Aminoglycoside therapy Current use and future prospects

The microbiological, pharmacokinetic, toxicological and clinical aspects of aminoglycosides are reviewed. Aminoglycosides still have an important place in serious infections in neutropenic patients, endocarditis andPseudomonas aeruginosa infections, all in combination with beta-lactams. Monotherapy (with streptomycin) is indicated in less common diseases like tularaemia and bubonic plague. Several experimental studies support a oncedaily dosing regimen for aminoglycosides (comparable or better efficacy with less ototoxicity and nephrotoxicity). Only a very limited number of prospective comparative studies have been performed, and much more data on efficacy, development of resistance and toxicity is needed before once-daily administration can be recommended. The choice of an aminoglycoside should be based primarily on the local sensitivity patterns and cost. Differences in ototoxicity and nephrotoxicity are usually minor. If the acquisition costs of amikacin decline, it is to be expected that amikacin will be the aminoglycoside of choice.     

Benzodiazepine concentrations in brain directly reflect receptor occupancy: studies of diazepam,lorazepam, and oxazepam

Groups of male CF-1 mice received 3 and 10 µmol/kg diazepam, lorazepam, and oxazepam intravenously. Between 1 min and 24 h after injection, benzodiazepine concentrations were determined by gas chromatography (GLC) in plasma and in one brain hemisphere; in the other hemisphere, ex vivo benzodiazepine receptor occupancy was measured using³H-flunitrazepam displacement. Based on GLC data, diazepam entered brain rapidly, and was also cleared rapidly, yielding desmethyldiazepam and oxazepam as metabolites in plasma and brain. However, lorazepam and oxazepam entered brain slowly, with brain:plasma equilibrium achieved at 30–60 min; thereafter, the drugs were eliminated from plasma and brain in parallel. The time course and extent of ex vivo occupancy were highly consistent with GLC data (for diazepam, GLC levels were expressed as the sum of diazepam, desmethyldiazepam, and oxazepam, with metabolite concentrations, normalized for molecular weight and for in vitro benzodiazepine receptor affinity.) Between-method correlations were 0.95 or higher. Thus benzodiazepine receptor occupancy is highly dependent on benzodiazepine concentrations in brain. Differences in the time-course of onset and duration of pharmacologic activity between the highly lipophilic benzodiazepine diazepam and the less lipophilic hydroxylated derivatives lorazepam and oxazepam are largely explained by differences in systemic kinetics and in the rate of uptake into brain.Supported in part by grants MH-34223, DA-05258, and AG-00106 from the United States Public Health Service     

格列齐特片的人体药代动力学及其相对生物利用度研究

建立了ＨＰＬＣ方法测定人血浆中格列齐特的药物浓度。采用反相柱和乙腈甲醇水（１５∶４５∶４０）（ｐＨ３．５）作为流动相，格列吡嗪作为内标，检测波长为λ２２８ｎｍ。研究了１０名健康受试者随机交叉口服某药厂研制的格列齐特片剂和标准参比制剂格列齐特片８０ｍｇ后，用ＨＰＬＣ法测定血浆中药物浓度。估算某药厂研制的格列齐特片和标准参比制剂的生物半衰期分别为９．９２±３．５２ｈ和９．９７±３．４５ｈ，达峰时间分别为３．５０±０．７１ｈ和３．８５±２．２６ｈ，峰浓度分别为５．７８±０．９５μｇ／ｍｌ和６．１４±１．５６μｇ／ｍｌ。以标准参比制剂为对照，用面积法估算的某药厂研制的格列齐特片剂的相对生物利用度为１．０１±０１１。经方差分析和双单侧检验两制剂的ＡＵＣ０４８和ＡＵＣ０∞及Ｃｍａｘ，结果表明两制剂生物等效。     

乙醇摄入对小鼠肝功能及磺胺嘧啶代谢动力学的影响

动态观察了乙醇摄入对小鼠肝功能及磺胺嘧啶（ＳＤ）代谢动力学的影响。结果表明，每天以２５ｇ／ｋｇ乙醇摄入２周，ＳＧＳＴ活性明显升高，随着摄入时间的延长，在一定时间范围内呈进行性增高，同时，ＳＡＬＴ活性也与乙醇摄入时间呈明显正相关，提示长期乙醇摄入对肝脏的不利影响。乙醇对肝匀浆中ＧＳＴ和苯胺羟化酶活性呈双重作用，早期具有诱导酶活性的作用，但诱导的时间和强度不同，后期则可抑制酶的活性。ＳＤ在小鼠体内的代谢符合二房室模型，乙醇对ＳＤ的代谢具有双相作用，早期使ＳＤ代谢加速，后期则使代谢延缓，表明乙醇对代谢ＳＤ的Ｎ乙酰化酶可能具有酶促酶抑双重作用。     

Pharmacokinetics of prednisolone in children with the nephrotic syndrome

The aim of this study was to establish whether the criteria for the clinical effectiveness of steroids are correlated with the pharmacokinetics of prednisolone in children treated with prednisone during an attack of idiopathic nephrotic syndrome (INS). Thirteen patients with nephrosis were included. Prednisolone, prednisone and cortisol levels were measured using a specific high-performance liquid chromatography assay after an oral dose of 1 mg/kg body weight of prednisone taken at the onset of the disease. All the pharmacokinetic parameters, including the conversion of prednisone to prednisolone were similar to the data already published in children with INS. No correlation was found between the values of pharmacokinetic parameters and criteria of clinical effectiveness. Hypo-albuminaemia was significantly correlated with the area under the plasma-concentration curve but not with the elimination half-life of prednisolone. Moreover, the prednisolone elimination half-life correlated with the urinary exretion of 17-hydroxycorticosteroids achieved in the first 6h. The present study suggests that routine measurements of prednisolone kinetics do not help when assessing the treatment of children with INS.     

