Pharmacokinetic/Pharmacodynamic Analysis for Doripenem Regimens in Intensive Care Unit Patient.

Doripenem (DRPM) is a broad-spectrum antibacterial agent often used as empirical therapy for critically ill patients, although there is a lack of studies validating the recommended dosage regimen for patients admitted to intensive care unit (ICU), based on pharmacokinetic (PK)/pharmacodynamic (PD) index. In this study, we estimated the free time above minimum inhibitory concentration (fT>MIC (%)) of DRPM using population PK analysis of 12 patients in ICU, and evaluated the validity of the dosage regimen stratified by creatinine clearance. Using a 2-compartment population PK model reported previously, the mean total clearance or distribution volume of DRPM estimated by Bayesian estimation was significantly lower or higher than that of based on population PK model. The estimated fT>MIC (%) of the recommended standard (normal renal function: 0.5 g every 8 h, moderate: 0.25 g every 8 h, severe renal impairment: 0.25 g every 12 h) and higher doses (normal: 1.0 g every 8 h, moderate: 0.5 g every 8 h, severe: 0.25 g every 8 h) against MICs of 0.5, 1 and 2 µg/mL exceeded 40% in all patients. When stratified by creatinine clearance, the PK/PD breakpoints estimated by Monte Carlo simulation in three grades of renal function tended to be higher than the previously reported PK/PD breakpoints for patients with urinary tract infection, an infection of lesser severity than ICU patients. These results suggest that the dosage regimen stratified by renal function derived from Japanese package insert may be sufficient to achieve effective treatment in ICU patients.

Metabolomics strategy reveals therapeutical assessment of limonin on nonbacterial prostatitis.

Limonin has been found to possess significant anti-inflammatory properties in animal tests and with, human cells, however, its precise metabolism mechanism has not been well explored. The aim of this study was to investigate the anti-inflammatory effects of limonin in a nonbacterial prostatitis (NBP) animal model. Global metabolite profiling was performed by ultra-high-performance liquid chromatography combined with time-of-flight mass spectrometry (UPLC/ESI-TOFMS) and in conjunction with multivariate data analysis and pathway analysis which were integrated to explore differentiating metabolites and clarify the mechanism of limonin against capsaicin-induced NBP. Limonin has a potential protective function revealed by the metabolic profiling of limonin-treated rats located closer to the normal group. Twenty potential biomarker candidates and several key metabolic pathways contributing to the treatment of NBP were discovered and identified. Among the pathways, the related glycine, serine and threonine metabolism, glycerophospholipid metabolism were acutely perturbed. The changes in metabolites were restored to their base-line levels after limonin treatment, which might be through regulating the perturbed pathways to the normal state. The results indicate that changed biomarkers and pathways may provide evidence and insight into limonin action mechanisms and enable us to increase research productivity toward metabolomics in therapeutical assessment and drug discovery.

Penetration of piperacillin-tazobactam into human prostate tissue and dosing considerations for prostatitis based on site-specific pharmacokinetics and pharmacodynamics.

This study aimed to investigate the penetration of PIPC-TAZ into human prostate, and to assess effectiveness of PIPC-TAZ against prostatitis by evaluating site-specific PK-PD. Patients with prostatic hypertrophy (n = 47) prophylactically received a 0.5 h infusion of PIPC-TAZ (8:1.2-0.25 g or 4-0.5 g) before transurethral resection of the prostate. PIPC-TAZ concentrations in plasma (0.5-5 h) and prostate tissue (0.5-1.5 h) were analyzed with a three-compartment PK model. The estimated model parameters were, then used to estimate the drug exposure time above the minimum inhibitory concentration for bacteria (T > MIC, the PD indicator for antibacterial effects) in prostate tissue for six PIPC-TAZ regimens (2.25 or 4.5 g; once, twice, three times or four times daily; 0.5 h infusions). Prostate tissue/plasma ratio of PIPC was about 36% both for the maximum drug concentration (Cmax) and the area under the drug concentration-time curve (AUC). Against MIC distributions for isolates of Escherichia coli, Klebsiella species and Proteus species, regimens of 4.5 g twice daily and 2.25 g three times daily achieved a >90% probability of attaining the bacteriostatic target for PIPC (30% T > MIC) in prostate tissue; regimens of 4.5 g three times daily and 2.25 g four times daily achieved a >90% probability of attaining the bactericidal target for PIPC (50% T > MIC) in prostate tissue. However, against Pseudomonas aeruginosa isolates, none of the tested regimens achieved a >90% probability. PIPC-TAZ is appropriate for the treatment of prostatitis from the site-specific PK-PD perspective.

Method of assessment of the dynamics of salivary function in rats during the experiment.

The dynamics of salivary function was studied on 80 laboratory rats. It was found that construction of a graph showing the dynamics of stimulated salivation in small laboratory animals could be successfully used in various studies.

A population pharmacokinetic analysis of the penetration of the prostate by levofloxacin.

Prostatitis has remained a pathological entity that is difficult to treat. Part of the difficulty revolves about the putative offending pathogens. For acute prostatitis, members of the Enterobacteriaceae, particularly Escherichia coli, play a central role, while intracellular pathogens such as Chlamydia are more frequently seen in chronic prostatitis. Consequently, a drug needs to be able to penetrate to this specialized site in both the acute and chronic infection forms of the disease and also have potent activity against the most common causative pathogens, both intracellular and extracellular. Levofloxacin has such an activity profile. We wished to document its ability to penetrate to the site of infection. Patients undergoing prostatectomies were administered 500 mg of levofloxacin orally every 24 h for 2 days prior to surgery, and then on the day of surgery, 500 mg was administered as an hour-long, constant-rate intravenous (i.v.) infusion. A set of blood samples was obtained as guided by stochastic optimal design theory. Prostate biopsy times were determined by randomizing subjects into one of four groups, based on the interval after the i.v. dose. All plasma and prostate drug concentrations were comodeled by a population modeling program, BigNPEM, implemented on the Cray T3E Supercomputer housed at the Supercomputer Center at the University of California at San Diego. Penetration was determined as the ratio of the area under the concentration-time curve (AUC) of levofloxacin in the prostate to the plasma levofloxacin AUC. When calculated from the mean population parameters, this penetration ratio was 2.96. We also performed a 1,000-subject Monte Carlo simulation from the mean parameter vector and covariance matrix. The mean penetration ratio here was 4.14 with a 95% confidence interval of 0.20 to 19.6. Over 70% of the population had a penetration ratio in excess of 1.0. Levofloxacin adequately penetrates a noninflamed prostate and should be evaluated for the therapy of prostatitis.