Elimination Half-life In Humans Research Articles

Estimation of the Half-Lives of Recently Detected Per- and Polyfluorinated Alkyl Ethers in an Exposed Community.

To estimate half-lives for novel fluoroethers, the GenX Exposure Study obtained two serum measurements for per- and polyfluoroalkyl substances (PFAS) for 44 participants of age 12-86 years from North Carolina, collected 5 and 11 months after fluoroether discharges into the drinking water source were controlled. The estimated half-lives for these compounds were 127 days (95% confidence interval (95% CI) = 86, 243 days) for perfluorotetraoxadecanoic acid (PFO4DA), 296 days for Nafion byproduct 2 (95% CI = 176, 924 days), and 379 days (95% CI = 199, 3870 days) for perfluoro-3,5,7,9,11-pentaoxadodecanoic acid (PFO5DoA). Using these estimates and the literature values, a model was built that predicted PFAS half-lives using structural properties. Three chemical properties predicted 55% of the variance of PFAS half-lives based on 15 PFAS. A model with only molecular weight predicted 69% of the variance. Some properties can predict the half-lives of PFAS, but a deeper understanding is needed. These fluoroethers had biological half-lives longer than published half-lives for PFHxA and PFHpA (30-60 days) but shorter than those for PFOA and PFOS (800-1200 days). These are the first and possibly only estimates of human elimination half-lives of these fluoroethers.

Quantitative pharmacokinetic analyses of anterior and posterior elimination routes of intravitreal anti-VEGF macromolecules using published human and rabbit data

The purpose of this study was to evaluate the contribution of the anterior elimination route for four anti-vascular endothelial growth factor (anti-VEGF) macromolecules (aflibercept, bevacizumab, pegaptanib and ranibizumab) after intravitreal injection using published human and rabbit data and three previously described pharmacokinetic (PK) modeling methods.A PubMed search was used to identify published studies with concentration-time data. The data were utilized only if the intravitreally injected drugs were used as plain solutions and several criteria for a well-performed PK study were fulfilled. The three methods to analyze rabbit data were (1) the equation for vitreal elimination half-life based molecular size assuming anterior elimination, (2) Maurice equation and plot for the ratio of aqueous humor (AH) to vitreal concentration assuming anterior elimination, and (3) the equation for amount of macromolecule eliminated anteriorly based on the area under the curve in AH. The first and third methods were used for human data. In the second and third methods, AH flow rate is a key model parameter, and it was varied between 2 and 3 μl/min.The methods were applied to data from 9 rabbit studies (1 for aflibercept, 5 for bevacizumab, and 3 for ranibizumab) and 5 human studies (1 for aflibercept, 3 for bevacizumab, and 1 for ranibizumab). Experimental half-lives of anti-VEGF macromolecules in both vitreous and aqueous humor were close to those calculated with the equations for vitreal elimination half-life in humans and rabbits. Rabbit data analyzed with Maurice plot indicated that the contribution of anterior elimination was usually at least 75%. In most human and rabbit studies, the calculated percentage of anterior elimination was at least 51%. Variability between studies was extensive for bevacizumab and ranibizumab.The results suggest that the anterior elimination route dominates after intravitreal injection of anti-VEGF macromolecules. However, the clinical data are sparse and variability is extensive, the latter emphasizing the need of proper experimental design.

Perfluorooctane sulfonate induces autophagy-associated apoptosis through oxidative stress and the activation of extracellular signal-regulated kinases in renal tubular cells.

Perfluorooctane sulfonate (PFOS) is among the most abundant organic pollutants and is widely distributed in the environment, wildlife, and humans. Its toxic effects and biological hazards are associated with its long elimination half-life in humans. However, how it affects renal tubular cells (RTCs) remains unclear. In this study, PFOS was observed to mediate the increase in reactive oxygen species (ROS) generation, followed by the activation of the extracellular-signal-regulated kinase 1/2 (ERK1/2) pathway, which induced autophagy in RTCs. Although PFOS treatment induced autophagy after 6 h, prolonged treatment (24 h) reduced the autophagic flux by increasing lysosomal membrane permeability (LMP), leading to increased p62 protein accumulation and subsequent apoptosis. The increase in LMP was visualized through increased green fluorescence with acridine orange staining, and this was attenuated by 3-methyladenine, an autophagy inhibitor. N-acetyl cysteine and an inhibitor of the mitogen-activated protein kinase kinases (U0126) attenuated autophagy and apoptosis. Taken together, these results indicate that ROS activation and ROS-mediated phosphorylated ERK1/2 activation are essential to activate autophagy, resulting in the apoptosis of PFOS-treated RTCs. Our findings provide insight into the mechanism of PFOS-mediated renal toxicity.

