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An LC-MS method with natural isotope abundance correction and a 1H NMR relative quantitative method were established to determine the deuterium incorporation of donafenib tosilate, a new deuterated drug molecule. First, the peak areas of isotopic impurities (non-deuterated and incompletely deuterated impurities) and deuterated drug were recorded through the single ion monitoring (SIM) mode of the established LC-MS method and then corrected in terms of the natural isotope abundance offered by ChemDraw soft, removing the nature isotope interference from 13C, 37Cl, etc. The corrected areas were subsequently used to calculate mol% of isotopologues (D0, D1, D2, D3) and Atom% D, namely, deuterium incorporation. In addition, a 1H qNMR experiment was conducted with the aromatic proton at δ 8.63 and the residual proton of isotopic impurities at δ 2.79 as quantitative peaks. The mixture of DMSO-d6 and D2O (10∶1) was employed as the solvent to change the spin-coupling between the residual proton and active hydrogen so that the residual proton could be measured as the single peak, and the sensitivity was greatly improved. The acquisition parameters were also optimized, and Atom% 1H and the deuterium incorporation were then calculated. The two methods were applied to samples of three commercial batches, and the testing results were almost consistent. Both methods proved accurate, sensitive, fast and independent of standard substances and accurate weighing, which could be applied to the determination of the deuterium incorporation of donafenib tosilate and provide a reference for other deuterated drugs.
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Notoginsenosides， the saponins extracted from Panax notoginseng， have many pharmacological effects， such as anti-inflammation， anti-oxidation， anti-tumor， nervous system and cardiovascular system protection， microcirculation improvement and calcium overload inhibition. At present， notoginsenosides are widely used clinically for treating many diseases with good efficacy， especially for nervous system diseases such as stroke， stroke sequelae and Alzheimer's disease. In recent years， the mechanism underlying their neuroprotective effect has been continuously explored. To advance the applied research on notoginsenosides in the prevention and treatment of central nervous system diseases， this paper， combined with the latest reports， summarizes their neuroprotective effect and mechanisms in terms of regulating voltage-gated ion channels， protecting nerve cells and neurovascular unit， inhibiting oxidative stress and inflammatory reaction， promoting angiogenesis and reducing excitatory neurotoxicity. Although the protective mechanism of notoginsenosides for the nervous system mainly involves the above several aspects， some of them still remain to be fully elucidated， which necessitates the further exploration of neuroprotective effect of notoginsenosides with molecular biology， metabolomics， proteomics and other technologies.
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The enzymes CYP1 A2 and CYP3 A4 were measured by building a "Cocktail" probe drug and the incubation system of liver microsomes. The compatibility of Aconiti Lateralis Radix Praeparata combined with dried Rehmanniae Radix on CYP450 enzyme protein and gene expression was explored from the level of protein and molecular biology. It explored the molecular mechanism of compatibility detoxication of Aconiti Lateralis Radix Praeparata to provide scientific support for clinical safe and effective application of Aconiti Lateralis Radix Praeparata. The CYP450 enzyme activity was determined by using "Cocktail" probe drugs. The content of CYP450 enzyme was measured by CO reduction of differential spectrum method. The mRNA expression of CYP1 A2 and CYP3 A4 enzyme was detected by RT-PCR technology. Compared with the blank group, the CYP1 A2 and CYP3 A4 enzyme activity and mRNA expression were increased in the dried Rehmanniae Radix combined with Aconiti Lateralis Radix Praeparata group with significant differences(P<0.05), while the CYP3 A4 enzyme activity and mRNA expression were no influence in the Aconiti Lateralis Radix Praeparata group. The CYP3 A4 enzyme activity and mRNA expression were increased in the dried Rehmanniae Radix and the dried Rehmanniae Radix combined with Aconiti Lateralis Radix Praeparata group, and there were significant differences(P<0.05). The content of CYP450 enzyme was decreased in the Aconiti Lateralis Radix Praeparata group, contributed to extremely significant difference(P<0.01). The content of CYP450 enzyme was increased in the dried Rehmanniae Radix and the dried Rehmanniae Radix combined with Aconiti Lateralis Radix Praeparata group, and there were significant differences(P<0.05). The CYP1 A2 and CYP3 A4 enzyme activity and gene expression were enhanced after dried Rehmanniae Radix combined with Aconiti Lateralis Radix Praeparata. The metabolism of toxic ingredients of Aconiti Lateralis Radix Praeparata was accelerated to reach an effect of detoxication. The detoxication mechanism of compatibility of Aconiti Lateralis Radix Praeparata was verified from the viewpoint of liver metabolic enzymes.
