基于治疗药物监测及Bayesian反馈法的美罗培南注射剂药代动力学/药效学研究

由于抗菌药物的不合理使用,造成细菌耐药率逐年升高。抗菌药物的药物代谢动力学/药物效应动力学（PK/PD）研究可充分考虑病原体、宿主和药物三者的相互关系,反映抗菌药物杀菌效应及不良反应与血药浓度变化之间的关系,对抗菌药物的开发及使用等具有重要价值。从PK/PD模型、相关理论及其在临床应用等方面进行综述,旨在为临床合理使用抗菌药物,减少耐药菌的产生提供参考。

     

Pharmacokinetics and pharmacodynamics of a sustained-release biodegradable pellet containing imidapril, a new angiotensin-converting enzyme inhibitor in spontaneously hypertensive rats

The pharmacokinetics and pharmacodynamics (PK/PD) of a sustained-release biodegradable pellet containing imidapril, a new angiotensin-converting enzyme (ACE) inhibitor, were investigated in comparison with those of an osmotic pump in male spontaneously hypertensive rats (SHRs). A pellet was prepared from copolymer of -lactic acid and glycolic acid by the melt-pressing technique. Imidapril was released in vitro from the pellet at an approximately zero-order rate and the release profile was similar to that of the osmotic pump. Imidapril was administered subcutaneously via a pellet or an osmotic pump implanted under the skin in the back of SHRs. Plasma concentrations of imidaprilat as an active metabolite of imidapril, plasma ACE activity and systolic blood pressure (SBP) were determined periodically. The plasma concentration of imidaprilat during the administration of a pellet was maintained for 4 weeks, and the plasma concentration profile was close to that of the osmotic pump. Both groups of pellet and osmotic pump significantly inhibited plasma ACE activity and reduced SBP for 4 weeks, and these action profiles were similar in both groups. In addition, in vivo release profile of the pellet was close to the in vitro release profile, and the in vivo release profiles of the pellet and the osmotic pump were similar to each other. From these results, it was found that the PK/PD of a biodegradable pellet were close to those of the osmotic pump, and it was shown that the pellet may be a useful system to maintain the plasma concentration of imidaprilat for a long time.     

Influence of glucose and inhibitors of glycolysis on release of total proteins and enzymes from human leukocytes

We studied the influence of substrates and glycolysis inhibitors on the release of proteins and enzymes from human leukocytes. We show the relationship between metabolic level and percentage of enzyme release.Leukocyte kept alive in a nutrient-free bicarbonate medium liberate enzymes even though their metabolic state is satisfactory. The addition of glucose to the medium significantly decreases this phenomenon without affecting the energy level. Addition of glycolysis inhibitors increases it, reduces the energy level, and interferes with other metabolic pathways.The results are discussed and compared to those obtained by other authors using various cell models.     

In vivo effect of nitrogen dioxide on the activities of glycolytic enzymes in red blood cells of rats

The effects of short-term exposure to NO2 on the glycolytic enzymes of rat red cells were examined. Exposure to 10 ppm NO2 resulted in decrease in activities of pyruvate kinase (PK) and phosphofructokinase (PFK) at day 1 and then increased progressively. Exposure to 4 ppm NO2 caused progressive increases in these enzyme activities from the first day. At day 5, the PK and PFK activities of exposed animals became higher than those of controls followed by decreasing to the control level at day 10. Red blood cells were fractionated according to their ages. The specific activities of PK and PFK decreased as red cells became older. 7-day exposure to 4 ppm NO2 resulted in elevation of PK and PFK activities in all red cell subfractions. In addition, the amount of youngest cells decreased concomitant with increases in those of older cells. These findings suggest that NO2 inhalation enhances red cell turnover.     

