Distribution by Scientific Domains

Selected Abstracts

Pharmacokinetics of Levetiracetam and Its Enantiomer (R)-,-ethyl-2-oxo-pyrrolidine acetamide in Dogs

EPILEPSIA, Issue 7 2001
Nina Isoherranen
Summary: ,Purpose: The new antiepileptic drug, levetiracetam (LEV, ucb LO59), is a chiral molecule with one asymmetric carbon atom whose anticonvulsant activity is highly enantioselective. The purpose of this study was to evaluate and compare the pharmacokinetics (PK) of LEV [(S)-,-ethyl-2-oxo-pyrrolidine acetamide] and its enantiomer (R)-,-ethyl-2-oxo-pyrrolidine acetamide (REV) after i.v. administration to dogs. This is the first time that the pharmacokinetics of both enantiomers has been evaluated. Methods: Optically pure LEV and REV were synthesized, and 20 mg/kg of individual enantiomers was administered intravenously to six dogs. Plasma and urine samples were collected until 24 h, and the concentrations of LEV and REV were determined by an enantioselective assay. The levels of 2-pyrrolidone- N -butyric acid, an acid metabolite of LEV and REV, were determined by high-performance liquid chromatography (HPLC). The data were used for PK analysis of LEV and REV. Results: LEV and REV had similar mean SD values for clearance; 1.5 0.3 ml/min/kg and volume of distribution; 0.5 0.1 L/kg. The half-life (t1/2) and mean residence time (MRT) of REV (t1/2, 4.3 0.8 h, and MRT, 6.0 1.1 h) were, however, significantly longer than those of LEV (t1/2, 3.6 0.8 h, and MRT, 5.0 1.2 h). The renal clearance and fraction excreted unchanged for LEV and REV were significantly different. Conclusions: In addition to the enantioselective pharmacodynamics, ,-ethyl-2-oxo-pyrrolidine acetamide has enantioselective PK. The enantioselectivity was observed in renal clearance. Because REV has more favorable PK in dogs than LEV, the higher antiepileptic potency of LEV is more likely due to intrinsic pharmacodynamic activity rather than to enantioselective PK. [source]

Motivational enhancement and coping skills training for cocaine abusers: effects on substance use outcomes

ADDICTION, Issue 7 2004
Damaris J. Rohsenow
Abstract Aims This clinical trial investigated effects of motivational enhancement treatment (MET) and group coping-skills training (CST) tailored for cocaine dependence. Effects of MET were hypothesized to be greater with CST and for less motivated patients. Design and interventions A 2 2 design investigated two individual sessions of MET compared to meditation,relaxation (MRT), followed by four group sessions of CST versus drug education (ED), as daily adjuncts to intensive treatment. Setting The substance abuse program provided full-day treatment with a learning-theory and 12-Step orientation. Participants Cocaine-dependent patients were recruited. Measurements Assessment included treatment retention; change in cocaine-related urge, self-efficacy, pros and cons, and motivation; substance use and problems during 12-month follow-up. Findings Of 165 patients, follow-up status is known for 90% (n = 149). Patients in MET with low initial motivation to change reported less cocaine and alcohol relapse and use days and fewer alcohol problems than MET patients with higher initial motivation. MET produced more employment improvement than MRT, with no other significant benefit for MET. Patients with higher motivation had more cocaine use and alcohol problems after MET than MRT. Group CST reduced cocaine and alcohol use during follow-up for women only and reduced alcohol relapse for men and women. Conclusions MET is more beneficial for patients with lower initial motivation than for patients with high initial motivation. CST reduced cocaine and alcohol use for women only and reduced alcohol relapses, in contrast to results with lengthier individual CST. [source]

Sources of plant-derived carbon and stability of organic matter in soil: implications for global change

