Improvement of Parameter Estimations in Tumor Growth Inhibition Models on Xenografted Animals: Handling Sacrifice Censoring and Error Caused by Experimental Measurement on Larger Tumor Sizes.

The purpose of this study was to explore the impact of censoring due to animal sacrifice on parameter estimates and tumor volume calculated from two diameters in larger tumors during tumor growth experiments in preclinical studies. The type of measurement error that can be expected was also investigated. Different scenarios were challenged using the stochastic simulation and estimation process.

Combined Analysis of Phase I and Phase II Data to Enhance the Power of Pharmacogenetic Tests.

We show through a simulation study how the joint analysis of data from phase I and phase II studies enhances the power of pharmacogenetic tests in pharmacokinetic (PK) studies. PK profiles were simulated under different designs along with 176 genetic markers. The null scenarios assumed no genetic effect, while under the alternative scenarios, drug clearance was associated with six genetic markers randomly sampled in each simulated dataset.

Improvement of Parameter Estimations in Tumor Growth Inhibition Models on Xenografted Animals: a Novel Method to Handle the Interval Censoring Caused by Measurement of Smaller Tumors.

The purpose of this study was to explore the interval censoring induced by caliper measurements on smaller tumors during tumor growth experiments in preclinical studies and to show its impact on parameter estimations. A new approach, the so-called interval-M3 method, is proposed to specifically handle this type of data. Thereby, the interval-M3 method was challenged with different methods (including classical methods for handling below quantification limit values) using Stochastic Simulation and Estimation process to take into account the censoring.

Optimal sampling times for a drug and its metabolite using SIMCYP(®) simulations as prior information.

Background: Since 2007, it is mandatory for the pharmaceutical companies to submit a Paediatric Investigation Plan to the Paediatric Committee at the European Medicines Agency for any drug in development in adults, and it often leads to the need to conduct a pharmacokinetic study in children. Pharmacokinetic studies in children raise ethical and methodological issues. Because of limitation of sampling times, appropriate methods, such as the population approach, are necessary for analysis of the pharmacokinetic data.

Pharmacokinetics of the local anesthetic ropivacaine after transversus abdominis plane block in healthy volunteers.

Purpose: The transversus abdominis plane (TAP) block is a regional anesthetic technique used for pain control following abdominal surgical procedures. While a minimum of systemic side effects is usually expected after local anesthesia, it is unknown to which extent systemic absorption and redistribution to the abdominal wall contributes to the effects of anesthetics. The aim of this study was to determine concentration-time profiles of ropivacaine after the injection of 150 mg of ropivacaine into the lateral abdominal wall in various compartments.

Multiple-dose pharmacokinetics of telithromycin in peripheral soft tissues.

Based on clinicians' expectations of high concentrations of telithromycin (TEL) in tissues, combined with its excellent in vitro antimicrobial characteristics, TEL is casually considered as a potential therapeutic option for the therapy of minor cases of soft tissue or bite-wound infections. To clarify this clinically important issue, the present investigation was carried out to measure the pharmacokinetic profile of TEL in the interstitial space fluid (ISF) of skeletal muscle and subcutaneous adipose tissue by means of the microdialysis technique in 10 healthy subjects following repetitive daily doses of 800 mg TEL. These data were compared with free concentrations of TEL determined in plasma.

Plasma protein binding of fluoroquinolones affects antimicrobial activity.

Objectives: In contrast to most antimicrobial classes, there is a doubt about the impact of protein binding (PB) on the antimicrobial activity of fluoroquinolones. We set out to evaluate the suitability of previously used models for investigating the influence of PB on bacterial killing by fluoroquinolones.

Methods: PB of moxifloxacin and trovafloxacin was determined in Mueller-Hinton broth (MHB) containing different concentrations of human serum or albumin.

S-ibuprofen effectively inhibits thromboxane B2 levels and platelet function in an experimental model of lipopolysaccharide-stimulated and non-stimulated whole blood.

Objective: The present study aimed at testing the effect of S- and R-ibuprofen on thromboxane B(2) (TXB(2)), collagen-epinephrine closure time (CEPI-CT) and collagen-adenosine 5'-diphosphate closure time (CADP-CT) in lipopolysaccharide (LPS)-stimulated and non-stimulated human whole blood.

Materials And Methods: Whole blood was incubated with S- or R-ibuprofen with and without prior stimulation with LPS. To verify ibuprofen's potential effects on TXB(2), varying ratios of concentrations of S- and R-ibuprofen ranging from 0 to 100% were used.