Red cell pyruvate kinase deficiency: An optimised assay

As a result of using a variety of assay techniques, rather different values for the rate of the pyruvate kinase (PK) reaction were obtained. Kinetic measurements performed with red cell PK using the stopped-flow as well as the “classical” spectrophotometric method demonstrated that only the initiation of the reaction with ADP yields reproducible results in the standard assay. Moreover, the influence of substrate concentrations, activator concentrations, ionic strength, buffer system, temperature and duration of preincubation were thoroughly investigated and were shown to play an important role. As a consequence of our kinetic measurements, a modified optimised assay composition together with new normal values for erythrocyte PK activity in haemolysate are presented. For better characterisation and comparability of PK variants, we suggest the use of the optimised assay composition described and that the reaction be initiated with ADP.     

Predicting Plutonium Decorporation Efficacy after Intravenous Administration of DTPA Formulations: Study of Pharmacokinetic–Pharmacodynamic Relationships in Rats

Purpose The objectives of this study were: 1) to assess the relationship between plutonium decorporation (increased excretion and reduced retention in main organs of deposition) induced by intravenous liposome formulations of the chelating agent diethylene triamine pentaacetic acid (DTPA) and its pharmacokinetics, and 2) to model the renal excretion of plutonium after treatment with liposome-encapsulated DTPA in order to predict its efficacy and to optimise treatment schedules.Materials and Methods Pharmacokinetic parameters from plasma or urinary data (days 0–16 sample collections) were modelled versus decorporation efficacy, and best correlations were selected for their goodness of fit.Results The plutonium decorporation enhancement by DTPA liposomal formulations was well described by logistic models and the best correlation was observed with the area under the DTPA concentration curve of each formulation. The plutonium urinary excretion rates decreased mono-exponentially as a function of time after a single dose and the proposed model allowed a simple determination of the elimination half-life of the Pu–DTPA complex, a reasonably good approximation of the long-term efficacy of the treatments from truncated urinary data.Conclusions Both liposomal formulations of chelating agents and pharmacokinetic approaches to plutonium decorporation should be helpful in optimising treatment protocols.     

Pharmacokinetic/Pharmacodynamic Modeling of Total Lymphocytes and Selected Subtypes After Oral Budesonide

In the present pharmacokinetic/pharmacodynamic (PK/PD) evaluation, cortisol, total lymphocytes, and lymphocyte subpopulations were monitored following single oral doses of two oral formulations of 3 mg budesonide (BUD) (Dosage Forms A and B) in order to assess the differential effects that BUD may have on cortisol suppression and the modulation of blood lymphocyte subtypes. On a single occasion, five subjects received one 3 mg capsule of Dosage Form A, four received three capsules of Dosage Form A (single dose of 9 mg), and five received three capsules of Dosage Form B (single dose of 9 mg). Placebo capsules were administered to six subjects in the study. Cortisol concentrations, total lymphocyte counts, and lymphocyte subpopulation counts for the CD3, CD4, CD8, CD19, and CD56/16 were fitted to an in direct PK/PD response model that described the effects of BUD on serum cortisol concentrations as well as the combined effects of BUD and cortisol on total lymphocytes and the CD3, CD4, CD8, CD19, and CD56/16 subtypes. Data were also analyzed using noncompartmental methods. The PK/PD model fitted the data with the exception of data for CD56/16. The IC₅₀ value for unbound BUD acting on total lymphocytes was 0.276 ng/ml while the IC₅₀ values for unbound BUD acting on lymphocyte subtypes ranged from 0.150 ng/ml for CD4 to 0.364 ng/ml for CD8. The IC₅₀ values for the effects of BUD on serum cortisol were lower (0.079 ng/ml). The results of PK/PD modeling and noncompartmental analysis indicate that BUD has a smaller effect on the CD8 subtype and larger effects on the CD4 and CD19 subtypes, relative to the effect on total lymphocytes, and that cortisol suppression, although not a direct immunological biomarker, may be a more sensitive marker for the systemic effect of corticosteroids.     