Age-dependent human elimination half-lives of dioxin-like polychlorinated biphenyls derived from biomonitoring data in the general population

Constant elimination half-life is usually used in first-order one-compartment pharmacokinetic models to assess human exposure to dioxin-like polychlorinated biphenyls (PCBs). However, hepatic clearance rates are usually lower for elders than for young people. In this study, levels of 12 dioxin-like PCBs were determined in blood samples collected in 2012 from 305 individuals from the general population. We estimated the historical daily intake of dioxin-like PCBs for individuals with a validated annual exponential decay function. Based on the blood levels and historical daily intake levels, and using the maximum likelihood estimation by running the first-order one-compartment pharmacokinetic model, elimination rates were optimized as exponential functions of age for PCB118, PCB157, PCB189 and PCB126; linear functions of age for PCB114, PCB123, PCB167 and PCB169; and constant functions of age for PCB105 and PCB156. With the exception of PCB105 and PCB156, half-lives generally increased with age for individuals from 24 to 50 years old: from 0.805 to 1.95 years for PCB189, 2.08–4.54 years for PCB157, 3.32–5.58 years for PCB126, 3.52–6.81 years for PCB123, 5.24–12.29 years for PCB169, 6.60–14.40 years for PCB114, 7.50–14.01 years for PCB118, and 9.97–21.97 years for PCB167. The half-lives of PCB105 (5.79 years) and PCB156 (15.1 years) were independent of age. Our research for the first time clarified the effects of age on the elimination rate of dioxin-like PCBs in individuals from the general population, thus reducing uncertainty in future health risk assessments.

Historical intake and elimination of polychlorinated biphenyls and organochlorine pesticides by the Australian population reconstructed from biomonitoring data

Quantifying the competing rates of intake and elimination of persistent organic pollutants (POPs) in the human body is necessary to understand the levels and trends of POPs at a population level. In this paper we reconstruct the historical intake and elimination of ten polychlorinated biphenyls (PCBs) and five organochlorine pesticides (OCPs) from Australian biomonitoring data by fitting a population-level pharmacokinetic (PK) model. Our analysis exploits two sets of cross-sectional biomonitoring data for PCBs and OCPs in pooled blood serum samples from the Australian population that were collected in 2003 and 2009. The modeled adult reference intakes in 1975 for PCB congeners ranged from 0.89 to 24.5ng/kgbw/day, lower than the daily intakes of OCPs ranging from 73 to 970ng/kgbw/day. Modeled intake rates are declining with half-times from 1.1 to 1.3years for PCB congeners and 0.83 to 0.97years for OCPs. The shortest modeled intrinsic human elimination half-life among the compounds studied here is 6.4years for hexachlorobenzene, and the longest is 30years for PCB-74. Our results indicate that it is feasible to reconstruct intakes and to estimate intrinsic human elimination half-lives using the population-level PK model and biomonitoring data only. Our modeled intrinsic human elimination half-lives are in good agreement with values from a similar study carried out for the population of the United Kingdom, and are generally longer than reported values from other industrialized countries in the Northern Hemisphere.

Bounding uncertainties in intrinsic human elimination half-lives and intake of polybrominated diphenyl ethers in the North American population

We examine the balance between intake, intrinsic elimination half-lives and human body burdens measured in biomonitoring for polybrominated diphenyl ethers (PBDEs) in the North American population using the population-level pharmacokinetic model developed by Ritter et al. (2011). Empirical data are collected from two studies that made total intake estimates for the North American population for the years 2004 and 2005, and eight biomonitoring studies for the years 1992 to 2009. We assume intake of PBDEs increased exponentially to a peak in 2004, and has since exponentially declined. The model is fitted to the empirical PBDE intake and biomonitoring data on PBDE body burden using a least-square optimization method by adjusting the intake in 2004 and 2038, and the intrinsic elimination rate constants, which can be expressed as equivalent half-lives. We fit the model in two types of scenarios using different combinations of PBDE intake estimates and biomonitoring data. Our modeling results indicate that there is an inconsistency between the PBDE intake estimates and the biomonitoring data, and that the inconsistency is likely due to underestimation of population-level intake. More efforts are needed to better characterize intake rates and identify potentially-unrecognized exposure pathways. Additional age-stratified biomonitoring data, and time trends of PBDE intakes would better constrain the model and provide an improved estimation of the intrinsic elimination half-lives.

