Effect of omeprazole on the anticoagulant activity and the pharmacokinetics of warfarin enantiomers in rats

The effect of the proton pump inhibitor omeprazole on the anticoagulation and the pharmacokinetics of warfarin enantiomers was studied in rats. Omeprazole given intraperitoneally in a daily dose of 0.67 mg/kg over 8 days had no significant effect on the absorption, distribution and the total serum clearance values of the S- and R-enantiomers of warfarin. Omeprazole did not affect the pre-treatment baseline blood coagulation and the in vitro rat serum protein binding of warfarin enantiomers. In vitro study with rat liver microsomes showed that omeprazole had an inhibitory effect on the hydroxylation of warfarin enantiomers. Results obtained from in vivo urinary excretion study revealed that omeprazole inhibited the formation clearance of both S- and R-form oxidative metabolites, but increased that of the overall reductive metabolites, and the renal clearance of S- and R-enantiomers, of warfarin. As a consequence, the total serum clearance values for warfarin enantiomers remained unchanged and the hypoprothrombinaemic response produced by warfarin was not affected.     

几种中草药复配杀虫剂的急性毒性实验研究

为有效开发植物杀虫剂资源及今后的推广应用提供科学依据。用两种粉剂和两种醇剂的杀虫应用浓度给小白鼠灌,而家兔则行皮肤刺激试验。结果显示,除醒剂Y-13经口有中毒情况发生外,其它3种制剂均无中毒现象,醇剂Y-13的家兔皮肤也无刺激反应发生。作者认为:4种制剂在有杀虫效果的前提下,杀虫应用浓度对人和动物都较安全。有开发和推广应用价值。     

Acute tolerance to ethanol using drug discrimination and open-field procedures in rats

This study examined the phenomenon of acute tolerance to ethanol (ETOH) using drug discrimination learning (DDL), and open-field (OF) procedures. In DDL, rats were trained to discriminate between ETOH (1.2 g/kg) and saline. Doses of ETOH lower (0.6 and 0.9 g/kg), or higher (1.8 and 2.4 g/kg) than the training dose were tested to examine possible influence of ETOH pretreatment doses on the expression of acute tolerance. To assess concentrations of ETOH in the organism, a rebreathed air procedure was used. Equal concentrations after different ETOH doses were achieved by postponing the tests until sufficient time had elapsed. Only doses of ETOH higher than the training dose produced acute tolerance in the DDL procedure. For the response-time data no acute tolerance was observed. In the OF experiment, the occurrence of acute tolerance was examined for different spontaneous behaviours in drug-naive animals. At equal ETOH concentrations, the group examined during the descending phase of intoxication (1.8 g/kg, 60 min post-injection), reared significantly more than the group tested during the ascending phase (1.5 g/kg, 10 min post-injection). Other OF behaviours did not differ significantly between the two time intervals. Thus, it is suggested that acute tolerance is seen both in ETOH naive and in ETOH pre-exposed rats. However, in DDL acute tolerance was observed only when doses higher than the training dose of ETOH were evaluated.     

Multiple subcortical haemorrhages following lumbar metrizamide myelography

Summary The case is presented of a patient showing multiple subcortical haemorrhages after lumbar metrizamide myelography. This complication after intrathecally administered metrizamide contrast medium appears not to have been reported before. Several different possible explanations are proposed for the phenomena observed in this case.     

靶控输注异丙酚意识消失时血浆和效应室浓度的EC50与脑电双频谱指数的关系多中心大样本临床研究

目的 研究择期手术患者靶控输注（TCI）异丙酚意识消失时血浆、效应室靶浓度的50%患者意识消失时的药物浓度（EC50）与脑电双频谱指数（BIS）的关系。方法 5家医疗中心405例择期手术患者（国人）,ASAⅠ或Ⅱ级。靶控输注异丙酚,以血浆靶浓度1．2μg/ml为起点,到达预期血浆靶浓度后每30秒递增0．3μg/ml,直至患者意识消失。采用概率单位回归分析计算患者意识消失时异丙酚血浆靶浓度、效应室靶浓度的EC05、EC50和EC95及其所对应的BIS。结果 择期手术患者TCI异丙酚意识消失时异丙酚血浆靶浓度EC05、EC50和EC95分别是2．9μg/ml、3．8μg/ml和4．8μg/ml,效应室靶浓度EC05、EC50和EC95分别是1．3μg/ml、2．2μg/ml和3．2μg/ml,50%患者意识消失的BIS是58,5%和95%患者意识消失的BIS分别是77和40。结论 择期手术患者TCI异丙酚意识消失时血浆靶浓度和效应室靶浓度EC50及95%置信区间分别是3．8μg/ml（3．8～3．9μg/ml）和2．2μg/ml（2．2～2．3μg/ml）, 50%患者意识消失的BIS用95%置信区间是58（58～59）。     

