In Vitro and In Vivo Correlation of Hepatic Fraction of Metabolism by P450 in Dogs

1-Aminobenzotriazole (ABT) has been widely used as a nonspecific mechanism-based inhibitor of cytochrome P450 (P450) enzymes. It is extensively used in preclinical studies to determine the relative contribution of oxidative metabolism mediated by P450 in vitro and in vivo. The aim of present study was to understand the translation of fraction metabolized by P450 in dog hepatocytes to in vivo using ABT, for canagliflozin, known to be cleared by P450-mediated oxidation and UDP-glucuronosyltransferases–mediated glucuronidation, and 3 drug discovery project compounds mainly cleared by hepatic metabolism. In a dog hepatocyte, intrinsic clearance assay with and without preincubation of ABT, 3 Lilly compounds exhibited a wide range of fraction metabolized by P450. Subsequent metabolite profiling in dog hepatocytes demonstrated a combination of metabolism by P450 and UDP-glucuronosyltransferases. In vivo, dogs were pretreated with 50 mg/kg ABT or vehicle at 2 h before intravenous administration of canagliflozin and Lilly compounds. The areas under the concentration-time curve (AUC) were compared for the ABT-pretreated and vehicle-pretreated groups. The measured AUC_ABT/AUC_veh ratios were correlated to fraction of metabolism by P450 in dog hepatocytes, suggesting that in vitro ABT inhibition in hepatocytes is useful to rank order compounds for in vivo fraction of metabolism assessment.     

小剂量氯氨酮和咪唑安定对减轻硬膜外腔穿刺痛和术后镇痛的效应

目的　研究硬膜外腔穿刺前应用小剂量氯氨酮和咪唑安定 ,观察其镇静和有无预先镇痛的效果及安全性。方法　 6 0例择期行硬膜外腔麻醉 (复合全身麻醉 )的上腹部手术病人 ,随机分为两组 :氯氨酮和咪唑安定组 (TM组 ) 30例 ,手术前 1 5 min静脉给予氯氨酮 0 .3m g/ kg和咪唑安定 1 mg,用药 5 min后施行硬膜外腔穿刺 ,继之持续静脉输注氯按酮 3μg· kg- 1 · min- 1 和咪唑安定 0 .1μg· kg- 1 · min- 1 至手术结束前 1 5 min;对照组 (NS组 ) 30例静脉注射同等容量的生理盐水。患者术后均采用自控硬膜外镇痛 (PCEA) ,观察两组用药后 1 min、3min和 5 min时的镇静程度 (Ramsay分级评分 ) ,血压、心率、呼吸频率和脉搏血氧饱和度和术后 3、6、1 2、2 4、4 8h随访 PCEA用量、视觉模拟镇痛评分 (VAS)及患者有无精神异常。结果　TM组术后 3h和 6 h PECA用量显著少于 NS组 ,VAS评分明显低于NS组 ,Ramsay氏评分明显高于 NS组 ,其它监测指标均在正常范围 ,两组未有精神异常发生。结论　硬膜外腔穿刺前 ,预先静脉注射小剂量氯氨酮和咪唑安定 ,可明显减轻硬膜外穿刺痛 ,提高术后早期 PCEA镇痛质量 ,安全可靠     

探讨丙泊酚和咪达唑仑靶控输注在椎管内麻醉患者镇静中的应用

目的 探讨椎管内麻醉结合持续靶控输注丙泊酚和咪达唑仑在临床中的应用,观察其镇静效果.方法 对在本院自2011年12月~2013年1月接受治疗的80例患者资料进行回顾性分析,随机分为实验组和对照组两组,每组有40例患者.实验组患者注射丙泊酚镇静,而对照组注射咪达唑仑镇静,注射完后记录患者平卧10 min、注射镇静药后2 min、5 min、10 min以及手术结束前10 min、手术结束时的OAA/S镇静评分值.结果 两组患者生命体征基本平稳;OAA/S值在注射药物2 min到5 min后都明显下降.实验组患者OAA/S值与对照组患者相比偏高,且在注射5 min后及到手术结束前10 min都有明显下降,两组差异具有统计学意义（P＜0.05）.结论 椎管内麻醉结合丙泊酚、咪达唑仑采用持续靶控输注能够取得较好的镇静效果,且这样麻醉对患者生命体征影响较小.     