Mechanism of perfluorooctanesulfonate (PFOS)-induced apoptosis in the immunocyte

As a new type of persistent organic pollutant, perfluorooctane sulfonate (PFOS) has raised great concern in recent years due to its ubiquitous distribution in the general environment and its long elimination half-life in humans. PFOS has toxic and carcinogenic effects in animals and humans, but the effects of PFOS on apoptosis are still not clear. The present study aimed to determine the mode of cell death and its mechanism in splenocytes and thymocytes from adult male C57BL/6 mice administered 0, 1, 5, or 10 mg PFOS/kg/day by gavage daily for 7 days. The results showed that more apoptotic cells were present in PFOS-treated mice than in control mice. PFOS induced production of reactive oxygen species (ROS), dissipation of mitochondria membrane potential, and apoptosis of splenocytes and thymocytes. Moreover, activities of superoxide dismutase, catalase, and glutathione reductase were increased, whereas activities of glutathione-S-transferase and glutathione peroxidase were decreased, in splenocytes. Glutathione contents were reduced as well. Differential expressions of proteins such as p53, Bax, caspase-3, and caspase-9 were significantly up-regulated in PFOS-exposed hosts, whereas Bcl-2 expression was significantly down-regulated. One possible mechanism for the findings here was that PFOS could overwhelm homeostasis of anti-oxidative systems, boost ROS generation, impact on mitochondria, and affect protein expression of apoptotic regulators, the latter of which resulted in initiation of the apoptosis program. Results from this study may provide a new insight into the potential adverse effects of PFOS exposure on humans, at the cellular level.

Biomonitoring Equivalents for DDT/DDE

Biomonitoring Equivalents (BEs) are defined as the concentration or range of concentrations of a chemical or its metabolite in a biological medium (blood, urine, or other medium) that is consistent with an existing health-based exposure guideline such as a reference dose (RfD) or tolerable daily intake (TDI). BE values can be used as a screening tool for the evaluation of population-based biomonitoring data in the context of existing risk assessments. This study reviews available health based risk assessments and exposure guidance values for DDT (1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane, CAS #50-29-3) and related metabolites and degradation products DDE (1,1-dichloro-2,2-bis(p-chlorophenyl)ethane, CAS #72-55-90) and DDD (1,1-dichloro-2,2-bis(p-chloro-phenyl)ethane) based on both non-cancer and cancer risk assessments from the Food and Agriculture Organization/World Health Organization (FAO/WHO), the United States Environmental Protection Agency (US EPA), and other organizations. Laboratory data on distribution and toxicokinetics of DDT and metabolites and estimates of human elimination half-lives were used to estimate BE values (lipid-adjusted blood, serum, or plasma concentrations) corresponding to the various non-cancer exposure guidance values and cancer risk-specific doses. The BE values based on non-cancer risk assessments range from 5000 to 40,000 ng/g lipid for the sum of DDT, DDE, and DDD. The BE values corresponding to a 1E-05 cancer risk level for DDT and DDE based on the US EPA assessment are 300 and 500 ng/g lipid, respectively. Sources of uncertainty relating to both the basis for the BE values and their use in evaluation of biomonitoring data are discussed. The BE values derived here can be used as a screening tools for evaluation of population biomonitoring data for DDT and related compounds in the context of the existing risk assessment and can assist in prioritization of the potential need for additional risk assessment efforts for DDT relative to other chemicals.

