes show good agreement with experiment. Unfortunately, the B3LYP method predicts incorrect IR intensities of these hydrogen-bonded systems. The NBO analysis was performed to unravel the origin of the unusual intensity changes of two ν(C-H) stretching bands, in enflurane complexes.

In-vitro contracture testing for susceptibility to malignant hyperthermia: can halothane be replaced?

BACKGROUND: Malignant hyperthermia is a potentially lethal inherited hypermetabolic syndrome that develops in susceptible individuals following administration of depolarising neuromuscular relaxants or volatile anaesthetics. Genetic analysis can only confirm a diagnosis of malignant hyperthermia in about 70%, and in the remainder an in-vitro contracture test, with halothane and caffeine, on muscle obtained from open muscle biopsy is required to establish the diagnosis. As the licence for clinical use of halothane expired in 2005, its continuing availability is in doubt. More modern volatile anaesthetics such as enflurane, isoflurane, desflurane and sevoflurane are less potent triggers of malignant hyperthermia in humans and pigs. The aim of this study was to investigate whether these agents can be considered possible substitutes for halothane in a modified in-vitro contracture test. METHOD: With institutional review board approval and prior written consent, muscle bundles of 30 patients with a personal or family history of malignant hyperthermia were investigated. Of these, 13 were diagnosed malignant hyperthermia susceptible and 17 nonsusceptible. Surplus muscle was tested with increasing concentrations of enflurane, isoflurane, desflurane and sevoflurane. RESULTS: There were no differences in weight, length or predrug tension of the muscle bundles. At increasing concentration, all volatile anaesthetics except sevoflurane induced significantly greater contractures in malignant hyperthermia susceptible compared to malignant hyperthermia nonsusceptible muscle. In malignant hyperthermia susceptible muscle bundles, halothane led to significantly higher contractures compared to the other investigated substances. CONCLUSION: Halothane was the strongest discriminator for malignant hyperthermia in the in-vitro contracture tests. It remains the ideal substance for diagnostic testing and cannot simply be replaced by other agents in this test.

Effects of enflurane and propofol on seizure duration and recovery profiles in electroconvulsive therapy.

UNLABELLED: The aim of this study is to investigate effect of enflurane that is a pro-convulsive anesthetic agent and propofol on seizure durations and recovery times during electroconvulsive therapy. METHODS: The subjects were divided into two groups according to the induction anesthetics. Anesthesia was induced with enflurane 5% in group E or propofol 1.2 mg x kg(-1) in group P. After the loss of consciousness, 0.5 mg x kg(-1) of succinylcholine was given. The patients maintained normocapnia. RESULTS: There were no significant differences between groups regarding seizure times. Recovery times were shorter in group E, but postictal agitation was significantly lower in propofol group. DISCUSSION: High incidence of spike activity on EEG and grand mal seizure patterns could be induced by enflurane. But motor and EEG seizure times were not prolonged by enflurane in the presence normocapnia. In conclusion, propofol is more suitable anesthetic agent for ECT, but enflurane might be preferred in patients because of rapid recovery.

A putative cation channel and its novel regulator: cross-species conservation of effects on general anesthesia.

Volatile anesthetics like halothane and enflurane are of interest to clinicians and neuroscientists because of their ability to preferentially disrupt higher functions that make up the conscious state. All volatiles were once thought to act identically; if so, they should be affected equally by genetic variants. However, mutations in two distinct genes, one in Caenorhabditis and one in Drosophila, have been reported to produce much larger effects on the response to halothane than enflurane [1, 2]. To see whether this anesthesia signature is adventitious or fundamental, we have identified orthologs of each gene and determined the mutant phenotype within each species. The fly gene, narrow abdomen (na), encodes a putative ion channel whose sequence places it in a unique family; the nematode gene, unc-79, is identified here as encoding a large cytosolic protein that lacks obvious motifs. In Caenorhabditis, mutations that inactivate both of the na orthologs produce an Unc-79 phenotype; in Drosophila, mutations that inactivate the unc-79 ortholog produce an na phenotype. In each organism, studies of double mutants place the genes in the same pathway, and biochemical studies show that proteins of the UNC-79 family control NA protein levels by a posttranscriptional mechanism. Thus, the anesthetic signature reflects an evolutionarily conserved role for the na orthologs, implying its intimate involvement in drug action.

Cross-approximate entropy of cortical local field potentials quantifies effects of anesthesia--a pilot study in rats.