Effect of severity of sepsis on tissue concentrations of linezolid.

Objectives: In the present study, we examined whether differences in the severity of sepsis translate to differences in the pharmacokinetic profile of linezolid in plasma and the interstitium of target tissues after a single intravenous dose of 600 mg by means of the microdialysis technique.

Patients And Methods: A total of 24 patients were included in the trial. Sixteen patients suffered from septic shock and eight patients presented with severe sepsis.

Daptomycin: a review 4 years after first approval.

Daptomycin is the first approved member of a new class of antibiotics, namely the cyclic lipopeptides. Daptomycin has rapid bactericidal activity against Gram-positive pathogens. It acts by penetrating into the bacterial cell wall with consecutive formation of pores, loss of electrical membrane potential and inhibition of peptidoglycan synthesis.

Daptomycin does not exert immunomodulatory effects in an experimental endotoxin model of human whole blood.

Background: Recent studies have shown that distinct classes of antimicrobial agents might exert immunomodulatory effects in experimental settings. Daptomycin is the first member of the class of cyclic lipopeptide antibiotics, which exert their antimicrobial activity via a unique mode of action on the bacterial cytoplasmic membrane. Thus, we tested its ability to influence pro-inflammatory cytokines by use of an established experimental model of human endotoxemia.

Peripheral metabolism of (R)-[11C]verapamil in epilepsy patients.

Purpose: (R)-[(11)C]verapamil is a new PET tracer for P-glycoprotein-mediated transport at the blood-brain barrier. For kinetic analysis of (R)-[(11)C]verapamil PET data the measurement of a metabolite-corrected arterial input function is required. The aim of this study was to assess peripheral (R)-[(11)C]verapamil metabolism in patients with temporal lobe epilepsy and compare these data with previously reported data from healthy volunteers.

IL-1beta genotype-related effect of prednisolone on IL-1beta production in human peripheral blood mononuclear cells under acute inflammation.

Glucocorticoids such as prednisolone are used for their anti-inflammatory properties. But there is evidence to suggest that under certain conditions, glucocorticoids have pro-inflammatory effects, for example, enhancement of IL-1beta production. To date, it has been reported that IL-1beta production intensity was associated with single nucleotide polymorphisms at positions -1470, -511, and -31 in the promoter region and at position 3954 in exon 5 of the IL-1beta gene.

Comparison of a treatment strategy combining CCI-779 plus DTIC versus DTIC monotreatment in human melanoma in SCID mice.

This study compares the antineoplastic potential of a novel treatment strategy combining cell cycle inhibitor-779 (CCI-779) plus dacarbazine (DTIC) versus DTIC monotreatment, the current chemotherapeutic mainstay in combating metastatic melanoma. A controlled four-group parallel study design comprising 24-40 mice per tumor cell line was used in a severe combined immunodeficiency (SCID)-mouse xenotransplantation model. SCID mice were injected with 518A2, Mel-JUSO, or 607B human melanoma cells.

Pharmacoresistance in epilepsy: a pilot PET study with the P-glycoprotein substrate R-[(11)C]verapamil.

Purpose And Methods: Regional overexpression of the multidrug transporter P-glycoprotein (P-gp) in epileptic brain tissue may lower target site concentrations of antiepileptic drugs and thus contribute to pharmacoresistance in epilepsy. We used the P-gp substrate R-[(11)C]verapamil and positron emission tomography (PET) to test for differences in P-gp activity between epileptogenic and nonepileptogenic brain regions of patients with drug-resistant unilateral temporal lobe epilepsy (n = 7). We compared R-[(11)C]verapamil kinetics in homologous brain volumes of interest (VOIs) located ipsilateral and contralateral to the seizure focus.

CCI-779 plus cisplatin is highly effective against human melanoma in a SCID mouse xenotranplantation model.

Background: This study set out to investigate the antitumor effects of a treatment strategy combining the mTOR inhibitor CCI-779 with cisplatin in vitro and in a human melanoma SCID mouse model.

Methods: In vitro 518A2, Mel-JUSO or 607B cell lines were incubated with CCI-779, cisplatin and CCI-779 plus cisplatin. Based on these results, a 4-group, parallel, controlled experimental study design was initiated in vivo.

Clinical scoring system for the prediction of target site penetration of antimicrobials in patients with sepsis.

