bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of Thioether Compounds Formed from Alkaline Degradation Products of Enflurane
Authors: Orhan Hilmi , E. Vermeulen Nico P. , Sahin Gonul , M. Commandeur Jan N. 
Published: November 2003

Background
Renal toxicity has occasionally been observed after enflurane anesthesia. Although originally attributed to its oxidative metabolism to inorganic fluoride, serum levels of inorganic fluoride appear to be small to explain these renal effects. Formation of potentially nephrotoxic halogenated alkenes during alkaline degradation in carbon dioxide absorbers and subsequent bioactivation via the glutathione conjugation pathway may be considered as an alternative mechanism for renal toxicity. The aim of this study was to characterize the thioethers formed chemically and biosynthetically.

Methods
Alkaline degradation of enflurane was achieved by stirring with pulverized potassium hydroxide. Volatile degradation products were analyzed by 19F nuclear magnetic resonance (NMR) analysis of head space gasses trapped in dimethyl sulfoxide (DMSO). Thioethers were generated chemically by trapping head space gasses in DMSO containing N-acetyl-L-cysteine or 2-mercaptoacetic acid as model thiol compounds. Glutathione conjugates were generated biosynthetically by passing head space through rat liver fractions in presence of glutathione. Products formed were analyzed by gas chromatography-mass spectroscopy and 19F-NMR.

Results
Direct analysis of head space gasses showed formation of 1-chloro-1,2-difluorovinyl difluoromethyl ether and two unidentified fluorine-containing products as alkaline degradation products of enflurane. When trapped in DMSO-N-acetyl-L-cysteine-triethylamine, N-acetyl-S-(2-chloro-1,2-difluoro-1-(difluoromethoxy)ethyl)-L-cysteine was identified as the major product. Another N-acetyl-L-cysteine S-conjugate formed was N-acetyl-S-(2-chloro-1,1,2-trifluoroethyl)-L-cysteine, a potent nephrotoxin in rats. 19F-NMR analysis of glutathione conjugates formed after incubation with rat liver fractions resulted in formation of corresponding S-conjugates.

Conclusions
The current study demonstrates that alkaline degradation products of enflurane can be conjugated to thiol compounds, forming S-conjugates that could theoretically contribute to adverse renal effects observed occasionally with enflurane anesthesia. The N-acetyl-L-cysteine S-conjugates identified may be biomarkers to assess exposure of humans to alkaline degradation products of enflurane.
Roles of Carbon Monoxide in Leukocyte and Platelet Dynamics in Rat Mesentery during Sevoflurane Anesthesia
Authors: Morisaki Hiroshi , Katayama Tomihiro , Kotake Yoshifumi , Ito Masaharu , Tamatani Takuya , Sakamoto Shinji , Ishimura Yuzuru , Takeda Junzo , Suematsu Makoto 
Published: November 2003

Background
Heme oxygenase 1 (HO-1), induced by a variety of stressors, provides endogenous carbon monoxide (CO) and bilirubin, both of which play consequential roles in organs. The current study aimed to examine whether induction of HO-1 and its by-products modulated endothelial interaction with circulating leukocytes and platelets evoked by sevoflurane anesthesia in vivo.

Methods
Rats, pretreated with or without hemin, were anesthetized with sevoflurane in 100% O2, and lungs were mechanically ventilated. Platelets labeled with carboxyfluorescein diacetate succinimidyl ester and leukocyte behavior in mesenteric venules were visualized during sevoflurane anesthesia at 1,000 frames/s using intravital ultrahigh-speed intensified fluorescence videomicroscopy. To examine the mechanisms for the effects of HO-1 on leukocyte and platelet behavior, these studies were repeated with superfusion of either CO, bilirubin, or Nomega-nitro-L-arginine methyl ester (L-NAME).

Results
As reported previously, the elevation of sevoflurane concentration evoked adhesive responses of leukocytes, concurrent with platelet margination and rolling. Pretreatment with hemin, a HO-1 inducer, prevented such sevoflurane-elicited changes in the microvessels. These changes were restored by zinc protoporphyrin IX, a HO inhibitor, and repressed by CO but not by bilirubin. During sevoflurane anesthesia, however, nitric oxide suppression by L-NAME deteriorated microvascular flows irrespective of the presence or absence of the HO-1 induction.