Abstract Alterations in forest productivity and changes in the relative proportion of above- and belowground biomass may have nonlinear effects on soil organic matter (SOM) storage. To study the influence of plant litter inputs on SOM accumulation, the Detritus Input Removal and Transfer (DIRT) Experiment continuously alters above- and belowground plant inputs to soil by a combination of trenching, screening, and litter addition. Here, we used biogeochemical indicators [i.e., cupric oxide extractable lignin-derived phenols and suberin/cutin-derived substituted fatty acids (SFA)] to identify the dominant sources of plant biopolymers in SOM and various measures [i.e., soil density fractionation, laboratory incubation, and radiocarbon-based mean residence time (MRT)] to assess the stability of SOM in two contrasting forests within the DIRT Experiment: an aggrading deciduous forest and an old-growth coniferous forest. In the deciduous forest, removal of both above- and belowground inputs increased the total amount of SFA over threefold compared with the control, and shifted the SFA signature towards a root-dominated source. Concurrently, light fraction MRT increased by 101 years and C mineralization during incubation decreased compared with the control. Together, these data suggest that root-derived aliphatic compounds are a source of SOM with greater relative stability than leaf inputs at this site. In the coniferous forest, roots were an important source of soil lignin-derived phenols but needle-derived, rather than root-derived, aliphatic compounds were preferentially preserved in soil. Fresh wood additions elevated the amount of soil C recovered as light fraction material but also elevated mineralization during incubation compared with other DIRT treatments, suggesting that not all of the added soil C is directly stabilized. Aboveground needle litter additions, which are more N-rich than wood debris, resulted in accelerated mineralization of previously stored soil carbon. In summary, our work demonstrates that the dominant plant sources of SOM differed substantially between forest types. Furthermore, inputs to and losses from soil C pools likely will not be altered uniformly by changes in litter input rates. [source]

Sequestration and turnover of plant- and microbially derived sugars in a temperate grassland soil during 7 years exposed to elevated atmospheric pCO2

Abstract Temperate grasslands contribute about 20% to the global terrestrial carbon (C) budget with sugars contributing 10,50% to this soil C pool. Whether the observed increase of the atmospheric CO2 concentration (pCO2) leads to additional C sequestration into these ecosystems or enhanced mineralization of soil organic matter (SOM) is still unclear. Therefore, the aim of the presented study was to investigate the impact of elevated atmospheric pCO2 on C sequestration and turnover of plant- (arabinose and xylose) and microbially derived (fucose, rhamnose, galactose, mannose) sugars in soil, representing a labile SOM pool. The study was carried out at the Swiss Free Air Carbon Dioxide Enrichment (FACE) experiment near Zurich. For 7 years, Lolium perenne swards were exposed to ambient and elevated pCO2 (36 and 60 Pa, respectively). The additional CO2 in the FACE plots was depleted in 13C compared with ambient plots, so that ,new' (<7 years) C inputs could be determined by means of compound-specific stable isotope analysis (13C : 12C). Samples were fractionated into clay, silt, fine sand and coarse sand, which yielded relatively stable and labile SOM pools with different turnover rates. Total sugar sequestration into bulk soil after 7 years of exposure to elevated pCO2 was about 28% compared with the control plots. In both ambient and elevated plots, total sugar concentrations in particle size fractions increased in the order sandMRT) of the sugars were calculated according to two models revealing a few decades, mean values increasing in the order coarse sandMRT of labile (sugar) SOM under elevated pCO2 is in the same order of magnitude when compared with studies under ambient pCO2 though no direct comparison of elevated and ambient plots was possible. [source]

Pharmacokinetics of factors IX, recombinant human activated factor VII and factor XIII

Summary., There is now a volume of literature on the pharmacokinetics (PK) of coagulation factor concentrates, although the majority is on factor VIII (FVIII) and factor IX (FIX). PK of FIX and FVIII are different with FIX having a larger volume of distribution (Vdss), higher elimination clearance (CL), longer mean resident time (MRT) and longer terminal half-life (T1/2,,). Factor IX in vivo recovery (IVR) is also much shorter possibly due to reversible binding of FIX to the endothelium and possibly to platelets. There is considerable FIX PK variability between products (particularly between plasma-derived FIX and recombinant FIX), and between individuals. Important inter-individual factors leading to PK variability include age and body weight because plasma volume as a fraction of body weight decreases with increasing weight and hence age. Thus, IVR increases with body weight and hence age and is consequently lower in children than in adults. Absolute Vdss and CL increase linearly with body weight and age in children and adolescents, becoming stable in adults with more stable weight. Inter-individual variability also likely applies to other clotting factors, particularly to recombinant activated FVII (rFVIIa) but likely also to the less well studied factor XIII (FXIII). The former is known to have an extremely short T1/2,,, large Vdss, high CL, short MRT, whereas the latter has an extremely long T1/2,,, large Vdss, short CL and long MRT. Both are discussed in this article. Understanding of PK of specific clotting factors in individual patients is important in order to make decisions regarding appropriate dosage and dosage intervals to treat patients, and to allow by means of computer modelling the determination of dosage to achieve target trough level at various dosing intervals for patients undergoing prophylaxis. [source]

