Inhibition by Norfluoxetine, the Major Metabolite of Fluoxetine, of Voltage-Gated K+ Channels in Primary Cultured Rat Hippocampal Neurons / 대한마취과학회지

BACKGROUND: Fluoxetine (Prozac), a selective serotonin reuptake inhibitor, has been shown to be effective in the treatment of depression. We investigated the effects of norfluoxetine, the major active metabolite of fluoxetine, on voltage-gated K+ currents in primary cultured hippocampal neurons, and determined the potency and modes of actions of norfluoxetine. METHODS: Voltage-gated K+ currents were studied in primary cultured rat hippocampal neurons using the whole-cell configuration of the patch-clamp technique. Electrophysiological recordings were done in hippocampal neurons between 5-10 days in culture. Transient A-type K+ currents (KA) and delayed-rectifier K+ (KDR) currents were isolated from whole-cell K+ currents using a pulse protocol. RESULTS: Norfluoxetine accelerated the decay rate of whole-cell K+ currents, and thus decreased the current amplitude at the end of a pulse in a concentration-dependent manner. Norfluoxetine inhibited KA and KDR currents in a concentration-dependent manner with IC50's of 0.93 and 0.70micro M, respectively. Norfluoxetine also reduced the areas of KA currents and the steady-state KDR current over the range of test potentials, and the reduction was voltage-dependent (greater increase at more positive potentials). From the onset of the fractional block of KA currents by norfluoxetine during the initial 40 ms of a clamp step, we calculated k1 = 53.26/micro M.s for the association rate constant, and k2 = 70.24/s for the dissociation rate constant. The resulting apparent KD was 1.32micro M, which is similar to the IC50 value obtained from the concentration-response curve. CONCLUSIONS: Our results indicate that norfluoxetine, the major metabolite of fluoxetine, at therapeutic levels, produces a concentration- and voltage-dependent inhibition of KA and KDR currents in primary cultured hippocampal neurons. These effects could perturb the neuronal excitability in the hippocampus, and may contribute to the therapeutic antidepressant action of fluoxetine.

Atypical Increases of BIS according to Effect Site Concentration of Propofol in Severely Burn Patients Undergoing Early Escharectomy / 대한마취과학회지

BACKGROUND: This bispectral index, which is used for intravenous anesthetics and inhalation anesthesia, is a scale of sedation and hypnotic effect, which is widely used in clinics. Atypical changes in BIS are expected due to increased cardiac output, decreased blood albumin concentrations and renal function in severe burn patients undergoing early escharectomy. The aim of this study was to compare BIS according to effected site concentrations of propofol during anesthetic induction using propofol TCI in severe burn and nonburn patients. METHODS: Forty patients were classified as twenty nonburn elective surgical patients (group 1) and twenty burn patients scheduled for escharectomy (group 2). For induction, a propofol TCI device incorporating a prefilled syringe was adjusted to a target concentration of 6mug/ml in flash mode. The bispectral index was checked before induction and at each effect site concentration of propofol (0.5mug/ml interval) until an effect site concentration of 4.5mug/ml. Other suspected contributory factors such as cardiac index, creatinine clearance and albumin were checked simultaneously. The unpaired t-test and repeated measures ANOVA were performed for the statistical analysis. RESULTS: Below an effect site concentration of propofol of 3mug/ml, no BIS difference was evident between group 1 and group 2. However, at 3.5mug/ml, group 1 was 41.1+/-13.5 and group 2 was 54.7+/-16.6 and at 4mug/ml, group 1 was 40.1+/-2.6 and group 2 was 50.1+/-13.1. Among the suspected contributing factors, cardiac index and albumin showed significant differences between groups 1 and 2 (cardiac index: 3.4+/-0.5 L/min/m2 vs 2.7+/-0.3 L/min/m2, albumin: 4.1+/-0.3 g/dl vs 2.6+/-0.3 g/dl, P<0.05). Creatinine clearance showed no significant difference between the groups. CONCLUSIONS: Severe burn patients who are expecting early escharectomy had higher BIS values than nonburn patients from an effect site concentration of propofol of 3.5mug/ml. This study suggest that cardiac index should be considered as a factor that influences propofol.