Conclusions
These results indicate that endogenous CO via HO-1 induction attenuates sevoflurane-induced microvascular endothelial interactions with leukocytes and platelets, although local nitric oxide levels appear to dominate microvascular flow in situ.
Effects of Halothane on Sarcoplasmic Reticulum Calcium Release Channels in Porcine Airway Smooth Muscle Cells
Authors: Pabelick Christina M. , Prakash Yedatore S. , Kannan Mathur S. , Warner David O. , Sieck Gary C. 
Published: November 2003

Background
Volatile anesthetics relax airway smooth muscle (ASM) by altering intracellular Ca2+ concentration ([Ca2+]i). The authors hypothesized that relaxation is produced by decreasing sarcoplasmic reticulum Ca2+ content via increased Ca2+ "leak" through both inositol trisphosphate (IP3) and ryanodine receptor channels.

Methods
Enzymatically dissociated porcine ASM cells were exposed to acetylcholine in the presence or absence of 2 minimum alveolar concentration (MAC) halothane, and IP3 levels were measured using radioimmunoreceptor assay. Other cells were loaded with the Ca2+ indicator fluo-3 and imaged using real-time confocal microscopy.

Results
Halothane increased IP3 concentrations in the presence and absence of acetylcholine. Inhibition of phospholipase C blunted the IP3 response to halothane. Exposure to 2 MAC halothane induced a transient [Ca2+]i response, suggesting depletion of sarcoplasmic reticulum Ca2+. Exposure to 20 microM Xestospongin D, a cell-permeant IP3 receptor antagonist, resulted in a 45+/-13% decrease in the [Ca2+]i response to halothane compared with halothane exposure alone. In permeabilized cells, Xestospongin D or 0.5 mg/ml heparin decreased the [Ca2+]i response to halothane by 65+/-13% and 68+/-22%, respectively, compared with halothane alone. In both intact and permeabilized cells, 20 microM ryanodine blunted the [Ca2+]i response to halothane by 32+/-13% and 39+/-21%, respectively, compared with halothane alone. Simultaneous exposure to Xestospongin D and ryanodine completely inhibited the [Ca2+]i response to halothane.

Conclusions
The authors conclude that halothane reduces sarcoplasmic reticulum Ca2+ content in ASM cells via increased Ca2+ leak through both IP3 receptor and ryanodine receptor channels. Effects on IP3 receptor channels are both direct and indirect via elevation of IP3 levels.
A Double-blind, Randomized Comparison of IV Lorazepam versus Midazolam for Sedation of ICU Patients via a Pharmacologic Model
Authors: Barr Juliana , Zomorodi Katayoun , Bertaccini Edward J. , Shafer Steven L. , Geller Eran 
Published: November 2003

Background
Benzodiazepines, such as lorazepam and midazolam, are frequently administered to surgical intensive care unit (ICU) patients for postoperative sedation. To date, the pharmacology of lorazepam in critically ill patients has not been described. The aim of the current study was to characterize and compare the pharmacokinetics and pharmacodynamics of lorazepam and midazolam administered as continuous intravenous infusions for postoperative sedation of surgical ICU patients.

Methods
With Institutional Review Board approval, 24 consenting adult surgical patients were given either lorazepam or midazolam in a double-blind fashion (together with either intravenous fentanyl or epidural morphine for analgesia) through target-controlled intravenous infusions titrated to maintain a moderate level of sedation for 12-72 h postoperatively. Moderate sedation was defined as a Ramsay Sedation Scale score of 3 or 4. Sedation scores were measured, together with benzodiazepine plasma concentrations. Population pharmacokinetic and pharmacodynamic parameters were estimated using nonlinear mixed-effects modeling.

Results
A two-compartment model best described the pharmacokinetics of both lorazepam and midazolam. The pharmacodynamic model predicted depth of sedation for both midazolam and lorazepam with 76% accuracy. The estimated sedative potency of lorazepam was twice that of midazolam. The predicted C50,ss (plasma benzodiazepine concentrations where P(Sedation > or = ss) = 50%) values for midazolam (sedation score [SS] > or = n, where n = a Ramsay Sedation Score of 2, 3, ... 6) were 68, 101, 208, 304, and 375 ng/ml. The corresponding predicted C50,ss values for lorazepam were 34, 51, 104, 152, and 188 ng/ml, respectively. Age, fentanyl administration, and the resolving effects of surgery and anesthesia were significant covariates of benzodiazepine sedation. The relative amnestic potency of lorazepam to midazolam was 4 (observed). The predicted emergence times from sedation after a 72-h benzodiazepine infusion for light (SS = 3) and deep (SS = 5) sedation in a typical patient were 3.6 and 14.9 h for midazolam infusions and 11.9 and 31.1 h for lorazepam infusions, respectively.