Effects of hydroxysafflor yellow A on the activity and mRNA expression of four CYP isozymes in rats

Ethnopharmacological relevance

In traditional therapy with Chinese medicine, hydroxysafflor yellow A (HSYA), a main active component isolated from the dried flower of Carthamus tinctorius L., is the principal efficiency ingredient of Safflor Yellow Injection. Now HSYA has been demonstrated to have good pharmacological activities of antioxidation, myocardial and cerebral protective and neuroprotective effects. The purpose of this study was to find out whether HSYA influences the effect on rat cytochrome P450 (CYP) enzymes (CYP1A2, CYP2C11, CYP2D4 and CYP3A1) by using cocktail probe drugs in vivo; the influence on the levels of CYP mRNA was also studied.

Materials and methods

A cocktail solution at a dose of 5 mL/kg, which contained phenacetin (20 mg/kg), tolbutamide (5 mg/kg), dextromethorphan (20 mg/kg) and midazolam (10 mg/kg), was given as oral administration to rats treated with short or long period of intravenous HSYA via the caudal vein. Blood samples were collected at a series of time-points and the concentrations of probe drugs in plasma were determined by HPLC–MS/MS. The corresponding pharmacokinetic parameters were calculated by the software of DAS 2.0. In addition, real-time RT-PCR was performed to determine the effect of HSYA on the mRNA expression of CYP1A2, CYP2C11, CYP2D4 and CYP3A1 in rat liver.

Results

HSYA had significant inhibition effects on CYP1A2 and CYP2C11 in rats as oriented from the pharmacokinetic profiles of the probe drugs. Furthermore, HSYA had no effects on rat CYP2D4. However, CYP3A1 enzyme activity was induced by HSYA. The mRNA expression results were in accordance with the pharmacokinetic results.

Conclusions

HSYA can either inhibit or induce activities of CYP1A2, CYP2C11 and CYP3A1. Therefore, co-administration of some CYP substrates with HSYA may need dose adjustment to avoid an undesirable herb–drug interaction.     

咪达唑仑配合地佐辛在甲状腺手术中应用效果观察

目的观察咪达唑仑配合地佐辛在甲状腺手术中的应用效果。方法选取2010年1月—2013年1月采用颈丛麻醉方式行甲状腺手术的患者100例,分为观察组与对照组,均采用利多卡因与罗哌卡因麻醉,并分别使用咪达唑仑配合地佐辛以及单用咪唑达仑进行镇痛与镇静,对两组手术开始15min、30min与术后的镇痛与镇静效果,以及术前和手术开始5min、15min、30min患者的BP、RR及HR情况分别进行比较,并对两组发生的不良情况统计比较。结果手术15min、30min和术后观察组患者的镇痛相对更明显,镇静效果上观察组相对明显,但不具显著性;术前以及术中观察组在BP、RR及HR上的波动相对更小,两组不良反应情况无明显差异;观察组整体效果更明显。结论咪达唑仑配合地佐辛在甲状腺手术中应用效果明显,值得临床推广。     

臂丛神经腋路阻滞法在学龄前儿童上肢手术中的应用

目的观察臂丛神经阻滞复合氯胺酮麻醉在小儿上肢手术中的应用效果。方法选择单侧上肢骨折行切开内固定手术的患儿60例,随机分为治疗组30例和对照组30例:治疗组患儿采用臂丛神经阻滞麻醉,术中给予氯胺酮强化;对照组采用氯胺酮复合咪唑安定全身麻醉。观察手术中HR、SpO2、MAP的变化;观察麻醉期间氯胺酮的用量及术毕神志恢复情况。结果治疗组患儿术后立即清醒,术后1小时哭闹和术后2小时哭闹的人数均多于对照组的患儿,(P<0.05)。治疗组氯胺酮总用量明显小于对照组(P<0.05);治疗组HR及MAP增高,SpO2下降的人数明显小于对照组(P<0.05)。结论臂丛神经阻滞复合氯胺酮麻醉效果完善,安全系数高,全麻药用量小,是小儿上肢手术较为理想的麻醉方法。     