Estimation of mean residence times of subsurface waters using seasonal variation in deuterium excess in a small headwater catchment in Japan

Naoki Kabeya
Abstract We measured deuterium excess (d = ,D , 8,18O) in throughfall, groundwater, soil water, spring water, and stream water for 3 years in a small headwater catchment (Matsuzawa, 068 ha) in the Kiryu Experimental Watershed in Japan. The d value represents a kinetic effect produced when water evaporates. The d value of the throughfall showed a sinusoidal change (amplitude: 69, relative to Vienna standard mean ocean water (V-SMOW)) derived from seasonal changes in the source of water vapour. The amplitude of this sinusoidal change was attenuated to 13,69, V-SMOW in soil water, groundwater, spring water, and stream water. It is thought that these attenuations derive from hydrodynamic transport processes in the subsurface and mixing processes at an outflow point (stream or spring) or a well. The mean residence time (MRT) of water was estimated from d value variations using an exponential-piston flow model and a dispersion model. MRTs for soil water were 0,5 months and were not necessarily proportional to the depth. This may imply the existence of bypass flow in the soil. Groundwater in the hillslope zone had short residence times, similar to those of the soil water. For groundwater in the saturated zone near the spring outflow point, the MRTs differed between shallow and deeper groundwater; shallow groundwater had a shorter residence time (5,8 months) than deeper groundwater (more than 9 months). The MRT of stream water (8,9 months) was between that of shallow groundwater near the spring and deeper groundwater near the spring. The seasonal variation in the d value of precipitation arises from changes in isotopic water vapour composition associated with seasonal activity of the Asian monsoon mechanism. The d value is probably an effective tracer for estimating the MRT of subsurface water not only in Japan, but also in other East Asian countries influenced by the Asian monsoon. Copyright 2006 John Wiley & Sons, Ltd. [source]

MR colonography without bowel purgation for the assessment of inflammatory bowel diseases: Diagnostic accuracy and patient acceptance

Jost Langhorst MD
Abstract Background: The purpose of this pilot study was to assess the diagnostic accuracy of MR colonography (MRC) without bowel cleansing regarding its ability to quantify inflammatory bowel disease (IBD). In addition, patient acceptance was compared with conventional colonoscopy (CC). Methods: In all, 29 patients with IBD (17 ulcerative colitis; 12 Crohn's disease) were included. While CC was performed after bowel cleansing as the gold standard, MRC was based on a fecal tagging technique and performed 48,72 hours prior to CC. The presence of inflammation in each of 7 ileocolonic segments was rated for every procedure. Patients evaluated both modalities and dedicated aspects of the examination according to a 10-point-scale (1 = good, 10 = poor acceptance). Furthermore, preferences for future examinations were investigated. Results: Inflammatory segments were found by means of CC in 23 and by MRC in 14 patients. Overall sensitivity and specificity of MRC in a segment-based detection were 32% and 88%, respectively. Concerning severely inflamed segments, sensitivity increased to 53% for MRC. Overall acceptance of CC was significantly higher compared to MRC (mean value (mv) for MRT = 6.0; CC = 4.1; P = 0.003). For MRC, the placement of the rectal tube (mv = 7.3), and for CC bowel purgation (mv = 6.5), were rated as the most unpleasant. A total of 67% of patients voted for CC as the favorable tool for future examinations. Conclusions: The presented data indicate that ,fecal tagging MRC' is not suitable for an adequate quantification of inflammatory diseases of the large bowel. Furthermore, overall acceptance of endoscopic colonoscopy was superior to MRC. (Inflamm Bowel Dis 2007) [source]

