Growth,regression and cell death in rat liver as related to tissue levels of the hepatomitogen cyproterone acetate

Previous studies have shown that xenobiotic compounds such as the environmental pollutant -hexa-chlorocyclohexane (-HCH) and the synthetic sex steroid cyproterone acetate (CPA) induce growth of rat liver by hypertrophy and hyperplasia. After withdrawal of the growth stimuli, liver hypertrophy was usually found to be readily reversible. Conflicting observations were made concerning the fate of liver hyperplasia: hepatic hyperplasia persisted when induced by -HCH but was found to be partially reversible when induced by CPA. The present study confirms the reversibility of hepatic hyperplasia induced by CPA in rats: about 30% of liver DNA present at maximal liver enlargement disappeared within 6 days after cessation of CPA treatment. Simultaneously, a dramatic increase in the rate of cell elimination by apoptosis was found. Glutamate-pyruvate transaminase and alkaline phosphatase in serum did not show major increases, suggesting that cell death was not due to lytic membrane damage. Furthermore, if treatment with CPA was continued or resumed, the enhanced DNA content persisted and the number of apoptotic bodies was greatly reduced. These observations suggest that the occurrence of cell death is due to withdrawal of the growth stimulus CPA. It may reflect a regulatory phenomenon serving to maintain homeostasis of cell number.Further studies showed that CPA is rapidly eliminated from rat liver and serum: t 1/2 in the liver is about 11 h. In contrast, -HCH was previously found to be eliminated more slowly: t 1/2 approximately 144 h. The present study revealed that -HCH, CPA and nafenopin lower the number of apoptotic bodies. This suggests that inducers of liver growth can inhibit hepatocellular death by apoptosis. It is concluded that the regression of hyperplasia after CPA withdrawal may be due to its rapid elimination. On the other hand the relatively long persistence of -HCH may result in inhibition of cell death and thereby stabilize hepatic hyperplasia.Abbreviations CPA cyproterone acetate - -HCH -hexachlorocyclohexane - PB phenobarbital - NAF nafenopin - AB apoptotic body - b.w. body weight - p. admin. post-administration - GPT glutamate-pyruvate transaminase - ALP alkaline phosphatase Dedicated to Professor W. Koransky on the occasion of his 65th birthday     

Boric acid single dose pharmacokinetics after intravenous administration to man

Eighth young adult male volunteers with a basic (alimentary) plasma boric acid concentration of <0.10–0.46 mg/l were given a single dose of boric acid (562–611 mg) by 20 min IV infusion. The plasma concentration curves, followed for 3 days, best fitted a three-compartment open model, although two subjects had to be left out due to inconstant basal plasma concentration values or failure to fit to the three-compartment model. The 120 h urinary excretion was 98.7±9.1% of dose, Cl_tot 54.6±8.0 ml/min/1.73 m², t_1/2 21.0±4.9 h and distribution volumes V₁, V₂, and V₃: 0.251±0.099, 0.456±0.067 and 0.340±0.128 l/kg.     

Behandlung mit Mexiletin

Summary Pharmacokinetics of the antiarrhythmic agent mexiletine were found to be highly variable. Ineffective or toxic doses can be avoided by monitoring mexiletine concentrations in patients plasma. However, the success of antiarrhythmic therapy is mainly determined by the severety of the underlying disease. Therefore, the efficacy of treatment with mexiletine should be controlled by Holter monitoring.