Prospective multicenter evaluation of fecal tumor pyruvate kinase type M2 (M2-PK) as a screening biomarker for colorectal neoplasia

Proliferating cells, particularly the tumor cells, express a dimeric isoenzyme of pyruvate kinase, termed M2-PK. It's a direct target of several oncoproteins; the determination of fecal tumor pyruvate kinase type M2 (M2-PK) might be another promising tool for colorectal cancer (CRC) screening. In this study, we have evaluated fecal M2-PK as a screening biomarker for colorectal neoplasia. It was compared against fecal occult blood (FOB) and colonoscopy. Three hundred and seventeen consecutive subjects from 4 different centers were included. Stool specimens were collected before purgation, processed appropriately and were tested for FOB and quantitatively analyzed for M2-PK. Colonoscopies were performed by experienced endoscopists who were unaware of fecal assay results. At cutoff value of 4 U/ml, fecal M2-PK assay had a sensitivity, specificity, PPV and NPV of 81.1, 86.7, 71.1 and 61.9% respectively for diagnosing CRC whereas FOBT showed a sensitivity of 36.5%, specificity of 92.2%, PPV of 72.9% and NPV of 71.5% for CRC. Such low specificity of fecal M2-PK will lead to unacceptably high number of false positives if it is used for mass CRC screening, leading to unindicated colonoscopies with its associated inconveniences, risks and costs. CRC screening test must have high specificity; a high sensitivity is not as vital. To conclude, M2-PK was found to be a poor screening biomarker for CR neoplasia in a subject population at above average risk based on its prospective comparison with colonoscopy. These marginal performance characteristics do not permit its use as a screening tool for CR neoplasia in present clinical settings.     

Biodistribution and metabolism of immunostimulatory oligodeoxynucleotide CPG 7909 in mouse and rat tissues following subcutaneous administration

To evaluate pharmacokinetics (PK) and biodistribution, CPG 7909, a 24-mer immunostimulatory fully phosphorothioated oligodeoxynucleotide (PS-ODN), was administered by subcutaneous injection at 2, 5 and 12.5mg/kg to mice and at 9mg/kg to rats. Parent compound and metabolites were isolated from plasma and tissues and quantified by capillary gel electrophoresis with UV detection (CGE-UV) and molecular masses were determined by matrix-assisted-laser-desorption-ionization time of flight detection (MALDI-TOF). An established method for PS-ODN isolation from plasma and tissue was modified to prevent oxidation of the phosphorothioate bonds during the extraction process, significantly increasing sensitivity in the subsequent MALDI-TOF analysis. Concentrations of CPG 7909 and metabolites were highest at the injection site (>600mg/kg at 4h). Maximal concentrations in local (draining) lymph nodes (LLN), kidney and liver were 10-15% of that at the injection site. The highest total amount of PS-ODN (percentage of administered dose) was found in the liver (32% at 4h), followed closely by the injection site (23% at 4h). Only very low levels of CPG 7909 and metabolites were found in plasma and only during the first hours. Metabolites identified by MALDI-TOF were similar for both species and all analyzed tissues, although the relative amounts of the different metabolites varied with tissue and over time. Degradation of CPG 7909 in vivo occurred predominantly by 3'exonucleases with additional cleavage by endonucleases.     

Prediction of headache response in migraine treatment

Triptans are efficacious for the acute treatment of migraine attacks. Yet, defining a concentration-effect relation for these compounds is difficult as the dynamics of the migraine attack are not thoroughly understood. The objective of this investigation was to develop a disease model to predict measures of headache in randomized placebo-controlled clinical trials investigating oral sumatriptan as a paradigm compound. A hidden Markov model based on the states of response (no relief, relief, and pain free) and headache scores (observed variable) was used in conjunction with population pharmacokinetics. Model parameters were capable of predicting the course of headache relief, pain-free status and headache recurrence. It was shown that sumatriptan shortens mean transit times between states by up to 5 h. The potency of sumatriptan (EC(50)) was 9 ng/ml. These findings demonstrate the value of combining pharmacokinetic and efficacy information to model disease and characterize time-independent drug properties in a population of migraineurs.