Pharmacokinetics of antimalarials and proposals for dosage regimens.

Blood level data for the antimalarials amodiaquine, chloroguanide, chloroquine, pyrimethamine, quinine and sulphadoxine have been retrieved from the literature and pharmacokinetically analyzed. Minimum, average and maximum blood level concentrations at steady state in suppressive treatment and peak concentrations in therapeutic treatment were predicted and blood level-time curves simulated. Based on the computer-predicted data, changes in dosage regimens are proposed to reduce the fluctuations between maximum and minimum levels in suppressive treatment, and for obtaining maximum peak levels in therapeutic treatment already with the loading dose.     

An efficient control strategy for dosage regimens

In medical drug therapy, efficient dosage strategies are needed to maintain target drug concentrations. The relationship between the concentration of a drug and the dosages is often described by compartment models in which the parameters are unknown, although prior knowledge may be available and can be updated after blood samples are taken during the therapy. Currently MAP (maximum a posteriori) Bayesian is the most often used control strategy in this setting. We show by simulation in a one-compartment context that the performance of the MAP Bayesian strategy depends on the assumptions in prior distribution of the parameters as well as the cost function. We propose an alternative control strategy, VU, that outperforms and is more robust than the MAP Bayesian strategy in a variety of problem settings. Partially funded by Palo Alto Institute for Research and Education, Inc.     

DPP-4抑制剂的用药方案

2型糖尿病的发病机制包括胰岛素抵抗和进行性B细胞分泌不足两个环节,通过肠促胰岛素(incretin)的作用而改善胰岛B和A细胞分泌功能及胰岛素敏感性,为2型糖尿病的治疗开辟了新的途径.     

Comparison of antibiotic dosage regimens using pharmacokinetic and microbiologic factors

A pharmacokinetic meta-analysis was performed for 33 antibiotics used in treating infections caused by microorganisms for which the antibiotics are considered to be agents of first choice or primary alternatives. The pharmacokinetic indices assessed were the following components of the steady-state blood concentration-time profile: the magnitude of the peak antibiotic serum concentration at steady state compared with the minimum inhibitory concentration (CSSmax/MIC) and the intensity index, a dimensionless term that reflects the contribution of the peak serum antibiotic concentration and the duration that this concentration is above the MIC. Substantial differences in CSSmax/MIC and intensity-index values were observed among antibiotics within an antibiotic class for individual microorganisms and for groups of microorganisms. Piperacillin, amikacin, and tetracycline showed the best mean performances of the ureido penicillins, aminoglycosides, and tetracyclines, respectively. For the cephalosporins, cefadroxil displayed the highest mean values of the first-generation cephalosporins; cefuroxime and cefotetan showed the greatest measures for the second-generation agents; and all third-generation cephalosporins demonstrated very high mean performance indices. Meta-analysis of pharmacokinetic performance factors is a useful technique for making intergroup and intragroup comparisons of antibiotics.     

血肌酐值法预测地高辛个体化给药方案

在地高辛常规监测中，用血肌酐值法预测个体化药动学参数和给药方案。结果表明，８４例病人的地高辛药物动力学参数预测值为，ＣＬ７６±２１ｍｌ／（ｋｇ·ｈ），Ｖｄ７．０５±１．２０Ｌ／ｋｇ，Ｔ１／２６６±７ｈ。预测的个体化剂量为３．１±０．９μｇ／（ｋｇ·ｄ），预测的稳态血药浓度（Ｃ＿（ｓｓ））为１．２４±０．３８μｇ／Ｌ，与实测Ｃ＿（ｓｓ）１．２±０．４μｇ／Ｌ比较，差异无显著性（Ｐ＞０．０５）。     

基于群体药物代谢动力学模型的万古霉素给药方案优化研究进展

万古霉素为糖肽类抗菌药,是临床上用于耐甲氧西林金黄色葡萄球菌感染的一线用药。大量研究表明,万古霉素的PK/PD参数AUC0~24 h/MIC≥400与其临床疗效密切相关。但是,万古霉素在不同人群中的药物代谢动力学行为差异较大,因此,通过群体药物代谢动力学模型来实施万古霉素的优化给药尤为重要。本文对近年来万古霉素在不同群体中药物代谢动力学模型研究进展和基于PPK给药方案的优化研究进展综述如下,以期为临床万古霉素的合理使用提供依据。     

The comparability of dosage regimens of Lanoxin tablets and Lanoxicaps.

1 Twice daily administration of 0.25 mg digoxin tablets (Lanoxin) or of 0.2 mg digoxin in solution in soft gelatin capsules (Lanoxicaps) produced similar mean steady state plasma digoxin concentrations in ten healthy volunteers. Respective values were 1.07 +/- 0.075 and 0.95 +/- 0.048 ng ml-1. 2 During continued administration, peak plasma concentrations occurred earlier after capsules with a tendency to higher peak levels. However, area under curve determinations over 7 h were similar. 3 Approximately 10% less digoxin was recovered in urine collected in a 12 h dosage interval during the lower dosage administration of capsules. Mean percentage urinary recovery of administered dose was 57% for tablets and 65% for capsules. 4 The enhanced bioavailability of Lanoxicaps was associated with reduced between-subject variability in plasma concentration. 5 Lanoxicaps (0.2 mg) should be approximately equivalent in effect to digoxin tablets (0.25 mg) currently available in the United Kingdom, though improved consistency would be anticipated.     

