ABSTRACT
The voltage-gated Na channel subtype Nav1.7 is important for pain and itch in rodents and humans. We previously showed that a Nav1.7-targeting monoclonal antibody (SVmab) reduces Na currents and pain and itch responses in mice. Here, we investigated whether recombinant SVmab (rSVmab) binds to and blocks Nav1.7 similar to SVmab. ELISA tests revealed that SVmab was capable of binding to Nav1.7-expressing HEK293 cells, mouse DRG neurons, human nerve tissue, and the voltage-sensor domain II of Nav1.7. In contrast, rSVmab showed no or weak binding to Nav1.7 in these tests. Patch-clamp recordings showed that SVmab, but not rSVmab, markedly inhibited Na currents in Nav1.7-expressing HEK293 cells. Notably, electrical field stimulation increased the blocking activity of SVmab and rSVmab in Nav1.7-expressing HEK293 cells. SVmab was more effective than rSVmab in inhibiting paclitaxel-induced mechanical allodynia. SVmab also bound to human DRG neurons and inhibited their Na currents. Finally, potential reasons for the differential efficacy of SVmab and rSVmab and future directions are discussed.
Subject(s)
Animals , Female , Humans , Male , Mice , Antibodies, Monoclonal , Therapeutic Uses , Biotin , Metabolism , Cells, Cultured , Disease Models, Animal , Ganglia, Spinal , Cell Biology , HEK293 Cells , Hybridomas , Chemistry , Hyperalgesia , Drug Therapy , Mice, Inbred C57BL , Metabolism , Chemistry , Allergy and Immunology , Metabolism , Neuralgia , Drug Therapy , Metabolism , Protein Binding , Recombinant Proteins , Therapeutic Uses , Sensory Receptor Cells , PhysiologyABSTRACT
Objective·To observe the changes of perfusion index (PI),bispectral index (BIS),heart rate (HR),systolic blood pressure (SBP) and respiratory rate (RR) under pulling stimuli in children undergoing open inguinal hernia repairs with spontaneous ventilation,so as to evaluate the clinical value of PI in monitoring the stress response.Methods·Thirty children undergoing selective open inguinal hernia repairs with American Society of Anesthesiologists (ASA) physical status Ⅰ or Ⅱ were recruited.Anesthesia was induced with fentanyl and propofol,and was maintained with sevoflurane after the insertion of laryngeal mask.The PI,BIS,HR,SBP and RR were observed at the following time points:before induction of anesthesia (T0),before pulling hernia sac (T1),at the time point of pulling hernia sac (T2),1 min after pulling hernia sac (T3) and 5 min after pulling hernia sac (T4).Results·Compared with the baseline level at T0,the PI value at T1,T3 and T4 increased significantly (P=0.000,P=0.033 and P=0.000,respectively).The BIS,HR and SBP values at T1-T4 were significantly lower than baseline levels at T0(all P=0.000).The PI values at T2 and T3 reduced significantly compared with T1.The HR value at T2 was significantly higher than that ofT1 (P=0.033).Compared with the SBP values at T1,the SBP values at T3 and T4 were significantly higher (P=0.000 and P=0.011,respectively).And the RR values at T2 and T3 were higher than that at T1 (both P=0.000).The proportion of children with positive stress response based on PI was significantly higher than that based on other variables (all P=0.000).Conclusion·Perfusion index can reflect the noxious stimuli of the pulling hernia sac effectively and immediately.
ABSTRACT
Objective To estimate the value for the plasma-effect site equilibration rate constant(Ke0)of propofol using the time to peak effect(Tpeak)method and two pharmacokinetic models for propofol.Methods The Tpeak after a submaximal bolus dose 1.5 mg?kg~(-1) of propofol was measured with AAI A-line auditory evoked potential monitor in 36 patients scheduled for elective surgery under general anesthesia.Using Tpeak and two sets of pharmacokinetic parameters for propofol reported by Marsh and Shafer,the Ke0 was estimated according to the method described by Minto.Results The mean Tpeak was(142?62)s in 30 patients.The Ke0 was 0.626 min~(-1) with the model by Marsh and 0.914 min~(-1) with the model by Shafer.The corresponding t_(1/2) Ke0 values were 1.107 min and 0.759 min respectively(P＜0.01).Conclusion The Ke0 value of propofol estimated depends on the pharmacokinetic models used.The values we estimated in Chinese patients are significantly different from the values reported by foreign authors