Conclusions
The pharmacology of intravenous infusions of lorazepam differs significantly from that of midazolam in critically ill patients. This results in significant delays in emergence from sedation with lorazepam as compared with midazolam when administered for ICU sedation.
Fiberoptic Orotracheal Intubation on Anesthetized Patients
Authors: Naik Viren N. , Matsumoto Edward D. , Houston Patricia L. , Hamstra Stanley J. , Yeung Raymond Y.-M. , Mallon Joseph S. , Martire Terry M. 
Published: November 2003

Background
With increasing pressure to use operating room time efficiently, opportunities for residents to learn fiberoptic orotracheal intubation in the operating room have declined. The purpose of this study was to determine whether fiberoptic orotracheal intubation skills learned outside the operating room on a simple model could be transferred into the clinical setting.

Methods
First-year anesthesiology residents and first- and second-year internal medicine residents were recruited. Subjects were randomized to a didactic-teaching-only group (n = 12) or a model-training group (n = 12). The didactic-teaching group received a detailed lecture from an expert bronchoscopist. The model-training group was guided, by experts, through tasks performed on a simple model designed to refine fiberoptic manipulation skills. After the training session, subjects performed a fiberoptic orotracheal intubation on healthy, consenting, anesthetized, paralyzed female patients undergoing elective surgery with predicted "easy" laryngoscopic intubations. Two blinded anesthesiologists evaluated each subject.

Results
After the training session, the model group significantly outperformed the didactic group in the operating room when evaluated with a global rating scale (P < 0.01)and checklist (P0.05). Model-trained subjects completed the fiberoptic orotracheal intubation significantly faster than didactic-trained subjects (P < 0.01). Model-trained subjects were also more successful at achieving tracheal intubation than the didactic group (P < 0.005).

Conclusion
Fiberoptic orotracheal intubation skills training on a simple model is more effective than conventional didactic instruction for transfer to the clinical setting. Incorporating an extraoperative model into the training of fiberoptic orotracheal intubation may greatly reduce the time and pressures that accompany teaching this skill in the operating room.
Effects of Desflurane and Sevoflurane on Length-dependent Regulation of Myocardial Function in Coronary Surgery Patients
Authors: De Hert Stefan G. , Van der Linden Philippe J. , ten Broecke Pieter W. , Vermeylen Kris T. , Rodrigus Inez E. , Stockman Bernard A. 
Published: November 2003

Background
Desflurane and sevoflurane have negative inotropic effects. The current study investigated whether these effects resulted in an altered left ventricular response to increased cardiac load and affected length-dependent regulation of myocardial function. Length-dependent regulation of myocardial function refers to the ability of the heart to improve its performance when preload is increased.

Methods
A high-fidelity pressure catheter was positioned in the left ventricle and left atrium in 20 coronary surgery patients with a preoperative ejection fraction greater than 40%. Studies were performed before the initiation of cardiopulmonary bypass. Left ventricular response to increased cardiac load, obtained by leg elevation, was assessed during control conditions and during increasing concentrations of desflurane (2, 4, and 6% end tidal; n = 10) or sevoflurane (1, 2, and 3% end tidal; n = 10). Effects on contraction were evaluated by analysis of changes in maximal rate of pressure development. Effects on relaxation were assessed by analysis of changes in minimum rate of pressure development and by analysis of the load dependence of myocardial relaxation (R = slope of the relation between time constant tau of isovolumic relaxation and end-systolic pressure). Peak left atrial-left ventricular pressure gradients were analyzed during early left ventricular filling.

Results
With both desflurane and sevoflurane, maximal and minimum rates of pressure development decreased while tau increased. Peak left atrial-left ventricular pressure gradients remained unchanged. The hemodynamic effects of leg elevation were similar at the different concentrations. Changes in parameters of contraction and relaxation during leg elevation were coupled and were not altered by desflurane or sevoflurane.