Intrinsic Human Elimination Half-Lives of Polychlorinated Biphenyls Derived from the Temporal Evolution of Cross-Sectional Biomonitoring Data from the United Kingdom

BackgroundMost empirical estimates of human elimination kinetics for persistent chemicals reflect apparent elimination half-lives that represent the aggregated effect of intrinsic elimination, ongoing exposure, and changes in body weight. However, estimates of intrinsic elimination at background levels are required for risk assessments for the general population.ObjectiveTo estimate intrinsic human elimination half-lives at background levels for nine polychlorinated biphenyl (PCB) congeners, we used a novel approach based on population data.MethodsWe used a population pharmacokinetic model to interpret two sets of congener-specific cross-sectional age–concentration biomonitoring data of PCB concentrations measured in lipid and blood samples that were collected from 229 individuals in 1990 and 2003. Our method is novel because it exploits information about changes in concentration in the human population along two dimensions: age and calendar time.ResultsOur approach extracted information about both elimination kinetics and exposure trends from biomonitoring data. The longest intrinsic human elimination half-lives estimated in this study are 15.5 years for PCB‐170, 14.4 years for PCB‐153, and 11.5 years for PCB‐180.ConclusionsOur results are further evidence that a maximum intrinsic elimination half-life for persistent chemicals such as PCBs exists and is approximately 10–15 years. A clear conceptual distinction between apparent and intrinsic half-lives is required to reduce the uncertainty in elimination half-lives of persistent chemicals. The method presented here estimates intrinsic elimination half-lives and the exposure trends of persistent pollutants using cross-sectional data available from a large and growing number of biomonitoring programs.

Risk Assessment in Extrapolation of Pharmacokinetics from Preclinical Data to Humans

Prediction of pharmacokinetics in humans is essential for translating preclinical data to humans and planning safe and efficient clinical studies. The performance of various methods in extrapolation of preclinical pharmacokinetic data to humans is usually benchmarked by the fraction of predictions falling within a predefined interval that is centred on the value observed clinically. Recently, such an approach was used to compare physiologically based pharmacokinetic (PBPK) modelling and allometry in predicting the pharmacokinetics of a set of compounds in humans. Here, we present an analysis of the same dataset, focusing on predictions falling outside such a relatively narrow and centrally located interval. These are the main risk determinants in extrapolation of preclinical pharmacokinetic data to humans and should therefore be thoroughly understood in a risk mitigation approach to the design of early-phase human studies. Values that had been previously predicted by allometry and by PBPK modelling in terms of the apparent total clearance after oral administration, apparent volume of distribution, area under the plasma concentration-time curve, maximum plasma drug concentration, time to reach the maximum plasma concentration and terminal elimination half-life in humans were used to generate a log-transformed dataset of predicted/observed ratios. The probabilities of mispredicting the values of these pharmacokinetic parameters using PBPK modelling and allometry were estimated by a bootstrap procedure on this set of ratios. Our results, albeit from a limited dataset, indicated that although PBPK modelling yielded higher fractions of satisfactory predictions than allometry, both methodologies were associated with a significant and occasionally high probability of obtaining mispredictions of pharmacokinetic parameters by factors of >2, >3 and >10. In line with recent proposals to extend the goals of early-phase human studies beyond safety and tolerability, and considering the need to mitigate risks in studies dealing with novel and highly potent drug candidates, we discuss these results in a pharmacological context. Concise recommendations are given regarding the use of allometric and PBPK extrapolation methodologies in the translation process. The results presented here should alert clinical investigators to the limitations inherent in all approaches to prediction of human pharmacokinetics from preclinical data. We propose an adaptive approach to the design of early-phase clinical studies, particularly when dealing with compounds that are characterized by novel and only partially understood pharmacological profiles.

Acetaminophen elimination half-life in humans is unaffected by short-term consumption of sulfur amino acid-free diet.

Sulfation and glutathione (GSH) conjugation are important pathways for elimination of acetaminophen (APAP). Previous studies in rodents show that limitation of dietary sulfur amino acids (SAAs) reduces biosynthesis of 3'-phosphoadenosine-5'-phosphosulfate, the precursor for sulfation, and GSH, the precursor for the mercapturatic acid pathway. The amount of SAA needed for the metabolism of two doses of APAP is equivalent to 62% of the recommended dietary allowance (RDA) for SAA in humans. A decrease in the activity of these metabolic pathways could lead to decreased elimination of the reactive metabolite of APAP and possibly affect risk of APAP use. To determine whether intake of a SAA-deficient diet alters APAP metabolism, a pilot clinical study with a double-blind, cross-over design was performed. Subjects received the RDA for SAA for 3 days for equilibration. After admission to the clinical research unit, subjects were given a chemically defined diet with 100 or 0% of the RDA for SAA for 2 days. On day 3, two doses of APAP (15 mg/kg) or placebo were given successively within a 6-h interval. Plasma samples were collected at baseline and hourly for 12 h, and two 6-h urine aliquots were collected during this time course. The data show that SAA limitation 1) did not change the pattern of APAP metabolites in plasma or urine and 2) did not alter APAP pharmacokinetics. Thus, the results show that 2 days of diet completely devoid of SAA have no effect on APAP metabolism or disposition in healthy humans.