老年患者不同靶浓度罗库溴铵肌松效应的比较

目的比较老年患者不同靶浓度罗库溴铵的肌松效应。方法择期全麻老年患者100例,ASAⅡ级,随机分为4组(n=25),A组、B组和C组麻醉诱导气管插管时效应室靶浓度(Ce)为3μg/ ml,术中维持Ce分别为0.6、0.8、1.0μg/ml;D组麻醉诱导气管插管时Ce为3.3μg/ml,术中维持Ce为0_8μg/ml。记录肌松起效时间、恢复时间和恢复指数。评价气管插管条件和术中肌松程度。记录手术及TCI时间、罗库溴铵总用药量和期间用药量[总用药量,(体重×TCI时间)]。结果4组均可顺利完成气管插管,D组起效时间较A组、B组和C组缩短(P<0.05);A组肌松满意率低,B组、C组和D组均可维持满意肌松,但C组罗库溴铵用量较多,术中肌松程度较大,术后恢复时间较长(P<0.05)。结论麻醉诱导气管插管时罗库溴铵Ce为3.3μg/ml、术中麻醉维持Ce为0.8μg/ml,可产生满意的肌松条件,且有利于术后肌松恢复,是一种适用于老年患者合理的TCI给药方案。     

不同剂量瑞芬太尼复合靶控输注异丙酚对心脏瓣膜置换术病人气管插管时血液动力学反应的影响

目的 评价不同剂量瑞芬太尼复合靶控输注(TCI)异丙酚对心脏瓣膜置换术病人气管插管时血液动力学反应的影响.方法 拟行心脏瓣膜置换术的风湿性心脏病病人30例,随机分为3组(n=10):芬太尼组(Ⅰ组)、小剂量瑞芬太尼组(Ⅱ组)和大剂量瑞芬太尼组(Ⅲ组).麻醉诱导:Ⅰ组静脉注射芬太尼10 μg/kg,然后持续静脉输注芬太尼10 μg·kg-1·h-1;Ⅱ组和Ⅲ组静脉注射瑞芬太尼1μg/kg,然后分别持续静脉输注瑞芬太尼0.5、1.0 μg·kg-1·min-1.3组静脉注射芬太尼或瑞芬太尼后3min开始TCI异丙酚,初始血浆靶浓度为1.0 μg/ml,逐渐递增至2.0 μg/ml.静脉注射罗库溴铵0.6 mg/kg后气管插管.分别在麻醉诱导前(T0)、诱导期间血压最低值时(T1)、插管前即刻(T2)、插管后1 min(T3)、插管后2 min(T4)及插管后5 min(T5)时记录心率(HR)、平均动脉压(MAP)、中心静脉压(CVP)、肺毛细血管楔压(PCWP)、心脏指数(CI)、外周血管阻力指数(SVRI)及左室每搏功指数(LVSWI),并于上述时点测定混合静脉血氧饱和度(S(v)O2).记录诱导期间低血压及气管插管心血管反应的发生情况.结果 3组间麻醉诱导期间低血压及气管插管心血管反应的发生率差异无统计学意义(P＞0.05).与T0比较,各组T1,2时HR和MAP均降低,Ⅱ组T3时HR和MAP升高,Ⅲ组T4时MAP降低,Ⅰ组和Ⅱ组T2-4时S(v)O2升高(P＜0.05);3组间各时点CVP、PCWP、CI、LVSWI和S(v)O2差异无统计学意义(P＞0.05).结论 复合TCI异丙酚(血浆靶浓度2.0 μg/ml)时,静脉注射瑞芬太尼1 μg/kg负荷剂量后,持续静脉输注0.5 μg·kg-1·min-1麻醉诱导时血压和HR下降适度,可较好地抑制心脏瓣膜置换术病人气管插管时血液动力学反应.     