Conclusions
Despite their negative inotropic and lusitropic effects, neither desflurane nor sevoflurane adversely affect length-dependent regulation of left ventricular function. In the conditions of our study, the ability of the left ventricular to respond to increased cardiac load is not altered by the use of desflurane or sevoflurane.
Nonhalogenated Alkane Anesthetics Fail to Potentiate Agonist Actions on Two Ligand-gated Ion Channels
Authors: Raines Douglas E. , Claycomb Robert J. , Scheller Michaela , Forman Stuart A. 
Published: November 2003

Background
Although ether, alcohol, and halogenated alkane anesthetics potentiate agonist actions or increase the apparent agonist affinity of ligand-gated ion channels at clinically relevant concentrations, the effects of nonhalogenated alkane anesthetics on ligand-gated ion channels have not been studied. The current study assessed the abilities of two representative nonhalogenated alkane anesthetics (cyclopropane and butane) to potentiate agonist actions or increase the apparent agonist affinity of two representative ligand-gated ion channels: the nicotinic acetylcholine receptor and y-aminobutyric acid type A (GABA(A)) receptor.

Methods
Nicotinic acetylcholine receptors were obtained from the electroplax organ of Torpedo nobiliana, and human GABA(A) receptors (alpha1beta2gamma2L) were expressed in human embryonic kidney 293 cells. The Torpedo nicotinic acetylcholine receptors apparent agonist affinity in the presence and absence of anesthetic was assessed by measuring the apparent rates of desensitization induced by a range of acetylcholine concentrations. The GABA(A) receptor's apparent agonist affinity in the presence and absence of anesthetic was assessed by measuring the peak currents induced by a range of GABA concentrations.

Results
Neither cyclopropane nor butane potentiated agonist actions or increased the apparent agonist affinity (reduced the apparent agonist dissociation constant) of the Torpedo nicotinic acetylcholine receptor or GABA(A) receptor. At clinically relevant concentrations, cyclopropane and butane reduced the apparent rate of Torpedo nicotinic acetylcholine receptor desensitization induced by low concentrations of agonist.

Conclusions
Our results suggest that the in vivo central nervous system depressant effects of nonhalogenated alkane anesthetics do not result from their abilities to potentiate agonist actions on ligand-gated ion channels. Other targets or mechanisms more likely account for the anesthetic activities of nonhalogenated alkane anesthetics.
Halothane but Not Isoflurane Attenuates Interleukin 1β– induced Nitric Oxide Synthase in Vascular Smooth Muscle
Authors: Maeda Hiroshi , Iranami Hiroshi , Yamamoto Manabu , Ogawa Koji , Morikawa Yoshihiro , Senba Emiko , Hatano Yoshio 
Published: November 2003

Background
Inducible nitric oxide synthase (iNOS) is induced by endotoxin or cytokines, such as interleukin (IL)-1, through a protein synthesis pathway. Halothane reportedly inhibits protein synthesis in various tissues. The aim of the current study was to examine the effect of halothane on the IL-1beta-evoked induction of NOS in vascular smooth muscle.

Methods
After removal of the endothelium, arterial rings of rat aorta were mounted in an isometric force recording system. The effects of halothane (1.0-3.0%) or isoflurane (3.0%) on IL-1beta (20 ng/ml)-induced inhibition of the contractile responses to KCl (30 mM) and phenylephrine (10(-9)-10(-5) M) were studied. The cyclic guanosine monophosphate and cyclic adenosine monophosphate contents were determined by radioimmunoassay. Expression of iNOS and iNOS mRNA were measured by Western or Northern blot analysis, respectively.

Results
Halothane (1.0-3.0%) but not isoflurane (3%) significantly reduced the ML-1beta-induced inhibition of contraction in a concentration-dependent manner. The cyclic guanosine monophosphate content of the vascular smooth muscle increased significantly after a 5-h exposure to IL-1beta. Halothane at 3.0% significantly inhibited the increase in cyclic guanosine monophosphate content induced by IL-1beta. Halothane had no effect on cyclic adenosine monophosphate content. IL-1beta-induced expression of iNOS and iNOS mRNA in the rat aorta were inhibited significantly by halothane.

