Pharmacodynamics of Phenobarbital Anesthesia and Pentylenetetrazol-Induced Maximal Seizures in a Rat Model of Neoplastic Spinal Cord Compression

The purpose of this investigation was to determine whether paraplegia induced by neoplastic cord compression affects the pharmacodynamics of phenobarbital general anesthesia or of pentylenetet-razol (PTZ)-induced convulsions. Paraplegic rats harboring a thora-columbar epidural tumor, or an identical hindlimb tumor mass, received an i.v. infusion of phenobarbital until the onset of anesthesia. At that point, the phenobarbital concentrations in the CSF and serum were measured. Similarly, PTZ was infused until the onset of maximal seizures. It was found that changes related to systemic tumor growth and newly developed paraplegia due to neoplastic spinal cord compression did not attenuate the pharmacodynamics of phenobarbital. However, sustained paraplegia of 4 days duration reduced CNS sensitivity to the hypnotic action of the barbiturate as evidenced by the higher cerebrospinal fluid phenobarbital concentration required to induce anesthesia (170 ± 31 vs 125 ± 20 mg/L; P < 0.05). On the other hand, sustained paraplegia did not affect brain threshold concentration for PTZ-induced seizures.     

Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the in vivo and in vitro dechlorination of pentachlorophenol

The metabolism of pentachlorophenol has been studied in the rat after pretreatments with phenobarbital, 3-methyl-cholanthrene or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In addition to the previously identified metabolite, tetrachloro-p-hydroquinone, trichloro-p-hydroquinone has been identified in urine as a metabolite. The formation of the latter represents a type of dechlorination different from that of the formation of tetrachlorohydroquinone. The inducing agents, 3-methylcholanthrene and TCDD have similar effects on the dechlorination and increase the formation of tetrachloro-p-hydroquinone more pronounced than does phenobarbital. In contrast to phenobarbital they also increase the formation of trichloro-p-hydroquinone and the total elimination of pentachlorophenol and its metabolites. The in vivo findings are supported by in vitro studies with microsomes from rats pretreated with phenobarbital or TCDD. Use of the inhibitor -diethylaminoethyl-diphenyl propylacetate (SKF 525-A) in vitro showed a more pronounced inhibition on microsomes from phenobarbital-treated rats than on microsomes from untreated or TCDD-treated rats.Gas chromatography-mass spectrometry have been used for the identification and quantification of pentachlorophenol and its metabolites.

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Zusammenfassung Der Metabolismus von Pentachlorphenol nach Vorbehandlung der Versuchstiere (Ratten) mit phenobarbital, 3-Methylcholantren oder 2,3,7,8-Tetrachlordibenzo-p-Dioxin (TCDD) ist untersucht worden. Zu dem schon früher nachgewiesenen Metaboliten Tetrachlor-p-Hydrochinon wurde nun auch Trichlor-p-Hydrochinon als Harnmetabolit festgestellt. Die Bildung des letzteren stellt eine andere Art von Dechlorierung dar als diejenige die bei der Entstehung von Tetrachlor-p-Hydrochinon vorliegt. 3-Methylcholantren und TCDD haben ähnlichen Einfluß auf die Dechlorierung und steigern die Bildung von Tetrachlor-p-Hydrochinon mehr ausgeprägt als es bei phenobarbital der Fall ist. Im Gegensatz zu phenobarbital steigern sie auch die Bildung von Tri-chlor-p-Hydrochinon sowie die totale Eliminierung von Pentachlorphenol und von Metaboliten. Die in vivo-Befunde werden von in vitro-Studien mit Mikrosomen von mit phenobarbital oder TCDD vorbehandelten Ratten gestützt. Anwendung des Inhibitors -Diethylaminoethyl-Diphenyl-Propylacetat (SKF 525-A) zeigte in vitro eine ausgeprägtere Inhibition der Mikrosomen von mit phenobarbital behandelten Ratten als der Mikrosomen von unbehandelten oder TCDD-behandelten Ratten. Nachweis und Bestimmung von Pentachlorphenol und seinen Metaboliten wurden gaschromatographisch-massenspektrometrisch durchgeführt.

