Seongwook Jeong

Comprehensive In Vitro Analysis of Voriconazole Inhibition of Eight Cytochrome P450 (CYP) Enzymes: Major Effect on CYPs 2B6, 2C9, 2C19, and 3A

ABSTRACT Voriconazole is an effective antifungal drug, but adverse drug-drug interactions associated with its use are of major clinical concern. To identify the mechanisms of these interactions, we tested the inhibitory potency of voriconazole with eight human cytochrome P450 (CYP) enzymes. Isoform-specific probes were incubated with human liver microsomes (HLMs) (or expressed CYPs) and cofactors in the absence and the presence of voriconazole. Preincubation experiments were performed to test mechanism-based inactivation. In pilot experiments, voriconazole showed inhibition of CYP2B6, CYP2C9, CYP2C19, and CYP3A (half-maximal [50%] inhibitory concentrations, <6 μM); its effect on CYP1A2, CYP2A6, CYP2C8, and CYP2D6 was marginal (<25% inhibition at 100 μM voriconazole). Further detailed experiments with HLMs showed that voriconazole is a potent competitive inhibitor of CYP2B6 (Ki < 0.5), CYP2C9 (Ki = 2.79 μM), and CYP2C19 (Ki = 5.1 μM). The inhibition of CYP3A by voriconazole was explained by noncompetitive (Ki = 2.97 μM) and competitive (Ki = 0.66 μM) modes of inhibition. Prediction of the in vivo interaction of voriconazole from these in vitro data suggests that voriconazole would substantially increase the exposure of drugs metabolized by CYP2B6, CYP2C9, CYP2C19, and CYP3A. Clinicians should be aware of these interactions and monitor patients for adverse effects or failure of therapy.

Electroencephalographic approximate entropy changes in healthy volunteers during remifentanil infusion.

Background:The aim of this study was to investigate the independent effect of remifentanil on the approximate entropy (ApEn) in frontoparietal montages. The authors investigated which montages were relevant to assess the remifentanil effect on the electroencephalogram. Spectral edge frequency and the canonical univariate parameter were used as comparators. Methods:Twenty-eight healthy volunteers were enrolled. With recording of the electroencephalogram at the F3, F4, Cz, P3, and P4 montages, remifentanil was infused at the rate of 1–8 &mgr;g · kg−1 · min−1 for 15–20 min. The relation between remifentanil concentration and the electroencephalographic parameters were tested by Spearman correlation. Signal-to-noise ratio, artifact robustness, coefficient of variation of the median baseline and maximal electroencephalographic effects, and ratio of average maximal electroencephalographic effect to interindividual baseline variability were measured. The performance of ApEn as an index of remifentanil effect site concentrations was tested by prediction probability. Results:Approximate entropy showed significant correlation (R = −0.6465, P < 0.0001) with remifentanil concentration. It provided comparable signal-to-noise ratio, artifact robustness, and ratio of average maximal electroencephalographic effect to interindividual baseline variability to 95% spectral edge frequency. The coefficients of variation of the median baseline and maximal electroencephalo graphic effects were smallest in ApEn. Parietal montages showed higher ratios of average maximal electroencephalographic effect to interindividual baseline variability for all electroencephalographic parameters and lower coefficients of variation of the baseline values for ApEn and 95% spectral edge frequency than frontal montages. The prediction probability of ApEn was 0.7730. Conclusions:Approximate entropy derived from a parietal montage is appropriate for the assessment of the remifentanil effect on the electroencephalogram.

Effect of curcumin (Curcuma longa extract) on LPS-induced acute lung injury is mediated by the activation of AMPK.

PurposeCurcumin, a biphenolic compound extracted from turmeric (Curcuma longa), possesses potent anti-inflammatory activity. The present study investigated whether curcumin could increase 5′ adenosine monophosphate-activated protein kinase (AMPK) activity in macrophages and modulate the severity of lipopolysaccharide (LPS)-induced acute lung injury.MethodsMacrophages were treated with curcumin and then exposed (or not) to LPS. Acute lung injury was induced by intratracheal administration of LPS in BALB/c mice.ResultsCurcumin increased phosphorylation of AMPK and acetyl-CoA carboxylase (ACC), a downstream target of AMPK, in a time- and concentration-dependent manner. Curcumin did not increase phosphorylation of liver kinase B1, a primary kinase upstream of AMPK. STO-609, an inhibitor of calcium2+/calmodulin-dependent protein kinase kinase, diminished curcumin-induced AMPK phosphorylation, but transforming growth factor-beta-activated kinase 1 inhibitor did not. Curcumin also diminished the LPS-induced increase in phosphorylation of inhibitory κB-alpha and the production of tumor necrosis factor alpha (TNF-α), macrophage inflammatory protein (MIP)-2, and interleukin (IL)-6 by macrophages. Systemic administration of curcumin significantly decreased the production of TNF-α, MIP-2, and IL-6 as well as neutrophil accumulation in bronchoalveolar lavage fluid, and also decreased pulmonary myeloperoxidase levels and the wet/dry weight ratio in mice subjected to LPS treatment.ConclusionThese results suggest that the protective effect of curcumin on LPS-induced acute lung injury is associated with AMPK activation.