Conclusion
The current study demonstrated that halothane but not isoflurane inhibits IL-1beta-stimulated hyporesponsiveness to vasoconstrictive agents in vascular smooth muscle and that this inhibitory effect of halothane involves the inhibition of iNOS mRNA expression. Thus, these findings suggest that halothane may have some sites to affect nitric oxide-signaling pathway.
Opioid Peptide–expressing Leukocytes
Authors: Rittner Heike L. , Brack Alexander , Machelska Halina , Mousa Shaaban A. , Bauer Monika , Schäfer Michael , Stein Christoph 
Published: November 2003

Background
Inflammatory pain can be effectively controlled by an interaction of opioid receptors on peripheral sensory nerve terminals with opioid peptides released from immune cells upon stressful stimulation. To define the source of opioid peptide production, we sought to identify and quantify populations of opioid-containing cells during the course of Freund's complete adjuvant-induced hind paw inflammation in the rat. In parallel, we examined the development of stress-induced local analgesia in the paw.

Methods
At 2, 6, and 96 h after Freund's complete adjuvant inoculation, cells were characterized by flow cytometry using a monoclonal pan-opioid antibody (3E7) and antibodies against cell surface antigens and by immunohistochemistry using a polyclonal antibody to beta-endorphin. After magnetic cell sorting, the beta-endorphin content was quantified by radioimmunoassay. Pain responses before and after cold water swim stress were evaluated by paw pressure thresholds.

Results
In early inflammation, 66% of opioid peptide-producing (3E7+) leukocytes were HIS48+ granulocytes. In contrast, at later stages (96 h), the majority of 3E7+ immune cells were ED1+ monocytes or macrophages (73%). During the 4 days after Freund's complete adjuvant inoculation, the number of 3E7+ cells increased 5.6-fold (P < 0.001, Kruskal-Wallis test) and the beta-endorphin content in the paw multiplied 3.9-fold (P < 0.05, Kruskal-Wallis test). In parallel, cold water swim stress-induced analgesia increased by 160% (P < 0.01, analysis of variance).

Conclusions
The degree of endogenous pain inhibition is proportional to the number of opioid peptide-producing cells, and distinct leukocyte lineages contribute to this function at different stages of inflammation. These mechanisms may be important for understanding pain in immunosuppressed states such as cancer, diabetes, or AIDS and for the design of novel therapeutic strategies in inflammatory diseases.
Halothane-dependent Lipid Peroxidation in Human Liver Microsomes Is Catalyzed by Cytochrome P4502A6 (CYP2A6)
Authors: Minoda Yuko , Kharasch Evan D. 
Published: November 2003

Background
Halothane is extensively (approximately 50%) metabolized in humans and undergoes both oxidative and reductive cytochrome P450-catalyzed hepatic biotransformation. Halothane is reduced under low oxygen tensions by CYP2A6 and CYP3A4 in human liver microsome to an unstable free radical, and then to the volatile metabolites chlorodifluoroethene (CDE) and chlorotrifluoroethane (CTE). The free radical is also thought to initiate lipid peroxidation. Halothane-dependent lipid peroxidation has been shown in animals in vitro and in vivo but has not been evaluated in humans. This investigation tested the hypothesis that halothane causes lipid peroxidation in human liver microsomes, identified P450 isoforms responsible for halothane-dependent lipid peroxidation, and tested the hypothesis that lipid peroxidation is prevented by inhibiting halothane reduction.

Methods
Halothane metabolism was determined using human liver microsomes or cDNA-expressed P450. Lipid peroxidation was quantified by malondialdehyde (MDA) formation using high-pressure liquid chromatography-ultraviolet analysis of the thiobarbituric acid-MDA adduct. CTE and CDE were determined by gas chromatography-mass spectrometry.

Results
Halothane caused MDA formation in human liver microsomes at rates much lower than in rat liver microsomes. Human liver microsomal MDA production exhibited biphasic enzyme kinetics, similar to CDE and CTE production. MDA production was inhibited by the CYP2A6 inhibitor methoxsalen but not by the CYP3A4 inhibitor troleandomycin. Halothane-dependent MDA production was catalyzed by cDNA-expressed CYP2A6 but not CYP3A4 or P450 reductase alone. CYP2A6-catalyzed MDA production was inhibited by methoxsalen or anti-CYP2A6 antibody.

Conclusions
Halothane causes lipid peroxidation in human liver microsomes, which is catalyzed by CYP2A6, and inhibition of halothane reduction prevents halothane-dependent lipid peroxidation in vitro.