Simulation of lid-driven cavity flows by parallel lattice Boltzmann method using multi-relaxation-time scheme

J.-S. Wu
Abstract Two-dimensional near-incompressible steady lid-driven cavity flows (Re = 100,7,500) are simulated using multi-relaxation-time (MRT) model in the parallel lattice Boltzmann BGK Bhatnager,Gross,Krook method (LBGK). Results are compared with those using single-relaxation-time (SRT) model in the LBGK method and previous simulation data using Navier,Stokes equations for the same flow conditions. Effects of variation of relaxation parameters in the MRT model, effects of number of the lattice points, improved computational convergence and reduced spatial oscillations of solution near geometrically singular points in the flow field using LBGK method due to MRT model are highlighted in the study. In summary, lattice Boltzmann method using MRT model introduces much less spatial oscillations near geometrical singular points, which is important for the successful simulation of higher Reynolds number flows. Copyright 2004 John Wiley & Sons, Ltd. [source]

Pharmacokinetics of oxolinic acid in gilthead sea bream, Sparus aurata L.

G Rigos
This is the first study on the pharmacokinetic parameters of oxolinic acid (OA) in gilthead sea bream, Sparus aurata L. The kinetic profile of OA was studied after a single intravascular injection (20 mg kg,1) in 100 g fish at 20 C. The distribution half-life (t1/2,) and the elimination half-life (t1/2,) of the drug were found to be short (0.51 and 12.60 h, respectively). The drug penetration from the plasma to the tissues was adequate as the apparent volume of distribution of the drug at steady-state (Vd(ss)) was found to be 2.11 L kg,1. The mean residence time (MRT) of OA was short (14.25 h) and the total clearance rate (ClT) of the drug was low (0.15 L kg,1 h,1). The bioavailability (F,%) of OA following oral administration (30 mg kg,1) was also low (14%). Maximum values were observed for muscle at 0.5 h after injection, with levels declining as with subsequent sampling. At the first two time points (0.5 and 1 h) plasma levels of OA were higher than muscle, however, the reverse was evident for subsequent samples. Following oral administration, highest muscle levels were found at 16 h and, with the exception of the 24-h sampling, muscle OA concentrations were higher than plasma at all time points. The fast elimination of OA suggests short withdrawal times with reference to human consumption of treated fish. [source]

Retention of 125I-labeled recombinant human bone morphogenetic protein-2 by biphasic calcium phosphate or a composite sponge in a rabbit posterolateral spine arthrodesis model

John Louis-Ugbo
The purpose of this study was to characterize the retention kinetics of recombinant human bone morphogenetic protein-2 (rhBMP-2) applied to two calcium-based delivery matrices. Biphasic calcium phosphate (BCP) and a composite containing BCP in an absorbable collagen sponge (BCP/ACS) were evaluated using a spinal fusion model in rabbits. rhBMP-2 labeled with radioactive iodine (125I) was used as a tracer to assess in vivo retention of rhBMP-2 in the presence of these materials (nine animals per material studied). Over a 36 day study period, animals were assessed for the following: percent administered dose retained at the implant site as measured by scintigraphic imaging (counting) with a gamma camera (all animals), radiography of the implant site (all animals), radioactivity in blood and plasma (all animals), and radioactivity in the urine and feces (three animals for each material). Radioactivity data were corrected for the decay of 125I and the attenuation between the implant in vivo and the gamma camera. Differences observed between the two materials for the area under the retention vs. time profile (AUC; 988%day for BCP vs. 1070%day for BCP/ACS, p = 0.57) and the mean residence time (MRT; 10.2 days for BCP vs. 7.6 days for BCP/ACS, p = 0.06) were not statistically significant. Initial retention/incorporation of rhBMP-2 was slightly higher for rhBMP-2/BCP/ACS than for rhBMP-2/BCP (96.8% vs. 86.0%, p lt; 0.05). Animals receiving rhBMP-2/BCP showed a longer terminal retention half-life (t1/2) than did those receiving rhBMP-2/BCP/ACS (7.5 vs. 4.5 days, p < 0.05). The urinary radioactivity recovery data supported the data obtained by scintigraphy. Over the 36 day collection period, essentially complete recovery of radioactivity (dose) in urine was observed for rhBMP-2/BCP and rhBMP-2/BCP/ACS and the majority of the radioactivity (approximately 95%) was soluble in trichloroacetic acid, suggesting extensive catabolism of rhBMP-2 before renal excretion. Fecal recovery of radioactivity was low, approximately 2,3%. In conclusion, rhBMP-2 was retained at the implant site when delivered with either BCP or BCP/ACS based on mean residence time and area under the retention curve vs. time profile. Use of these matrices resulted in detectable rhBMP-2 levels at the surgical site for over a week in contrast to data reported with several other matrices that lasted less time. Systemic catabolism and elimination of the rhBMP-2 was extensive and systemic presence of the protein was negligible. 2002 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved. [source]

