Preparation of barbiturate optical isomers and their effects on GABA(A) receptors.

Tomlin SL, Jenkins A, Lieb WR, Franks NP.

Biophysics Section, The Blackett Laboratory, Imperial College of Science, Technology and Medicine, London, United Kingdom.

BACKGROUND: Barbiturate anesthetics are optically active and usually exist in two mirror-image enantiomeric forms. Their stereoselective effects in mammals are well known, but remarkably few data are available concerning their effects on anesthetic targets in vitro. This is in part because of the lack of availability of pure barbiturate enantiomers. Such in vitro data could be used to test the relevance of putative molecular targets. METHODS: A high-performance liquid chromatography technique using a permethylated beta-cyclodextrin column was used to separate the optical isomers of three barbiturates in preparative quantities. The effects of the isomers on GABA-induced currents in stably transfected mouse fibroblast cells were investigated using the whole-cell patch-clamp technique. RESULTS: Highly purified optical isomers of hexobarbital, pentobarbital, and thiopental were prepared, and their effects were studied on a gamma-aminobutyric acid type A receptor of defined subunit composition. For each of the three barbiturates, both enantiomers potentiated gamma-aminobutyric acid-induced currents at pharmacologically relevant concentrations, with the S-enantiomer being more potent than the R-enantiomer by a factor of between 1.7 and 3.5. The degree of stereoselectivity did not vary greatly with anesthetic concentration. CONCLUSIONS: The rank order and degree of stereoselectivity that we have observed for the enantiomers of hexobarbital, pentobarbital, and thiopental acting on the gamma-aminobutyric acid type A receptor are entirely consistent with this receptor playing a central role in the anesthetic actions of barbiturates.

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Depth of EEG suppression and outcome in barbiturate anesthetic treatment for refractory status epilepticus.

Krishnamurthy KB, Drislane FW.

Department of Neurology, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, Massachusetts 02215, USA.

PURPOSE: Barbiturate anesthetic treatment of patients with refractory status epilepticus (RSE) is often titrated to a burst-suppression record on the EEG. We sought to determine whether the depth of EEG suppression correlated with persistent seizure control in such patients. METHODS: We reviewed the EEGs and clinical course of patients treated with pentobarbital (PTB) for RSE. Persistent seizure control or relapse to status epilepticus after the taper of PTB was determined with reference to the depth of EEG suppression during treatment. RESULTS: Of 35 patients tapering PTB, persistent seizure control was achieved in six of 12 patients reaching a burst-suppression record at greatest depth of EEG suppression and in 17 of 20 patients reaching a "flat" record; three patients with neither pattern had persistent control. Survival also was somewhat better in the more suppressed group. Isolated epileptiform discharges during the barbiturate infusion did not correlate with outcome. Recurrence of electrographic status after PTB taper predicted clinical relapse. CONCLUSIONS: The EEG is important in managing PTB treatment for patients with RSE. Some period of intense seizure and EEG suppression may help in preventing relapse of status after the PTB taper. It is not necessary to suppress all epileptiform discharges, but persistent clinical and EEG monitoring is necessary to avoid relapses.

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Granulocyte colony-stimulating factor ameliorates life-threatening infections after combined therapy with barbiturates and mild hypothermia in patients with severe head injuries.

Ishikawa K, Tanaka H, Takaoka M, Ogura H, Shiozaki T, Hosotsubo H, Shimazu T, Yoshioka T, Sugimoto H.

Department of Traumatology, Osaka University Medical School, Japan.

OBJECTIVE: The objective of this study was to clarify the effects of recombinant human granulocyte colony-stimulating factor (rhG-CSF) administration on infections in patients with severe head injuries after combined therapy with high-dose barbiturates and mild hypothermia. PATIENTS AND METHODS: Since 1996, we have administered rhG-CSF to eight patients with severe head injuries for 5 days (group G). Their treatment results were compared with those of 22 patients cared for earlier without rhG-CSF treatment (group N). All patients in both groups met the criteria of total leukocyte count (TLC) less than 5,000/mm3, C-reactive protein (CRP) over 10 mg/dL, and the presence of an infectious complication. Changes in the TLC, CRP, respiratory index, intracranial pressure, and infectious condition were evaluated in both groups. In addition, the nucleated cell count and differentiation from bone marrow aspiration, neutrophil functions, serum concentrations of interleukin-6, and plasma concentration of leukocyte elastase were evaluated in group G. RESULTS: In group G, TLC, nucleated cell count, and neutrophil functions significantly increased, whereas CRP, respiratory index, and interleukin-6 decreased reciprocally. There was no deterioration of intracranial pressure and leukocyte elastase. Consequently, seven of the eight patients in group G recovered from life-threatening infections, and none of the eight patients died. However, in group N, CRP and respiratory index remained high and TLC did not increase as much as it did in group G. Infections continued after 5 days in 17 of the 22 patients, 7 of whom died from severe infections during hospitalization. CONCLUSION: Administration of rhG-CSF ameliorated life-threatening infections without causing lung injury or increasing brain swelling in patients with severe head injuries who were treated with combined therapy involving high-dose barbiturates and mild hypothermia.

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Effects of barbiturates on hypoxic cultures of brain derived microvascular endothelial cells.

Fischer S, Renz D, Schaper W, Karliczek GF.

Department of Anesthesiology and Intensive Care, Max-Planck Institute for Physiological and Clinical Research, Bad Nauheim, Germany.

An in vitro model of the blood-brain barrier (BBB) consisting of porcine brain derived microvascular endothelial cells (BMEC) seeded onto collagen-coated polycarbonate membranes was used to investigate the effects of the barbiturates, methohexital and thiopental, on permeability properties of the endothelial cell monolayer under hypoxia. The permeability of cultured BMEC to ions and sucrose increased significantly during 6 h of hypoxia in a reversible manner. Cells were resistant to hypoxia for up to 24 h, but 48 h resulted in marked damage as assessed by the release of lactate dehydrogenase activity into the culture medium. The hypoxia-induced increase of the permeability was unchanged in the presence of superoxide dismutase (SOD) and catalase. Methohexital and thiopental decreased the hypoxia-induced permeability increase in a concentration-dependent manner and permeability changes were abolished completely at the barbiturate concentration of 50 micrograms/ml. The barbiturates had no effect on the intracellular cAMP content which started to decline after 3 h of hypoxia. Results suggest that barbiturates at high concentrations might be able to prevent permeability changes of the BBB during cerebral ischemia.

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