多黏菌素类药物的肾毒性及其优化给药方案研究进展

多重耐药及泛耐药革兰阴性菌的流行给临床抗感染治疗带来了巨大挑战.由于新型抗菌药物研究开发缓慢,多黏菌素这类曾因严重的神经毒性和肾毒性而逐渐停止使用的抗生素又重回人们视野,并成为了治疗重症难治性革兰阴性菌感染的主要药物.然而,肾毒性仍严重影响此类药物的临床治疗效果.其肾毒性机制复杂,并且临床上存在着许多肾毒性危险因素,因...     

Individualized aminoglycoside dosage regimens in patients with cystic fibrosis

Individualized dosage regimens have recently been recommended for patients treated with aminoglycoside antibiotics. We have developed a calculator-based program for our patients with cystic fibrosis and have studied 93 courses of intravenous aminoglycoside treatment, comparing predicted and measured values in 45 courses. Pharmacokinetic parameters differed notably among subjects: this was reflected by widely variable total daily aminoglycoside dosage requirements. The mean daily dosage requirements (+/- SD) for tobramycin (62 treatment courses) was 13.0 +/- 3.74 mg/kg, and for gentamicin (26 treatment courses) was 11.5 +/- 2.6 mg/kg. The accuracy of the program was evaluated by its ability to predict peak and trough values in individuals: 84 percent of measured peaks were within 2 micrograms/ml of the predicted level. Nephrotoxicity was observed in one patient, ototoxicity in three. This program provides a simple, safe, and effective method of tailoring an aminoglycoside regimen to the patient's needs.     

Aminoglycoside adaptive resistance: importance for effective dosage regimens

There are various pharmacodynamic features of the aminoglycosides that are thought to contribute to the benefits of once-daily administration, of which the ability to induce adaptive resistance is the least understood and discussed. However, this may be the most important characteristic conferring increased efficacy with extended interval dose administration. Adaptive resistance describes a reversible refractoriness to the bactericidal effect of an antibacterial agent. It is well documented for the aminoglycosides but has also been seen with the quinolones. It does not appear to be caused by a genetic mutational change but rather by a protective phenotypic alteration in bacterial characteristics. This includes reversible down-regulation of the active transport of aminoglycosides into gram-negative bacteria. In vitro, animal and clinical studies have shown that marked adaptive resistance of gram-negative bacteria to aminoglycosides occurs within 1-2 hours of the first dose. The duration of adaptive resistance relates directly to the half-life of elimination of the aminoglycoside. With normal human aminoglycoside pharmacokinetics, the resistance may be maximal for up to 16 hours after a single dose of aminoglycoside, followed by partial return of bacterial susceptibility at 24 hours and complete recovery at around 40 hours. With conventional dosage regimens, second and subsequent doses of aminoglycoside are given at the time of maximal resistance and this practice is also likely to reinforce the resistance. Dose administration at 24 hour intervals, or longer, may increase efficacy by allowing time for adaptive resistance to reverse.     

Clinical pharmacokinetics of mebikar. Computation of individual dosage regimens

The authors review the principles of calculating the optimal dosage regimens of mebicar used in the treatment of borderline psychopathological abnormalities in alcoholics. Mebicar administered to patients according to the calculated dosage regimens ensures the positive clinical effect. This is supported by the clinicopsychopathological and electrophysiological data.     

Pharmacokinetic and microbiologic evaluation of dosage regimens for newer cephalosporins and penicillins

A retrospective pharmacokinetic analysis was performed for eight newer cephalosporins and penicillins and one aminoglycoside used in treating 10 microorganisms for which the antibiotics are considered to be primary alternatives. The pharmacokinetic indices assessed were the three components of the steady-state temporal blood concentration profile: (1) the magnitude of the peak antibiotic blood level at steady state compared with the mininum inhibitory concentration (CSSmax/MIC), (2) the number of hours that the blood level is greater than the MIC during a 72-hour treatment period, and (3) the intensity index, which is a dimensionless term that reflects the contributions of both the peak serum level of the antibiotic and duration of this level above the MIC. Substantial differences were demonstrated in pharmacokinetic indices for dosage regimens used in treating specific microorganisms for which the antibiotics are considered the primary alternative agents. Moxalactam, cefoxitin, and piperacillin demonstrated the best pharmacokinetic performances for the third-generation cephalosporin, second-generation cephalosporin, and newer penicillin groups, respectively. The data suggest that some antibiotics, notably moxalactam and cefotaxime, may be effective at lower doses than commonly recommended, while others, like cefoperazone, cefamandole, and azlocillin, are probably often ineffective even at high doses.     

用蒙特卡罗模型探索头孢他美钠的给药方案

目的用蒙特卡罗模型,研究注射用头孢他美钠在犬体内的药效学与药动学的关系,探索合理的给药方案,为临床用药提供参考。方法 6只健康beagle犬(A、B组)交叉静脉注射190mg或264mg头孢他美钠,不同时间点取血,采用HPLC法测定血药浓度,用一室模型计算药动学参数,用蒙特卡罗模型预测头孢他美钠在四种不同给药方案下的治疗效果。结果 190mg组的犬主要药动学参数T1/2,CL,V为(1.21±0.24)h,(115.46±13.02)mL/h/kg,(202.50±50.91)mL/kg。264mg组的犬主要药动学参数T1/2,CL,V为(1.27±0.51)h,(105.75±11.22)mL/h/kg,(189.94±62.23)mL/kg,通过蒙特卡罗模拟,得到头孢他美钠在不同给药方案下的PK-PD曲线及敏感性折点。结论敏感菌感染并以%T>MIC90≥50%为治疗目标时建议选择333mg静脉注射,每8h给药一次(q8h,下同)或500mg,3h静脉滴注,q12h;以%T>MIC90≥65%为治疗目标时建议选择333mg,3h静脉滴注,q8h;耐药菌感染则需要加大剂量或重新选择新的给药方案。