Herrn Prof. Dr. G. Schütterle zum 60. Geburtstag gewidmet     

巴氨西林的人体药代动力学研究

目的建立正常人血浆中巴氨西林浓度的HPLC测定方法,研究巴氨西林在正常人体内的药代动力学行为.方法采用反相高效液相色谱-紫外检测的方法,测定巴氨西林在人体中的主要代谢产物氨苄西林的血药浓度.流动相11mmol/LKH\-2PO\-4(含0.1ml/L冰醋酸)-甲醇(78∶22,v/v).色谱柱为HypersilODS2,5μm,150mm×4.6mmID,紫外检测波长231nm.测定20名男性健康志愿受试者单剂量口服800mg巴氨西林片后血药浓度-时间过程.结果方法的专属性较好,血浆中杂质不干扰样品的测定.方法的回收率大于90%,日间日内变异系数低浓度小于20%,高浓度小于10%,线性范围0.316～20.220μg/ml(r=0.9998,n=5),最低检测浓度0.316μg/ml,符合生物样品分析要求.受试者口服巴氨西林片800mg后,以巴氨西林体内的主要活性代谢产物氨苄西林估算的末端相半衰期(T1/2)1.13±0.31h,峰时间(Tmax)0.81±0.30h,峰浓度(Cmax)10.75±2.53μg/ml,MRT2.01±0.40h,21.25±4.20μg·     

阿昔洛韦片在人体中药动力学及其相对生物利用度研究

目的比较两种阿昔洛韦片生物利用度和药代动力学。方法测定10名受试者单剂量交叉口服600mg阿昔洛韦受试片和参比片后血药浓度,计算相应的药代动力学参数。结果受试者口服两种阿昔洛韦片计算的峰浓度Cmax、Tmax和AUC分别为Cmax1.24±0.49和1.17±0.20μg/ml,Tmax1.9±0.6h和2.1±1.1h,AUC7.56±1.80和7.56±2.10μg     

双氯酚酸钾片人体生物等效性研究

目的评价双氯酚酸钾实验制剂和参比制剂的生物等效性。方法8名健康男性志愿者交叉单剂量口服双氯酚酸钾实验制剂或参比制剂50mg,采用反相高效液相色谱法测定经时过程血药浓度,血药浓度时间数据用3p97药代动力学实用程序拟合,计算其药代动力学参数。结果实验制剂和参比制剂主要药代动力学参数Ka分别为(3．042±1．356)h     

非洛地平缓释胶囊药物动力学与相对生物利用度

建立气相色谱-电子捕获法测定非洛地平血药浓度,比较国产非洛地平缓释胶囊和阿斯特拉公司缓释片的人体生物利用度,14名健康志愿者随机交叉口服两种制剂后,单剂量血浆中非洛地平浓度分别于3．07±0．92h和3．14±1．03h达到峰值4．75±1．38ng／ml和4．55±1．71ng／ml,药-时曲线下面积(AUC     

Metabolism and excretion study of DW116, a new fluoroquinolone, in rats

Metabolite identification and urinary and biliary excretion of the new fluoroquinolone antibacterial agent DW116 [1-(5-fluoro-2-pyridyl)-6-fluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, hydrochloride] after oral administration have been studied in Sprague-Dawley rats. The excretion kinetics were monoexponential. Most of the drug was eliminated via the hepatic and renal routes. Mean renal clearance of DW116 was 73.4 ml/hr/kg and mean biliary clearance was 83.8 ml/hr/kg. The major metabolite excreted in the bile was identified as the glucuronide ester of the parent drug using base-hydrolysis of the conjugate metabolite followed by co-HPLC with standard compound,¹⁹F-NMR and LC-MS methods. The glucuronide conjugate was also found in urine. The mean urinary recoveries of free and total (free plus glucuronide ester) DW116 were 28.6±2.7% and 36.4±1.8% of the administered dose and the corresponding biliary recoveries were 14.4±5.5% and 37.0±7.6%, respectively.     

Antiepileptic drug treatment in the nineties in The Netherlands.

In this review the state of the art of treating patients with epilepsy in the nineties in the Netherlands is presented. It describes general strategies for treatment with antiepileptic drugs and the history of development of the classical anticonvulsant drugs. Eight new drugs, including vigabatrin, lamotrigine, felbamate, oxcarbazepine, gabapentin, tiagabine, levetiracetam and topiramate are discussed. A review of their pharmacological and clinical properties is presented. Dutch experience with these drugs is included.