Anaesthetic requirement and stress hormone responses in patients undergoing lumbar spine surgery: anterior vs. posterior approach.

Background: The intensity of nociceptive stimuli reflects the severity of tissue injury. The anaesthetic requirement and stress hormonal responses were determined to learn whether they differ according to different surgical approaches (anterior vs. posterior) during the spinal surgery.

Changes in thalamo-frontal interaction under different levels of anesthesia in rats

Anesthesia is thought to be mediated by inhibiting the integration of information between different areas of the brain. Long-range thalamo-cortical interaction plays a critical role in inducing anesthesia-related unconsciousness. However, it remains unclear how this interaction change according to anesthetic depth. In this study, we aimed to investigate how different levels of anesthesia affect thalamo-frontal interactions. Prior to the experiment, electrodes were implanted to record local field potentials (LFPs). Isoflurane (ISO) was administered and LFPs were measured in rats from four different brain areas (left frontal, right frontal, left thalamus and right thalamus) at four different anesthesia levels: awake, deep (ISO 2.5vol%), light (ISO 1vol%) and recovery. Spectral granger causality (Spectral-GC) were calculated at the measured areas in accordance with anesthetic levels. Anesthesia led to a decrease in connectivity in the thalamo-frontal direction and an increase in connectivity in the frontal-thalamic direction. The changes in thalamo-frontal functional connectivity were prominent during deep anesthesia at high frequency bands. The connection strengths between the thalamus and the frontal area changed depending on the depth of anesthesia. The relationships between anesthetic levels and thalamo-frontal activity may shed light on the neural mechanism by which different levels of anesthesia act.

Impact of time interval between remifentanil and propofol on propofol injection pain

STUDY OBJECTIVE To determine the most effective time interval between remifentanil and propofol (TimeRP) for the prevention of propofol injection pain in association with remifentanil dosage. DESIGN Prospective randomized study. SETTING Operating room of a university hospital. PATIENTS Sixty American Society of Anesthesiologists physical status 1 and 2 patients scheduled for elective surgery under general anesthesia. INTERVENTIONS Patients were randomly assigned to 1 of 3 groups to receive remifentanil at dosages of 0.25, 0.5, or 0.75 μg/kg over 30 seconds before the injection of 1% propofol 2 mg/kg. TimeRP was defined as the time interval from the initiation of the remifentanil injection to the initiation of the propofol injection. TimeRP for each subsequent patient was determined by the response of the previous patient using an up-and-down sequential allocation method. Injection pain caused by propofol was evaluated using a 4-point scale during the propofol injection. MEASUREMENTS TimeRP50 was defined as the TimeRP at which propofol injection pain was absent in 50% of patients, and it was estimated using isotonic regression for each dose group. MAIN RESULTS TimeRP50 was significantly lower in the remifentanil 0.75 μg/kg group (38.6 seconds, 83% confidence interval [CI], 35.6-45.0) than in the 0.5 μg/kg group (65.0 seconds; 83% CI, 52.5-75.0) or the 0.25 μg/kg group (66.6 seconds; 83% CI, 57.1-76.5). CONCLUSIONS The efficacy of remifentanil pretreatment for preventing propofol injection pain can be influenced by the time interval between remifentanil and propofol as well as the remifentanil dose.

Use of triazolam and alprazolam as premedication for general anesthesia.

Background Triazolam has similar pharmacological properties as other benzodiazepines and is generally used as a sedative to treat insomnia. Alprazolam represents a possible alternative to midazolam for the premedication of surgical patients. The purpose of this study was to evaluate the anxiolytic, sedative, and amnestic properties of triazolam and alprazolam as pre-anesthetic medications. Methods Sixty adult patients were randomly allocated to receive oral triazolam 0.25 mg or alprazolam 0.5 mg one hour prior to surgery. A structured assessment interview was performed in the operating room (OR), the recovery room, and the ward. The levels of anxiety and sedation were assessed on a 7-point scale (0 = relaxation to 6 = very severe anxiety) and a 5-point scale (0 = alert to 4 = lack of responsiveness), respectively. The psychomotor performance was estimated using a digit symbol substitution test. As a memory test, we asked the patients the day after the surgery if they remembered being moved from the ward to the OR, and what object we had shown them in the OR. Results There were no significant differences between the groups with respect to anxiety and sedation. The postoperative interviews showed that 22.2% of the triazolam-treated patients experienced a loss of memory in the OR, against a 0% memory loss in the alprazolam-treated patients. In comparison with alprazolam 0.5 mg, triazolam 0.25 mg produced a higher incidence of amnesia without causing respiratory depression. Conclusions Oral triazolam 0.25 mg can be an effective preanesthetic medication for psychomotor performance.

