The magnitude of hemodynamic changes associated with tracheal intubation with the Trachlight is almost the same as that which occurs with the direct laryngoscope. Hemodynamic changes are likely to occur because of direct tracheal irritation rather than direct stimulation of the larynx.
Magnetic resonance water diffusion imaging can detect early ischemic changes in stroke. Using a middle cerebral artery occlusion model, we examined which range of values of the orientation-independent diffusion quantity Dav = 1/3Trace(D) = 1/3(Dxx + Dyy + Dzz) is an early noninvasive indicator of reduced cerebral perfusion and focal brain injury. Cats underwent either a 30-min occlusion followed by 3.5 h reperfusion (n = 7) or a 60-min occlusion followed by 4-h reperfusion (n = 6). Repeated measurements of CBF were made with radiolabeled microspheres, and acute focal injury was measured with triphenyltetrazolium chloride (TTC) staining. During occlusion, the decrease in Dav correlated with CBF for caudate [30-min occlusion (n = 13): p < 0.0001: 60-min occlusion (n = 6): p < 0.02] and for cortex [30-min occlusion (n = 12): p < 0.0001: 60-min occlusion (n = 5): p < 0.04]. Variable caudate and hemispheric injury levels were found among cats in both groups. The area of tissue injury demarcated by TTC began to correlate with the area of reduced Dav by 30 min of occlusion (p < 0.02), and this correlation improved (p < 0.0001) at 1, 1.5, and 2.0 h after the onset of occlusion. The time necessary to reach a one-to-one correspondence between the percent of hemisphere injured and the percent of hemispheric area with Dav < 0.65 x 10(-9) m2/s was 2 h after occlusion. Thus, the absolute value of Dav is a good indicator of the risk of tissue injury, whereas the combination of Dav and the length of time of Dav reduction is an excellent predictor of acute focal tissue injury demarcated by TTC staining.
Objectives Diazepam is widely used to relieve preoperative anxiety in patients. The objective of this study was to investigate the effects of polymorphism in CYP2C19 and the effects of CYP3A4 messenger ribonucleic acid (mRNA) content in blood on recovery from general anesthesia and on diazepam pharmacokinetics. Methods Sixty‐three Japanese patients were classified into the following 3 genotype (phenotype) groups on the basis of polymerase chain reaction–restriction fragment length polymorphism analysis of CYP2C19 polymorphism: no variants, *1/*1 (extensive metabolizer [EM]); 1 variant, *1/*2 or *1/*3 (intermediate metabolizer [IM]); and 2 variants, *2/*2, *2/*3, or *3/*3 (poor metabolizer [PM]). We assessed the effects of these polymorphisms and of CYP3A4 mRNA content in the lymphocytes on the patients' recovery from general anesthesia. Results CYP2C19 genotyping analysis in the 63 subjects showed that 32%, 46%, and 22% of subjects were classified into the EM, IM, and PM groups, respectively. The PM subjects showed a larger area under the curve representing the concentration of diazepam over a 24‐hour period (AUC0–24) (2088 ± 378 ng/mL · h−1, P = .0259), lower clearance of diazepam (0.049 ± 0.009 L · h−1 · kg−1, P = .0287), and longer emergence time (median, 18 minutes; 25th‐75th percentile range, 13–21 minutes; P<.001) in comparison with subjects in the EM group (AUC0–24, 1412 ± 312 ng/mL; clearance, 0.074 ± 0.018 L · h−1 · kg−1; and emergence time, 10 minutes, 8–12 minutes [median and 25th‐75th percentile range]). The IM group also showed a longer emergence time (median, 13 minutes; 25th‐75th percentile range, 9–20 minutes; P<.001) and a larger variation in this parameter in comparison with the EM group. The distributions of the CYP2C19 genotype were significantly different between the 2 groups (rapid emergence < 20 minutes, slow emergence > 20 minutes) (P = .0148). The mean value of the CYP3A4 mRNA level in the slow‐emergence group (mean ± SD, 4.80 ± 3.99 ×10−10) was significantly lower than that of the rapid‐emergence group (mean ± SD, 12.50 ± 11.90 ×10−10) (P = .0315). However, there was no significant correlation between emergence time and CYP3A4 mRNA levels (r = 0.239, P = .0601). Conclusion We found that the CYP2C19 genotype affects diazepam pharmacokinetics and emergence from general anesthesia and that the slow‐emergence group possesses lower levels of CYP3A4 mRNA than are found in the rapid‐emergence group. Clinical Pharmacology & Therapeutics (2005) 78, 647–655; doi:
Abstract. K + channels are key modulators of neuronal excitability, and mutations in certain types of these channels are known to cause epileptic seizures. Activation of K + channels is reported to suppress epileptic discharge; however, the types of K + -channel openers that are most effective as anti-epileptic agents are not well understood. We established a quantitative fluorescence assay using the Na + indicator sodium-binding benzofuran isophthalate (SBFI) for evaluation of various compounds on epileptiform activities induced by 4-aminopyridine (4-AP) in cultured rat hippocampal neurons. Among the K + -channel openers, the K V 7.2 / K V 7.3-channel openers retigabine and flupirtine and K Ca 2-channel openers NS309, DCEBIO, and 1-EBIO showed potent anti-epileptic effects similar to conventional antiepileptic drugs (AEDs). In contrast, the K Ca 1.1-channel openers NS1619, isopimaric acid, and chlorzoxazone demonstrated moderate inhibition. The K ir 6-channel openers minoxidil, cromakalim, and pinacidil did not show anti-epileptic effects. We concluded that K V 7.2 / K V 7.3, K Ca 2, and, to some extent, K Ca 1.1-channel openers, but not K ir 6-channel openers, suppress 4-AP-induced epileptiform activities in hippocampal neurons. These results suggest that the K + -channel openers for this category of K + channels might have therapeutic potential as new classes of antiepileptic drugs.
Sorafenib is associated with adverse cardiac effects, including left ventricular dysfunction. However, the precise mechanism remains unclear. Here, we aimed to establish the genes responsible for this cardiotoxicity using zebrafish and human cardiomyocytes. Fluorescent cardiac imaging using pigmentless zebrafish with green fluorescent protein hearts revealed that the ventricular dimensions of the longitudinal axis with sorafenib were significantly shorter than those of the control group. Transcriptome analysis of their hearts revealed that stanniocalcin 1 (stc1) was downregulated by sorafenib. stc1 knockdown in zebrafish revealed that reduction of stc1 decreased the longitudinal dimensions of zebrafish ventricles, similar to that which occurs during sorafenib treatment. STC1 downregulation and cytotoxicity were also seen in human cardiomyocytes exposed to sorafenib. To clarify the molecular function of stc1 in sorafenib-induced cardiotoxicity, we focused on oxidative stress in cardiomyocytes treated with sorafenib. Reactive oxygen species (ROS) production significantly increased in both species of human cardiomyocytes and zebrafish exposed to sorafenib and STC1 knockdown compared with the controls. Finally, we found that forced expression of stc1 normalized impairment, decreasing the longitudinal dimensions in zebrafish treated with sorafenib. Our study demonstrated that STC1 plays a protective role against ventricular dysfunction and ROS overproduction, which are induced by sorafenib treatment. We discovered for the first time that STC1 downregulation is responsible for sorafenib-induced cardiotoxicity through activated ROS generation.
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