Subject(s)
Aconitum , Drugs, Chinese Herbal , LiverABSTRACT
Objective Comparation of the effects of intravenous lidocaine and dexmedetomidine on coughing during extubation after endoscopic thyroidectomy. Methods 60 patients who underwent endoscopic thyroidectomy were randomly divided into group L, group D and group C, each group included 20 cases. Group L were given a loading lidocaine 1.5 mg/kg over 10 minutes before anesthesia induction, followed by a continuous intravenous lidocaine 1.5 mg/ (kg·h) until 30 min before the end of surgery. Group D were given a loading dexmedetomidine 0.5μg/kg over 10 minutes before anesthesia induction, followed by a continuous intravenous dexmedetomidine 0.4 μg/ (kg · h) until 30 min before the end of surgery. Group C were given intravenous infusion of equal volume normal saline. The incidence and severity of coughing were recorded within 2 minutes after extubation. Hemodynamic variables were measured at T0 (before anaesthesia induction) , T1 (immediately after extubation) , and T2 (5 min after extubation). The volume of drainage was recorded within 24 hours after surgery. Results The incidence and grade of cough were significantly lower in group L and group D than in group C (P < 0.05). Compared with group L and group D, MAP and HR were significantly increased in group C at T1 and T2 (P < 0.05). Compared with group C, the volume of drainage was significantly reduced in group L and group D within 24 hours after surgery (P < 0.05).Conclusion Intravenous lidocaine and dexmedetomidine can effectively inhibit coughing during extubation period after endoscopic thyroidectomy, and there is no significant difference between the two treatments.
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Objective To investigate the effect of different pressure CO2pneumoperitoneum on postoperative gastroeuteric function in female patients undergoing gynecological laparoscopic surgery. Methods A total of 120 female patients,aged 30-60 years,ASA physical status Ⅰ or Ⅱ,scheduled for elective gynecological laparoscopic surgery were randomly into three groups (n=40 in each).The pressure of CO2pneumoperitoneum were set at 6-8,9-11 and 12-14 mm Hg in group L,group M and group H,respectively.All patients were detected on an empty stomach of serum concentrations of D-lactic acid 6 hours before operation and after opration.In addition,pH,PaCO2and PaO2were recor-ded before anesthesia (T1),before pneumoperitoneum (T2),1 hour after pneumoperitoneum (T3)2 hours after pneumoperitoneum (T4)and 1 hour (T5)after stopping pneumoperitoneum.The time of pneumoperitoneum,the time of first flatus,intake and defecation,length of primary hospital stays after operation were recorded.Results Compared with 6 hours before operation,the serum concen-trations of D-lactic acid were obviously increased at postoperative 6 hours in all groups (P<0.05). Compared with group L,the serum concentrations of D-lactic acid at 6 hours after operation were ob-viously increased in group M and group H (P<0.05).PaO2in three groups was not different at T1-T5.Compared with group L,pH at T3,T4was significantly decreased in group M and group H (P<0.05).Compared with group L,PaCO2was significantly increased at T3-T5in group M and group H (P<0.05 ).Compared with group L,the time of first flatus,intake and defecation,length of primary hospital stays after operation were obviously delayed in group M and group H(P<0.05). Conclusion The low pressure of CO2pneumoperitoneum can reduce the damage of CO2pneumoper-itoneum on postoperative gastroeuteric function and avail the recovery of parents’postoperative gas-troeutericfunction in female patients undergoing gynecological laparoscopic surgery.