Effective Dose of Ramosetron for Prophylaxis of Postoperative Nausea and Vomiting in High-Risk Patients

Background. Postoperative nausea and vomiting (PONV) are common adverse events with an incidence of up to 80% in high-risk patients. Ramosetron, a selective 5-HT3 receptor antagonist, is widely used to prevent PONV. The purpose of this study was to evaluate the effective dose of ramosetron for the prevention of PONV in high-risk patients. Methods. Fifty-one patients were randomly allocated to 3 groups and were administered ramosetron 0.3 mg (group A), 0.45 mg (group B), or 0.6 mg (group C), at the end of their surgery. The episodes of PONV were assessed 1, 6, 24, and 48 hours after the injection and all the adverse events were observed. Results. The complete response rate in the postoperative period 6–24 hours after the anesthesia was higher in group C than in group A: 93% versus 44%. Group Cs experience score of Rhodes index was lower than group As: 0.81 ± 2.56 versus 3.94 ± 5.25. No adverse drug reaction could be observed in all groups. Conclusions. The effective dose of ramosetron to be injected for the near-complete prophylaxis of PONV 6 to 24 hours after surgery in high-risk patients is a 0.6 mg bolus injection at the end of the surgery.

Optimal effect-site concentration of remifentanil when combined with dexmedetomidine in patients undergoing cystoscopy

Background Cystoscopic procedure is a very common practice in the field of urology due to its ability to survey the bladder for a variety of indications. However, patients who undergo cystoscopy feel intense pain and discomfort. This study investigated the half maximal effective concentration (EC50) of remifentanil in preventing cystoscope insertion pain under sedation using dexmedetomidine. Methods The study was prospectively conducted on 18 male patients, aged 18 to 65. Remifentail infusion was initiated together with dexmedetomidine, and started at a dose of 2.4 ng/ml on the first patient. The effect-site concentration (Ce) of remifentanil for each subsequent patient was determined by the previous patients response using Dixons up-and-down method with an interval of 0.3 ng/ml. Patients received a loading dose of 1.0 µg/kg dexmedetomidine over 10 minutes, followed by a maintenance dose of 0.6 µg/kg/hr. After the patients OAA/S score (Observers Assessment of Alertness/Sedation scale) reached 3-4, and the Ce of remifentanil reached target concentration, the urologist was allowed to insert the cystoscope and the pain responses were observed. Results The effect-site concentration of remifentanil required to prevent cystoscope insertion pain in 50% of patients under sedation using dexmedetomidine was 1.30 ± 0.12 ng/ml by Dixons up-and-down method. The logistic regression curve of the probability of response showed that the EC50 and EC95 values (95% confidence limits) of remifentanil were 1.33 ng/ml (1.12-1.52 ng/ml) and 1.58 ng/ml (1.44-2.48 ng/ml), respectively. Conclusions Cystoscopic procedure can be carried out successfully without any pain or adverse effects by optimal remifentanil effect-site concentration (EC50, 1.33 ng/ml; EC95, 1.58 ng/ ml) combined with sedation using dexmedetomidine.

Anesthesiologist's satisfaction using between cisatracurium and rocuronium for the intubation in the anesthesia induced by remifentanil and propofol.

Background Although cisatracurium has many advantages in anesthetic practices, the best choice of a nondepolarizing neuromuscular blocking agent that can replace succinylcholine is rocuronium. However, it is reported that remifentanil with propofol might provide reliable intubating condition, even without a neuromuscular blocking agent; therefore, it might improve the intubating condition with cisatracurium. This study examined intubating conditions after administering rocuronium or cisatracurium in a rapid sequence induction with remifentanil-propofol. Methods Fifty two ASA physical status 1 or 2 adult patients scheduled for an elective surgery were enrolled in a randomized double-blinded trial. Anesthesia was induced in all patients with propofol 2.0 mg/kg and remifentanil 0.5 µg/kg, administered over 60 seconds. Rocuronium 0.9 mg/kg (3 × ED95, R group, n = 23) or cisatracurium 0.15 mg/kg (3 × ED95, C group, n = 29) was administered after the induction sequence. Laryngoscopy was attempted when the anesthesiologist thought it was 90 seconds after drug administration and appropriate time for intubation. The examiner, another anesthesiologist, recorded the exact time to intubation and suppression of maximal T1 on TOF. The intubating condition was assessed by the first anesthesiologist, as excellent, good, poor or not possible. Results The best time to laryngoscopy was predicted by measuring TOF and was found to be significantly longer in the C group (197 ± 53 s) than in the R group (102 ± 49 s) (P value < 0.05). However, time to larygoscopy, intubating condition during the laryngoscopy, and hemodynamic changes after intubation was similar in both groups. Conclusions Despite fundamentally slower onset time, cisatracurium can provide quite good intubating conditions, which were comparable to those achieved with equipotent doses of rocuronium, which is more expensive in anesthesia inducted with remifentanil and propofol.