A comparison of the antifibrillatory effect of midazolam and flunitrazepam in acute myocardial ischaemia in the dog

Summary

A study was carried out using a model of myocardial ischaemia in the dog after ligation of the left coronary artery to determine the effects of the benzodiazepines, flunitrazepam and midazolam, on the ventricular fibrillation threshold. The fibrillation threshold was measured twice within 15?min and 8?min after ligation. Fifteen minutes after the onset ofischaemic heart attack, 1.2?mg midazolam/kg or 0.25?mg flunitrazepam and midazolam, on the ventricular fibrillation threshold. The fibrillation threshold was measured twice within 15?min and 8?min after ligation. Fifteen minutes after the onset ofischaemic heart attack, 1.2?mg midazolam/kg or 0.25?mg of ischaemia. Their effects on haemodynamics were negligible. It is suggested that both benzodiazepines can be used for increasing electrical stability of the heart in patients with acute myocardial infarction and to inhibit the psychic stress response. Because of its short biological half-life and water solubility, allowing painless intravenous administration, midazolam offers a more flexible approach to pharmacotherapy immediately after acute heart attack according to the patient's current clinical status.     

布托啡诺联合咪哒唑仑对区域麻醉的镇静效果分析

目的探讨布托啡诺联合咪哒唑仑对区域麻醉的镇静效果。方法102例区域麻醉手术患者作为研究对象,随机分为实验组和对照组,实验组给予咪哒唑仑联合布托啡诺镇静,对照组给予咪哒唑仑联合芬太尼镇静。结果（1）两组感觉,运动阻滞起效时间和手术时间均差异无显著性（均P〉0．05）。（2）实验组MAP,HR和SPO,在围手术期基本稳定（P〉0．05）,对照组术中MAP和HR和实验组相比有显著性变化（MAP：实验组（87．0±13．3）mmHg,对照组（98．2±18．2）mmHg;HR：实验组（89．5±13．4）次／mine,对照组（81．2±16．5）次／mine）（MAP：t=4．537,P〈0．05;HR：t=4．537,P〈0．05）。结论咪哒唑仑联合布托啡诺用于区域麻醉,有效性和安全性高,值得临床考虑。     

曲马朵联合咪哒唑仑用于腹部术后非机械通气老年患者镇痛镇静效果观察

目的 观察曲马朵联合咪哒唑仑对腹部术后非机械通气老年患者的镇痛镇静效果和不良反应.方法 选择年龄>60岁择期腹部手术后患者320例,随机分为试验组和对照组,每组160例.试验组应用曲马朵联合咪哒唑仑镇痛,对照组单纯行曲马朵镇痛.观察两组镇痛镇静效果、48 h内曲马朵总用量、术后认知功能障碍及不良反应发生情况.结果 试验组术后不同时段视觉模拟评分(VAS)均低于对照组,Ramsay镇静评分均高于对照组,48 h内曲马朵总用量少于对照组,差异均有统计学意义(P<0.05);试验组术后认知功能障碍的发生率低于对照组,差异有统计学意义(P<0.01);两组均未发生明显不良反应.结论 曲马朵联合咪哒唑仑对腹部术后非机械通气老年患者的镇痛镇静效果满意,用药剂量少,给予预防性措施后,不良反应少,安全可行.     

咪哒唑仑联合氧化亚氮吸入麻醉在结肠镜检查中的应用

目的 探讨咪哒唑仑联合氧化亚氮吸入麻醉在结肠镜检查中的可行性和安全性.方法 108例均应用咪哒唑仑与氧化亚氮吸入麻醉行结肠镜检查,观察并记录给药前、给药后、检查第3分钟及退镜后心率(HR)、收缩压(SBP)、舒张压(DBP)和脉搏血氧饱和度(SpO2)的变化.结果 给药后、检查第3分钟及退镜后各项观察指标与给药前比较差异无统计学意义(P>0.05);Ramsay镇静评分2级以上占94.4%.提示镇静和镇痛效果好.结论 咪哒唑仑联合氧化亚氮吸入麻醉用于结肠镜检查过程中各项生命体征平稳,安全有效.