     

Urinary excretion ofD-glucaric acid,an indicator of drug metabolizing enzyme activity,in patients with impaired renal function

Summary The urinary excretion rate ofD-glucaric acid, an in vivo parameter of the activity of drug metabolizing enzymes, has been determined in patients with chronic renal insufficiency (glomerular filtration rate 4.5–80 ml/min/1.73 m²). The mean value of 22.3 µmoles/d (SD 7.2; n 28) was almost identical to that of healthy controls (22.1 µmoles/d, SD 7.3; n 22). Thus, no inhibitory or enhancing effect of renal insufficiency could be detected. The ability of this parameter to indicate alterations in the activity of hepatic drug metabolism, even in patients with renal insufficiency, was demonstrated by the increased excretion rate of glucaric acid (107 µmoles/d, SD 43.5; n 8; p<0.001) after treatment for 7 days with the enzyme inducer phenobarbital. No significant correlation was found between glucaric acid excretion and sex, age, body weight or body surface in 50 patients. Glucaric acid excretion, therefore, should not be related to the creatinine content of urine samples, since creatinine excretion decreases with severity of renal insufficiency and varies with sex, age, body weight and many other conditions. A single dose of dipyrone (Novalgin^®), a further in vivo indicator of drug metabolism, increased glucaric acid excretion on the same day, but no interference was found after a single dose of cortisol.     

The relative ethylumbelliferone dealkylase activity characterizing the effect of different inducers on the hydroxylase system in the liver musomes of female mice

d,l-Camphor was detected as a new inducer of hydroxylase in the liver musomes of female mice. After a 2-day inhalation of d,l-camphor, cyt. P-450 and the ethylumbelliferone dealkylase were increased by 250 per cent and the NADPH-cyt. P-450 reductase by 350 per cent. The product [NADPH-cyt. P-450 reductase activity × cyt. P450 concentration] was shown to be a suitable reference parameter for the ethylumbelliferone dealkylase activity in the liver musomes during the treatment with four different inducers. The relative dealkylase activity Q was much decreased during inhalation of cyclohexane or d,l-camphor.

$\text{Q =}\text{mU ethylumbelliferone dealkylase}\text{mU NADPH-cty. P-450 reductase × nmoles cty. P-450/mg protein}$

Obviously these two inducers preferably enhanced cyt. P-450 species with a low dealkylase activity. The Q-values were reproducible. Q was increased by 100 per cent during induction of a MC-sensitive mouse strain with 3-methylcholanthrene, but it was only moderately decreased by induction with phenobarbital. Corresponding to this, methylcholanthrene is known to selectively induce a cyt. P-448 with high dealkylase activity whereas phenobarbital is known to change the hydroxylase specificity in the liver musomes not very much.     

RF—HFLC法测定人血浆中苯巴比妥、苯妥英和卡马西平浓度

目的　建立血浆中苯巴比妥 (phenobarbital,PB)、苯妥英 (phenytion ,PT)和卡马西平 (carbamazepine ,CBZ)三种抗癫痫药的HPLC检测方法。方法　采用日本分光JASCO 15 0 0系列高效液相色谱仪 ,ODSHypersil柱 (15 0mm× 4 6mm ,5 μm) ,以艾司唑仑(estazolam ,EZ)为内标 ,流动相组成为甲醇 -乙腈 -水 -四甲基乙二胺 -冰醋酸 (5 0∶5 0∶10 0∶2∶1 5 ) ,流速为 0 8ml·min-1,紫外检测波长 2 5 4nm ,灵敏度AuFs=0 0 2。结果　血浆中 3种组分和内标均能很好地分离 ,无明显的干扰峰。PB线性范围为 2～ 5 0mg·L-1,r=0 9997;PT线性范围为 2～ 5 0mg·L-1,r=0 9998;CBZ线性范围为 0 5～ 2 0mg·L-1,r=0 9998,日内、日间RSD <5 %。结论　本法操作简便、结果可靠 ,适用于药物监测和中毒分析     