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Objective To investigate the effect of different pressure CO 2 pneumoperitoneum on early postoperative cognitive function in female patients undergoing gynecological laparoscopic sur-gery.Methods Ninety female patients,aged 40-60 years,ASA physical status Ⅰor Ⅱ,scheduled for elective gynecological laparoscopic surgery,were randomly divided into three groups (n = 30). The pressure of CO 2 pneumoperitoneum were set at 6-8,9-1 1 and 12-14 mm Hg in groups L,M and H,respectively.All of the patients were tested by the neuropsychology and questionnaire review to estimate whether the patient got cognitive decline at 24 h before the operation.The venous blood sam-ples 10 minutes before anesthesia (T1 ),at the end of surgery (T2 ),6 hours after surgery (T3 ),24 hours after surgery (T4 )and 72 hours after surgery (T5 )were collected for determination of serum concentrations of NSE and S100βprotein.The pH,PaCO 2 and PaO 2 were recorded before anesthesia (Ta ),before pneumoperitoneum (Tb ),1 hour after pneumoperitoneum (Tc ),2 hours after pneumo-peritoneum (Td )and 1 hour after stopping pneumoperitoneum (Te ).Results Scores of these tests in three groups were not different and there was no patient with cognitive decline after surgery.Com-pared with group H,the concentration of NSE at T2 and T3 was significantly lower in groups L and M (P <0.05).Compared with group H,the concentration of S100βprotein at T2 was significantly lower in groups L and M (P <0.05).Compared with group L,pH at Tc and Td was significantly decreased in groups M and H (P <0.05).Compared with group L,PaCO 2 was significantly increased at Tc-Te in groups M and H (P <0.05).Conclusion Different pressure of CO 2 pneumoperitoneum has no ob-vious effect on the early cognitive function,but low (6-8 mm Hg)CO 2 pneumoperitoneum can reduce the release of NSE and S100βprotein after operation.
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Objective To investigate the effect of different pressure CO2 pneumoperitoneum on function of liver and kidney in patients undergoing laparoscopic gastrectomy.Methods A total of sixty pa-tients,aged 40-65 years,scheduled for elective laparoscopic gastrectomy were randomly divided into three groups (n=20).The pressures of CO2 pneumoperitoneum were set at 6-8,9-11 and 12-14 mm Hg in group L,group M and group H respectively.The venous blood samples before pneumoperitoneum (T1 ),1 hour after pneumoperitoneum(T2 ),2 hour after pneumoperitoneum (T3 ),1 hour(T4 )and 24 hours(T5 )after stopping pneumoperitoneum were collected for determination of serum concentrations of NAG,Cys-C, ALT,AST,Cr,BUN and the amount of urine.pH,PaCO2 ,PaO2 were recorded at T1-T4 .Results ALT, AST,Cr and BUN were not different at T1-T5 in the three groups.Compared with group L,the concentra-tion of NAG and Cys-C at T2-T5 were significantly higher in the group M and H (P <0.05).Compared with group L,the amount of urine at T2-T5 was significantly lower in the group M and H (P <0.05 ), PaCO2 was significantly increased in the group H and M at T2-T4 (P <0.05).Conclusion The pressure of 6-8 mm Hg CO2 pneumoperitoneum can alleviate the damage of function of liver and kidney in patients un-dergoing laparoscopic gastrectomy.
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Scutellarin is the main effective constituent of breviscapine, a flavonoid mixture isolated from the dried whole plant of Erigeron breviscapus (Vant.) Hand-Mazz, and valsartan is used as an antihypertensive drug. These two drugs have already been clinically used together to treat diabetic nephropathy (DN) in China, and the combined medications showed some enhanced protection against DN. The aim of this study is to investigate the potential pharmacokinetic interaction between scutellarin and valsartan in rats. Breviscapine injection (20 mg x kg(-1), i.v.) and valsartan (15 mg x kg-, i.g.), either alone or together were given to 18 male Sprague-Dawley rats. Concentrations of scutellarin and valsartan were quantified by HPLC, and pharmacokinetic parameters were calculated by non-compartmental methods. We found that the pharmacokinetic parameters of scutellarin altered significantly after co-administration of oral valsartan. The plasma clearance (CL(p)) and the bile clearance (CL(b)) of scutellarin were reduced significantly in the presence of valsartan. After oral administration of valsartan with or without intravenous scutellarin, however, the pharmacokinetic parameters of valsartan were comparable. In conclusion, our data suggests that the concurrent use of valsartan reduces the biliary excretion of scutellarin, and this may be due to the inhibitory effect of valsartan on the biliary excretion of scutellarin mediated by Mrp2 (Multidrug resistance-associated protein 2).