Background And Objectives: The present study investigated the usefulness of routinely employed scoring systems in predicting tissue penetration of antimicrobials. In addition, a novel, easy to use scoring system was designed for the estimation of tissue penetration of antimicrobials in patients with sepsis.

Methods: Tissue pharmacokinetics were assessed in skeletal muscle and subcutaneous adipose tissue by use of the microdialysis technique in 34 patients with sepsis.

A pilot study testing whether concentrations of levofloxacin in interstitial space fluid of soft tissues may serve as a surrogate for predicting its pharmacokinetics in lung.

Recent observations indicate that pharmacokinetics of beta-lactam antibiotics in the lung can be predicted by the use of concentration versus time profiles in peripheral soft tissues. If this observation is transferred to other classes of antimicrobials, measurement of antimicrobial concentrations in peripheral tissues would enable prediction of the pharmacokinetics of antimicrobials at the site of the respiratory tract infection. We set out to test the hypothesis that concentrations of the fluoroquinolone levofloxacin in the respiratory tract can be predicted on the basis of knowledge of its pharmacokinetics in peripheral soft tissues.

The echinocandins: comparison of their pharmacokinetics, pharmacodynamics and clinical applications.

Caspofungin, micafungin and anidulafungin are three drugs of the echinocandin class of antifungals available for intravenous treatment of invasive candidiasis and aspergillosis. They exhibit high in vitro and in vivo activities against Candida spp. and Aspergillus spp.

A positron emission tomography microdosing study with a potential antiamyloid drug in healthy volunteers and patients with Alzheimer's disease.

This work describes a microdosing study with an investigational, carbon 11-labeled antiamyloid drug, 1,1'-methylene-di-(2-naphthol) (ST1859), and positron emission tomography (PET) in healthy volunteers (n = 3) and patients with Alzheimer's disease (n = 6). The study aimed to assess the distribution and local tissue pharmacokinetics of the study drug in its target organ, the human brain. Before PET studies were performed in humans, the toxicologic characteristics of ST1859 were investigated by an extended single-dose toxicity study according to guidelines of the Food and Drug Administration and European Medicines Agency, which are relevant for clinical trials with a single microdose.

Principles of antibiotic penetration into abscess fluid.

Although drainage is considered the gold standard in abscess treatment, abscesses of different sizes and locations have been successfully cured by means of antibiotic treatment alone. The penetration of an antibiotic into an encapsulated purulent lesion is limited and highly dependent on the degree of abscess maturation. In fact, in vivo pharmacokinetic data demonstrate that substantial antibiotic concentrations can be reached within abscesses in humans and animals, provided the choice of an appropriate agent and an optimal dosing regimen.

Genotype-dependent down-regulation of gene expression and function of MDR1 in human peripheral blood mononuclear cells under acute inflammation.

Recent advances in pharmacogenomics have suggested the association of clinical outcome of glucocorticoid-based anti-inflammatory therapy with a single nucleotide polymorphism at position 3435 in exon 26 (C3435T) of the MDR1 gene. In the present study, the effects of the MDR1 C3435T genotype on the time-dependent profiles of gene expression and function of MDR1/P-glycoprotein were evaluated in peripheral blood mononuclear cells (PBMCs) under lipopolysaccharide (LPS)-induced experimental acute inflammation. LPS treatment resulted in the rapid elevation of IL-1beta and TNF-alpha mRNA levels relative to beta-actin mRNA at 1 h, with a subsequent slight decrease at 3 h after the treatment, while the down-regulation of the relative concentration of MDR1 mRNA was found at 3 h, not at 1 h, after LPS treatment.

MDR1 T-129C polymorphism can be predictive of differentiation, and thereby prognosis of colorectal adenocarcinomas in Japanese.

The expression level of MDR1 mRNA was evaluated in colorectal adenocarcinomas and adjacent noncancerous colorectal tissues obtained from 21 Japanese patients. It was lower in the former than in the latter (p=0.012), suggesting its down-regulation as a consequence of malignant transformation of colorectal tissues, possibly with the suppression of differentiation.

Microdialysis versus other techniques for the clinical assessment of in vivo tissue drug distribution.

Quantification of target site pharmacokinetics (PK) is crucial for drug discovery and development. Clinical microdialysis (MD) has increasingly been employed for the description of drug distribution and receptor phase PK of the unbound fraction of various analytes. Costs for MD experiments are comparably low and given suitable analytics, target tissue PK of virtually any drug molecule can be quantified.