A Multi-Individual Pharmacokinetic Model Framework for Interpreting Time Trends of Persistent Chemicals in Human Populations: Application to a Postban Situation

BackgroundHuman milk and blood are monitored to detect time trends of persistent organic pollutants (POPs) in humans. It is current practice to use log-linear regression to fit time series of averaged cross-sectional biomonitoring data, here referred to as cross-sectional trend data (CSTD).ObjectiveThe goals of our study are to clarify the interpretation of half-lives derived from fitting exponential functions to declining CSTD and to provide a method of estimating human elimination half-lives from CSTD collected in a postban situation.MethodsWe developed a multi-individual pharmacokinetic model framework and present analytical solutions for a postban period. For this case, the framework quantitatively describes the relationships among the half-life for reduction of body burdens of POPs derived from CSTD, the half-life describing decline in daily intake, and the half-life of elimination from the human body.ResultsThe half-life derived from exponential fitting of CSTD collected under postban conditions describes the exposure trend and is independent of human elimination kinetics. We use a case study of DDT (dichlorodiphenyltrichloroethane) to show that CSTD can be combined with exposure data obtained from total diet studies to estimate elimination kinetics of POPs for humans under background exposure conditions.ConclusionsCSTD provide quantitative information about trends in human exposure and can be combined with exposure studies to estimate elimination kinetics. The full utility of these data has not been exploited so far. An efficient and informative monitoring strategy for banned POPs in humans would coordinate sampling of consistent sets of CSTD from young adults with total diet studies.

Postantibiotic Effects of Telavancin against 16 Gram-Positive Organisms

The in vitro postantibiotic effects (PAEs), postantibiotic sub-MIC effects (PA-SMEs), and sub-MIC effects of telavancin were determined for 16 gram-positive organisms. Telavancin staphylococcal, streptococcal, and enterococcal PAE ranges were 0.9 to 3.9 h, 0.4 to 6.7 h, and 0.3 to 2.2 h, respectively. The PA-SME ranges (0.4 times the MIC) for staphylococci, streptococci, and enterococci were 6.7 to >10.7 h, >10.7 to >11.0 h, and >10 to >10.8 h, respectively. The extended PAE of telavancin, together with its long elimination half-life in humans, supports once-daily dosing for this investigational drug.

Identification of Acepromazine in Hair: An Illustration of the Difficulties Encountered in Investigating Drug‐facilitated Crimes

After a drug-facilitated sexual assault (DFSA), a woman was found in a drowsy state at home. She remembered having drunk an unknown beverage by the accused. Blood samples (collected 8 hours after the DFSA), two glasses, and a teaspoon seized by the police were analyzed. Acepromazine, a phenothiazine tranquilizer used in human and veterinary medicine, was detected in the residue of one of the glasses. In spite of acepromazine absence in the victim's blood, the possible use of acepromazine in the DFSA was reported to the police. Two weeks later, a suspect admitted having orally administered acepromazine to the victim. Using a liquid chromatography-tandem mass spectrometry method, this compound was subsequently detected (31 pg/mg) in a sample of the victim's hair collected a month and a half after the DFSA. A potential short elimination half-life in humans and/or the well-known in vitro degradation of acepromazine could explain the negative blood result. DFSA toxicological investigations are challenging and can be complicated when a rather unusual substance is concerned. In particular, special care should be taken when interpreting the results, taking into account elimination and/or instability data, when available.