Subject(s)
Animals , Male , Rats , Administration, Intravenous , Administration, Oral , Antihypertensive Agents , Blood , Pharmacokinetics , Apigenin , Blood , Pharmacokinetics , Bile , Metabolism , Chromatography, High Pressure Liquid , Drug Interactions , Erigeron , Chemistry , Glucuronates , Blood , Pharmacokinetics , Metabolic Clearance Rate , Multidrug Resistance-Associated Proteins , Metabolism , Plants, Medicinal , Chemistry , Random Allocation , Rats, Sprague-Dawley , Valsartan , Blood , PharmacokineticsABSTRACT
Objective: To study the effects of glycosaminoglycan from scallop skirt (SS-GAG) on the expression of vascular endothelial growth factor (VEGF) and the mechanism of anti-atherosclerosis action of SS-GAG. Methods: U937 cells were incubated with 80mg/L oxidized low density lipoprotein (ox-LDL) for 48h to establish a macrophage-derived foam cell model. In addition, U937 cells were divided into 6 groups: ①control group; ②ox-LDL group; ③ox-LDL+200mg/L SS-GAG group; ④ox-LDL+400 mg/L SS-GAG group; ⑤ox-LDL+800 mg/L SS-GAG group; ⑥ox-LDL +Heparin 100 mg/L group.After 48h's incubation, the concentration of VEGF in the medium was determined by ELISA. Results: The expression of VEGF in U937 foam cells was obviously higher than that of the control group. After treatment with heparin (100 mg/L) and SS-GAG of different concentrations (200mg/L, 400 mg/L, 800 mg/L), the expression of VEGF decreased obviously, especially in the ox-LDL+800 mg/L SS-GAG group (P＜0.01). Conclusion: The antiatherogenic effect of SS-GAG is probably due to its ability to inhibit VEGF expression.
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Objective: To study the effects of glycosaminoglycan from scallop skirt (SS-GAG) on the expression of vascular endothelial growth factor (VEGF) and the mechanism of anti-atherosclerosis action of SS-GAG. Methods: U937 cells were incubated with 80mg/L oxidized low density lipoprotein (ox-LDL) for 48h to establish a macrophage-derived foam cell model. In addition, U937 cells were divided into 6 groups: ①control group; ②ox-LDL group; ③ox-LDL+200mg/L SS-GAG group; ④ox-LDL+400 mg/L SS-GAG group; ⑤ox-LDL+800 mg/L SS-GAG group; ⑥ox-LDL +Heparin 100 mg/L group.After 48h's incubation, the concentration of VEGF in the medium was determined by ELISA. Results: The expression of VEGF in U937 foam cells was obviously higher than that of the control group. After treatment with heparin (100 mg/L) and SS-GAG of different concentrations (200mg/L, 400 mg/L, 800 mg/L), the expression of VEGF decreased obviously, especially in the ox-LDL+800 mg/L SS-GAG group (P＜0.01). Conclusion: The antiatherogenic effect of SS-GAG is probably due to its ability to inhibit VEGF expression.
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AIM: To observe the effects of ketamine on preventing the increase of postoperative morphine requirement induced by fentanyl.METHODS: Sixty women undergoing total abdominal hysterectomy by spinal anaesthesia were assigned to 4 groups consisting of placebo(normal saline,C),fentanyl(3 bolus of 1 ?g/kg,at 15 min intervals,F),ketamine(infusion of 15 ?g?kg-1?min-1 ketamine from the skin incision until 20 min before the end of the surgery,K),ketamine and fentanyl(infusion of 15 ?g?kg-1?min-1 ketamine from the skin incision until 20 min before the end of the surgery plus 3 bolus of 1 ?g/kg fentanyl,at 15-min intervals,FK).The cumulative morphine consumption,pain score,and adverse effects(nausea, vomiting,hallucination,dizziness and itching) were recorded at 1,3,6,12,24,48 h postoperatively.RESULTS: There were no significant differences in age,weight,duration of surgery and the post-operative sensory block time.The cumulative morphine consumption in group F was significantly higher than those in group C at 3,6,12 h postoperatively(P