Serum digoxin and beta-methyldigoxin in elderly patients on hospital admission: correlation with home compliance and clinical variables

Summary Serum digoxin and beta-methyldigoxin (BMD) were measured in 165 elderly patients (age >60 years) admitted to hospital, of whom 109 had been treated at home with digoxin and 56 with BMD.The mean BMD level was significantly lower than that of digoxin (1.1 vs. 1.4 ng/ml). Creatinine clearance and daily dose were the variables most strongly associated with digoxin level, and the prescribed dose and serum albumin were the best predictors of the BMD concentration. Compliance was assessed by a compliance index (CI), namely the ratio of the measured glycoside concentration, corrected for creatinine clearance, over the expected steady-state dose, calculated from a hospitalized reference group. Compliant individuals in both treatment groups, i.e. those with a CI > the median value, were characterized by a lower daily dose and dosage frequency.Toxicity, whether clinical or electrocardiographic, was present in 9% of the patients and was associated only with a significantly higher mean serum level of the drug.     

A pharmacokinetic interaction between carbamazepine and olanzapine: observations on possible mechanism

Objective: Olanzapine is a novel antipsychotic, which is effective against both the positive and negative symptoms of schizophrenia and causes fewer extrapyramidal adverse effects than conventional antipsychotics. The purpose of the present study was to assess the potential for a pharmacokinetic interaction between olanzapine and carbamazepine, since these agents are likely to be used concomitantly in the treatment of manic psychotic disorder. Method: The pharmacokinetics of two single therapeutic doses of olanzapine were determined in 11 healthy volunteers. The first dose of olanzapine (10 mg) was taken alone and the second dose (10 mg) after 2 weeks of treatment with carbamazepine (200 mg BID). Measurement of urinary 6-hydroxycortisol/cortisol excretion was used as an endogenous marker to confirm that induction of CYP3A4 by carbamazepine had occurred. Results: The dose of olanzapine given after a 2-week pre-treatment with carbamazepine was cleared more rapidly than olanzapine given alone. Olanzapine pharmacokinetic values for C_max and AUC were significantly lower after the second dose, the elimination half-life was significantly shorter, and the clearance and volume of distribution were significantly increased. Conclusion: Carbamazepine has been shown to induce several P450 cytochromes including CYP3A4 and CYP1A2. Since CYP1A2 plays a role in the metabolic clearance of olanzapine, the interaction may be attributed to induction of CYP1A2 by carbamazepine, leading to increased first-pass and systemic metabolism of olanzapine. The interaction is not considered to be of clinical significance because olanzapine has a wide therapeutic index, and the changes in plasma concentration of olanzapine are within the fourfold variation that occurs without concern for safety in a patient population. Received: 22 July 1997 / Accepted in revised form: 1 June 1998     

Sex differences in plasma cocaine levels and subjective effects after acute cocaine administration in human volunteers

Gender differences after acute cocaine administration have received little attention in spite of the fact that males and females respond differently to many drugs. Seven male and seven female occasional cocaine users received both an intranasal dose of cocaine hydrochloride (0.9 mg/kg) and placebo powder in a randomized order and reported subjective effects via an instrumental joystick device and various questionnaires. Blood samples were withdrawn at 5-min intervals to assess pharmacokinetic differences. Male subjects achieved the highest peak plasma cocaine levels (144.4 ± 17.5 ng/ml), detected cocaine effects significantly faster than females and also experienced a greater number of episodes of intense good and bad effects. Women studied during the follicular phase of their menstrual cycle had peak plasma cocaine levels of 73.2 ± 9.9 ng/ml, which was significantly higher than when they were studied during their luteal phase (54.7 ± 8.7 ng/ml), but there were no differences in their subjective reports of cocaine effects. In spite of the different cocaine blood levels and subjective effects, peak heart rate increases did not differ between males and females suggesting that women may be more sensitive than males to the cardiovascular effects of cocaine. These data suggest that there are significant gender and menstrual cycle differences in the response to acute intranasal cocaine administration and these differences may have implications for the differential abuse of this drug.This paper is dedicated to Xavier Lamas, MD, PhD, who lost his life while ascending Mt. Everest, August 1995