Tigecycline

Tigecycline is a first-in-class glycylcycline, broad-spectrum, intravenous antibacterial developed to overcome the two major mechanisms of tetracycline resistance (ribosomal protection and efflux). The drug has been in use since 2005 for complicated intra-abdominal infections, and complicated skin and soft tissue structure infections, but is currently being assessed in the US for community-acquired pneumonia (CAP) in adults. In vitro, tigecycline had good activity against a range of Gram-positive, Gram-negative and atypical community-acquired respiratory tract pathogens implicated in CAP. Compared with other antibacterials, tigecycline has a prolonged post-antibiotic effect against key bacteria and a long serum elimination half-life in humans. The drug effectively penetrates lung tissue. The combined results of two well designed, phase III studies demonstrated that tigecycline 100 mg initially, followed by 50 mg every 12 hours for 7-14 days was not inferior to recommended dosages of levofloxacin in the treatment of hospitalized patients with CAP. Clinical cure rates were 89.7% versus 86.3% in the clinically evaluable population and 81.0% versus 79.7% in the clinical modified intent-to-treat population. Tigecycline was generally well tolerated in patients with CAP.

Comparing pharmacokinetic and pharmacodynamic profiles in female rats orally exposed to lovastatin by gavage versus diet

The objective of this study was to assess how the dosing method (i.e., gavage versus diet) affects the absorption and disposition of lovastatin, as well as its effect on two biological markers of exposure, such as serum levels of cholesterol and triglycerides. In preclinical safety studies the test agent is normally administered by gavage, but in chemoprevention efficacy studies the test agent is usually administered with the diet. Therefore, extrapolation of safety and efficacy data from laboratory animals to humans should consider the influence of the method of administration on the absorption, disposition and effect of the drug. Lovastatin, a blood cholesterol-lowering drug with a short elimination half-life in humans, was used to assess the influence of two different dosing methods on the drug pharmacokinetics and pharmacodynamics. Plasma and liver concentrations of lovastatin and its active metabolite lovastatin-Na were measured in female rats at sequential times after administration. Serum concentrations of triglycerides and cholesterol were measured at similar times and used as biomarkers of effect. Significant differences in pharmacokinetics and pharmacodynamics were observed after administration of lovastatin by the two oral dosing paradigms. In general, oral gavage resulted in higher peak and lower trough concentrations of lovastatin and lovastatin-Na in plasma and liver, lower area under the concentration–time curve of lovastatin-Na in plasma and liver, and less of an effect on the serum concentrations of triglycerides and cholesterol than the corresponding diet dosing. Although no inverse linear relationship was observed between pharmacokinetic and pharmacodynamic markers, in the case of serum cholesterol a visual trend could be observed which might have proven significant had data from a larger number of dose levels been available. As in our previous study with sulindac, this study illustrates potential limitations in trying to extrapolate from data obtained using different dosing schemes to potential safety and efficacy in humans.

Antimicrobial Spectrum and Potency of Dalbavancin Tested Against Clinical Isolates from Europe and North America (2003): Initial Results from an International Surveillance Protocol

Dalbavancin is a bactericidal dimethylaminopropyl amide glycopeptide derivative possessing an extended serum elimination half-life in humans that allows onceweekly dosing for the therapy of Gram-positive infections. Strains from this baseline surveillance protocol in North America (NA; USA and Canada) and Europe (EU, 14 countries) were sampled in 2003. A total of 7,765 Gram-positive isolates (3,695 from NA and 4,070 from EU) were tested by reference broth microdilution methods against dalbavancin and 10 comparator agents. Species were analyzed separately by resistance phenotypes such as methicillin- (oxacillin-) resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE) and penicillin- resistant Streptococcus pneumoniae. Dalbavancin and other glycopeptides were very active against staphylococci (n=4648) with dalbavancin being 16- to 32- fold more potent than vancomycin (MIC90, 0.06 versus 2 mg/L). MRSA rates were greater (31.6%) in NA than in EU (26.1%). Quinupristin/dalfopristin resistance (MIC, ≥ 2 mg/L; 0.1 - 0.5%) was documented more often in EU compared to NA. Dalbavancin (MIC50, 0.03 - 0.06 mg/L) was active against enterococci, except VanA resistance phenotypes. VRE rates were lower in EU (8.3%) then in NA (35.9%) from this resistance-enhanced enterococcal collection. Streptococci (dalbavancin MIC90, 0.016 - 0.03 mg/L) were generally most susceptible to glycopeptides (100.0%), quinupristin/dalfopristin (98.6 - 100.0%) and linezolid (100.0%); but dalbavancin was 16-fold more active than comparators. All vancomycin-susceptible enterococci and > 90% of vanB VRE had dalbavancin MIC values at ≤ 1 mg/L, but vanA VRE strains had dalbavancin MIC results ranging from 0.06 to > 8 mg/L (median MIC, ≥ 8 mg/L). Dalbavancin MIC values were not adversely influenced by geographic region or resistance phenotype (except vanA VRE). Infrequently isolated Gram-positive organisms such as Bacillus spp. (MIC90, 0.12 mg/L), Corynebacterium spp. (MIC90, 0.12 mg/L), Listeria monocytogenes (MIC90, 0.25 mg/L) and Micrococcus spp. (MIC90, 0.03 mg/L) were very susceptible to dalbavancin. In conclusion, these 2003 baseline resistance surveillance findings confirm the potent dalbavancin activity compared to several comparator agents against important Gram-positive pathogens. This high volume international survey indicates potential therapeutic roles for dalbavancin against many troublesome resistant Gram-positive phenotypes.