Population toxicokinetics of tetrachloroethylene

 In assessing the distribution and metabolism of toxic compounds in the body, measurements are not always feasible for ethical or technical reasons. Computer modeling offers a reasonable alternative, but the variability and complexity of biological systems pose unique challenges in model building and adjustment. Recent tools from population pharmacokinetics, Bayesian statistical inference, and physiological modeling can be brought together to solve these problems. As an example, we modeled the distribution and metabolism of tetrachloroethylene (PERC) in humans. We derive statistical distributions for the parameters of a physiological model of PERC, on the basis of data from Monster et al. (1979). The model adequately fits both prior physiological information and experimental data. An estimate of the relationship between PERC exposure and fraction metabolized is obtained. Our median population estimate for the fraction of inhaled tetrachloroethylene that is metabolized, at exposure levels exceeding current occupational standards, is 1.5% [95% confidence interval (0.52%, 4.1%)]. At levels approaching ambient inhalation exposure (0.001 ppm), the median estimate of the fraction metabolized is much higher, at 36% [95% confidence interval (15%, 58%)]. This disproportionality should be taken into account when deriving safe exposure limits for tetrachloroethylene and deserves to be verified by further experiments. Received: 20 April 1995/Accepted: 24 August 1995     

呋苄青霉素药代动力学及组织分布的研究

呋苄青霉素是由我国开发成功的一个酰脲类青霉素。本项研究采用微生物法,以狗和正常人为受试对象,以氧哌嗪青霉素和羧苄青霉素为对照进行药代动力学研究,结果表明,3个药的药—时曲线符合二室开放式模型,呋苄青霉素较其它对照药具较高的即刻血浓度和较低的肾清除率。用微生物法和放射自显影法测定的呋苄青霉素在小鼠体内组织分布汪明,呋苄青霉素广泛分布于体内各组织,尤其在肺、肝、肠中的浓度明显高于羧苄青霉素。     

肾上腺素对丁哌卡因肌间沟臂丛神经阻滞的药效学与药代动力学的影响

目的:了解肾上腺素对丁哌卡因肌间沟臂丛神经阻滞的药效学及药动学影响。方法:选择ASA Ⅰ～Ⅱ级肩部或上肢择期手术患者16例,随机分成两组,试验组与对照组各8例,分别用含或不含肾上腺素的0.75％丁哌卡因2mg/kg行肌间沟臂丛阻滞。对比观察两组的临床效果及药代动力学。结果:与对照组比较,试验组阻滞完善时间及镇痛时间延长(P<0.05或0.01)。试验组与对照组Cmax分别为0.8295±0.2893ug/ml和0.8898±0.2572ug/ml,Tmax分别为37.6018±8.3461分钟和29.3156±11.1991分钟(P>0.05)。药代动力学参数t1/2Ka及K_(21)两组间有显著性差异(P<0.05或0.01)。结论:肾上腺素能延长丁哌卡因的阻滞完善时间、镇痛维持时间及吸收半衰期,但对血药浓度无明显影响。     

阿魏酸在血瘀证兔体内的药代动力学

为验证及研究症治药动学假说（ｓｙｎｄｒｏｍｅａｎｄＴｒｅａｔｍｅｎｔＰｈａｒｍａｃｏｋｉｎｅｔｉｃｓ，Ｓ＆ＴＰＫ）的客观性和基本规律，本文以ＲＰ－ＨＰＬＣ法同时测定了活血祛瘀药物阿魏酸在正常及高分子右旋糖酐所制血瘀症（微循环障碍）兔体内经时浓度，以ＭＣＰＫＰ药动学程序在ＣＯＭＰＡＱ８０３８６机上自动拟合了药动学参数。统计结果表明，与正常组相比，阿魏酸在血瘀症兔体内的分布容积（Ｖ＿１和Ｖ＿Ｂ）及消除速率（ＣＬＢ）显著减小（Ｐ＜０．０５），半衰期（ｔ＿（１／２β）及相同时间段曲线下面积（ＡＵＱ）非常显著增加（Ｐ＜０．０１）。结论：实验结果基本符合Ｓ＆ＴＰＫ的观点：即同一药物在不同证兔体内的药代动力学参数经统计学处理有显著差异。     

Plasma concentrations and bioavailability of propranolol by oral, rectal, and intravenous administration in man

Eight normal male volunteers received 80 mg doses of propranolol by the oral and rectal routes and 2.2 mg by intravenous administration in a crossover fashion. Plasma concentrations of propranolol were measured by a gas chromatographic method using an electron capture detector. Individual subject concentration-time data were analysed and results indicated that the data fit a two compartment model with first order absorption. An approximately two-fold higher plasma propranolol concentration was observed after rectal administration as compared with oral dosing. Statistical analysis of the difference in the total AUCs indicates a significantly higher bioavailability of propranolol administered by the rectal route. The reduced bioavailability after oral administration indicates a substantial first pass effect but that it is possible to bypass the liver, at least partially, by giving the drug rectally to man.