褶合曲线分析法同时测定小儿复方苯巴比妥片中四组分的含量

目的：不经分离同时测定小儿复方苯巴比妥片中四组分的含量。方法：以褶合光谱为基础，结合当前最优秀的数值计算法——偏最小二乘法(PLS法)利用计算机信息处理技术的褶合曲线分析法。结果：小儿复方苯巴比妥片中阿司匹林、非那西丁、咖啡因和苯巴比妥四组分的平均回收率及相对标准偏差(RSD)分别为99．75，0．92％；100．47，0．56％；99．82，1．12％；100．08，0．86％。结论：该方法可以用于小儿复方苯巴比妥片剂的质量监控。     

我院门诊病人处方中精神药品药物利用调查分析

目的 :了解我院精神药品 (psychotropicsubstances)使用情况 ,促进合理用药。方法 :采用限定日剂量和药物利用指数为指标对我院门诊精神药品的处方进行调查和分析。结果 ;平均药物利用指数在 1.0 0左右 ,用药时间大于 4wk的达 79.0 9% ,合并用药大于 2种药物的占 13.14 %。结论 :我院精神药品的使用基本合理 ,但用药时间较长 ,合并用药频度较高     

HPLC法同时测定血清中苯巴比妥、苯妥英和卡马西平的浓度

目的 :建立快速测定血清中苯巴比妥、苯妥英和卡马西平浓度的方法。方法 :色谱柱DiamonsilC18(4 .6mm× 2 5 0mm ,5 μm) ,流动相甲醇∶水∶乙腈 (4 0∶4 5∶15 ) ,流速1.2ml·min-1,检测波长 2 4 0nm ,内标硝西泮 ,柱温 4 0℃。结果 :提取回收率为 84 .4～ 89.2 % ,日内和日间RSD均 <7.9% ;标准曲线相关性良好。对 10 4例患者作血清浓度监测 ,临床效果满意。结论 :本方法可作为苯巴比妥、苯妥英和卡马西平的血药浓度监测的常规方法。     

高效液相色谱法同时测定苯巴比妥、苯妥英、卡马西平的血药浓度

目的:建立以高效液相色谱法同时测定苯巴比妥、苯妥英、卡马西平血药浓度的方法。方法:取患者血清,经二氯甲烷提取后在C18柱上分析,流动相为甲醇-水(57:43),柱温为30℃,检测波长为254nm,流速为0.8ml/min。结果:苯巴比妥、苯妥英、卡马西平分别在2.5-40、2.5-40、1.25-20μg/ml范围内线性关系良好,日内和日间RSD<10％(n=5)。结论:本方法简便、稳定,用于苯巴比妥、苯妥英、卡马西平的血药浓度监测效果良好。     

MK-801与抗癫痫药合用对大鼠杏仁核点燃的影响

目的在大鼠杏仁核点燃模型研究MK-801(地佐西平)及其联合用药的抗癫痫作用。方法建立大鼠杏仁核慢性电刺激点燃模型,测定不同剂量的MK-801对点燃模型各项指标的影响,探讨MK-801与其他抗癫痫药的协同作用,用氨基脲诱发的小鼠惊厥模型测定MK-801抗惊厥作用。 结果MK-801(0.1～0.25 mg·kg^-1)可剂量依赖性抑制杏仁核点燃,缩短后放电时程,降低Racine's分级;在对点燃均无明显影响的剂量下,MK-801(0.05 mg·kg^-1)与抗癫痫药(苯巴比妥、丙戊酸及尼卡地平)合用可缩短后放电时程或降低Racine's分级。MK-801(0.1～0.25 mg·kg^-1)显著降低小鼠氨基脲诱发的发作潜伏期、惊厥发生率和死亡率。结论MK-801具有抑制大鼠杏仁核点燃的作用,增强苯巴比妥、丙戊酸及尼卡地平的抗癫痫活性,为临床的合并用药提供实验依据。