The Prediction of Methylmercury Elimination Half-Life in Humans using Animal Data: A Neural Network/Rough Sets Analysis

Artificial neural networks and Rough Sets methodology have been utilized to predict human pharmacokinetic elimination half-life data based on animal data training sets. Methylmercury (Hg) pharmacokinetic data was obtained from 37 literature references, which provided data on species, gender, age, weight, route of administration, dose, dose frequency, and elimination half-life based on either whole-body Hg analysis or blood Hg analysis. Data were categorized into various formats for analysis comparisons. Rough Sets methodology was utilized to identify and remove redundant independent variables. Artificial neural networks were used to produce models based on the animal data, which were in turn used to predict and compare to the human elimination half-life values. These neural network predictions were compared to allometric graphical plots of the same data. The best artificial neural network prediction was based on a "thermometer" categorical representation of the data.

Caractéristiques pharmacologiques de la rosuvastatine, un nouvel antagoniste de l’HMG-CoA réductase

Rosuvastatin is a new synthetic statin that produces a more potent and prolonged inhibition of HMG-CoA reductase than any of the other statins currently available. It is also characterised by a very low lipophilicity, which is close to that of pravastatin, and by a high hepatic selectivity. Rosuvastatin is not extensively metabolised, with little or no transformation by the different isoenzymes of cytochrome P450. It is mainly eliminated in the faeces, with an elimination half-life in humans of between 13 and 21hours. In patients with hypercholesterolaemia, rosuvastatin was associated with large dose-dependent reductions in low density lipoprotein (LDL)-cholesterol, by 50.5% at a dose of 10mg/day and up to 64.8% at a dose of 80mg. Each doubling of the dose of rosuvastatin results in an additional 4.5% decrease in blood LDL-cholesterol.In phase III studies, rosuvastatin decreased LDL-cholesterol significantly more than atorvastatin, pravastatin and simvastatin. Compared with the other statins, the decrease in triglyceride levels was similar and the increase in high density lipoprotein-cholesterol was more marked, with a significant difference in most cases. To date, there has not been an excess of adverse reactions, especially liver or muscle problems, compared with the reference statins. The safety of rosuvastatin can only be definitively established in post-marketing surveys.

薬物の臨床用量と反復投与毒性実験における無毒性量および体内動態との関連

One of the most important areas of the study of clinical pharmacology is the prediction of the clinical dose of new drugs from preclinical data . However, there are few scientific approaches to date. In this report, I therefore attempt to determine some reliable data for the prediction of the clinical dose of new drugs based on clinical data by collecting the nontoxic dose in repeated administration and the clinical dose and the elimination half -life of a variety of orally administered drugs.The present results clearly showed that, in spite of marked individual differences in the ratios of nontoxic dose and clinical dose, the distribution is unimodal with a median of 30 and 16, respectively, for rats and dogs. The elimination half-life in humans was generally longer than those in rats and dogs, and the ratios were markedly different among drugs, but the ratios were distributed in unimodality with a median of 3.01 and 1.90, respectively, for rats and dogs. There is a clear correlation between the ratio of the nontoxic dose/clinical dose and of human/rat or human/dog for the half-life . Therefore, taking into consideration of species differences in the rate of drug metabolism, I adjusted the nontoxic dose/clinical dose ratio. The new ratio of about 10 for nontoxic dose/clinical dose was obtained irrespective of rats and dogs by using the half-life .To further evaluate the validity and usefulness of the present data, it is necessary to collect data from many drugs and analyze the AUC (area under plasma concentration -time curve) and the peak plasma concentration in addition to the half -life.