BACKGROUND: Anesthetics dose-dependently shift electroencephalographic (EEG) activity towards high-amplitude, slow rhythms, indicative of a synchronization of neuronal activity in thalamocortical networks. Additionally, they uncouple brain areas in higher (gamma) frequency ranges possibly underlying conscious perception. It is currently thought that both effects may impair brain function by impeding proper information exchange between cortical areas. But what happens at the local network level? Local networks with strong excitatory interconnections may be more resilient towards global changes in brain rhythms, but depend heavily on locally projecting, inhibitory interneurons. As anesthetics bias cortical networks towards inhibition, we hypothesized that they may cause excessive synchrony and compromise information processing already on a small spatial scale. Using a recently introduced measure of signal independence, cross-approximate entropy (XApEn), we investigated to what degree anesthetics synchronized local cortical network activity. We recorded local field potentials (LFP) from the somatosensory cortex of three rats chronically implanted with multielectrode arrays and compared activity patterns under control (awake state) with those at increasing concentrations of isoflurane, enflurane and halothane. RESULTS: Cortical LFP signals were more synchronous, as expressed by XApEn, in the presence of anesthetics. Specifically, XApEn was a monotonously declining function of anesthetic concentration. Isoflurane and enflurane were indistinguishable; at a concentration of 1 MAC (the minimum alveolar concentration required to suppress movement in response to noxious stimuli in 50% of subjects) both volatile agents reduced XApEn by about 70%, whereas halothane was less potent (50% reduction). CONCLUSIONS: The results suggest that anesthetics strongly diminish the independence of operation of local cortical neuronal populations, and that the quantification of these effects in terms of XApEn has a similar discriminatory power as changes of spontaneous action potential rates. Thus, XApEn of field potentials recorded from local cortical networks provides valuable information on the anesthetic state of the brain.

Inhalational anesthetics stereochemistry: optical resolution of halothane, enflurane, and isoflurane.

Halothane (I), enflurane (II), and isoflurane (III), which are among the most important inhalation anesthetics, are currently administered as racemic mixtures. The pure enantiomers have not been described, and no analytical method for resolving the commercially available racemic mixtures has been reported. Complete optical resolution of (+/-)-I and (+/-)-III on per-n-pentylated alpha-cyclodextrin (Lipodex A) and of (+/-)-II and (+/-)-III on octakis(6-O-methyl-2,3-di-O-pentyl)-gamma-cyclodextrin capillary columns has been achieved, making rapid and convenient determination of enantiomeric ratios in samples of all three of these anesthetics possible.

Glutamatergic system: another target for the action of porphyrinogenic agents.

The N-methyl-diethyl-aspartate (NMDA) receptor has been reported to play an important role in several acute and chronic neuropathologic syndromes. 5-aminolevulinic acid (ALA) accumulates in acute porphyrias due to a deficiency in the heme biosynthetic pathway. Considering that glutamate uptake inhibition caused by ALA could be one of the reasons conducing to porphyric neuropathy, it was of interest to evaluate the effect of porphyrinogenic agents on NMDA glutamatergic system. To this end receptor levels and apparent affinity (Kd) were analyzed in mice brain cortex and cerebellum. NMDA levels were diminished after chronic Isoflurane anaesthesia in brain cortex. In cerebellum, a diminution was observed after acute Enflurane and Isoflurane and allylisopropylacetamide, while ethanol administration showed a significant increase. ALA administration diminished NMDA levels only in cerebellum. Affinity constant was only reduced in brain cortex after chronic Isoflurane treatment. In conclusion, glutamatergic system appears to be involved in the action of some of the porphyrinogenic drugs studied mainly in cerebellum. Receptors regulation should therefore be considered an important mechanism in the cellular response to specific drugs, with the aim of designing new therapies and elucidating the mechanisms leading to porphyric neuropathy and acute attack triggering.

The electrocortical effects of enflurane: experiment and theory.

BACKGROUND: High concentrations of enflurane will induce a characteristic electroencephalogram pattern consisting of periods of suppression alternating with large short paroxysmal epileptiform discharges (PEDs). In this study, we compared a theoretical computer model of this activity with real local field potential (LFP) data obtained from anesthetized rats. METHODS: After implantation of a high-density 8 x 8 electrode array in the visual cortex, the patterns of LFP and multiunit spike activity were recorded in rats during 0.5, 1.0, 1.5, and 2.0 minimum alveolar anesthetic concentration (MAC) enflurane anesthesia. These recordings were compared with computer simulations from a mean field model of neocortical dynamics. The neuronal effect of increasing enflurane concentration was simulated by prolonging the decay time constant of the inhibitory postsynaptic potential (IPSP). The amplitude of the excitatory postsynaptic potential (EPSP) was modulated, inverse to the neocortical firing rate. RESULTS: In the anesthetized rats, increasing enflurane concentrations consistently caused the appearance of suppression pattern (>1.5 MAC) in the LFP recordings. The mean rate of multiunit spike activity decreased from 2.54/s (0.5 MAC) to 0.19/s (2.0 MAC). At high MAC, the majority of the multiunit action potential events became synchronous with the PED. In the theoretical model, prolongation of the IPSP decay time and activity-dependent EPSP modulation resulted in output that was similar in morphology to that obtained from the experimental data. The propensity for rhythmic seizure-like activity in the model could be determined by analysis of the eigenvalues of the equations. CONCLUSION: It is possible to use a mean field theory of neocortical dynamics to replicate the PED pattern observed in LFPs in rats under enflurane anesthesia. This pattern requires a combination of a moderately increased total area under the IPSP, prolonged IPSP decay time, and also activity-dependent modulation of EPSP amplitude.