Tissue distribution of antihypertensive dipeptide, Val-Tyr, after its single oral administration to spontaneously hypertensive rats

Toshiro Matsui
Abstract The distribution of an antihypertensive dipeptide, Val-Tyr (VY), in the tissues of spontaneously hypertensive rats (SHR) was investigated in this study. A single oral administration of VY (10 mg/kg) to 18-week-old SHR resulted in a prolonged reduction of systolic blood pressure (SBP) up to 9 h (SBP0h198.0 3.6 mmHg; SBP9h 154.6 3.5 mmHg). As a result of VY determination, a roughly 10-fold higher increment of plasma VY level was observed at 1 h than that at 0 h, whereas thereafter the level declined rapidly. In tissues, VY was widely accumulated in the kidney, lung, heart, mesenteric artery and abdominal aorta with the area under the curve over 9 h of more than 40 pmol h/g tissue; of these a higher VY level was observed in the kidney and lung. In addition, a mean resident time (MRT) for each tissue (>5 h except for liver) revealed that VY preferably accumulated in the tissues rather than in the plasma (MRT 3.8 h). Significant reductions of tissue angiotensin I-converting enzyme activity and angiotensin II level were found in the abdominal aorta as well as in the kidney, suggesting that these organs could be a target site associated with the antihypertensive action of VY. Copyright 2004 European Peptide Society and John Wiley & Sons, Ltd. [source]

Volume of distribution at steady state for a linear pharmacokinetic system with peripheral elimination

Leonid M. Berezhkovskiy
Abstract The problem of finding the steady-state volume of distribution Vss for a linear pharmacokinetic system with peripheral drug elimination is considered. A commonly used equation Vss,=,(D/AUC)*MRT is applicable only for the systems with central (plasma) drug elimination. The following equation, Vss,=,(D/AUC)*MRTint, was obtained, where AUC is the commonly calculated area under the time curve of the total drug concentration in plasma after intravenous (iv) administration of bolus drug dose, D, and MRTint is the intrinsic mean residence time, which is the average time the drug spends in the body (system) after entering the systemic circulation (plasma). The value of MRTint cannot be found from a drug plasma concentration profile after an iv bolus drug input if a peripheral drug exit occurs. The obtained equation does not contain the assumption of an immediate equilibrium of protein and tissue binding in plasma and organs, and thus incorporates the rates of all possible reactions. If drug exits the system only through central compartment (plasma) and there is an instant equilibrium between bound and unbound drug fractions in plasma, then MRTint becomes equal to MRT,=,AUMC/AUC, which is calculated using the time course of the total drug concentration in plasma after an iv bolus injection. Thus, the obtained equation coincides with the traditional one, Vss,=,(D/AUC)*MRT, if the assumptions for validity of this equation are met. Experimental methods for determining the steady-state volume of distribution and MRTint, as well as the problem of determining whether peripheral drug elimination occurs, are considered. The equation for calculation of the tissue,plasma partition coefficient with the account of peripheral elimination is obtained. The difference between traditionally calculated Vss,=,(D/AUC)*MRT and the true value given by (D/AUC)*MRTint is discussed. 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:1628,1640, 2004 [source]

Contradistinction between doxorubicin and epirubicin: in-vivo metabolism, pharmacokinetics and toxicodynamics after single- and multiple-dosing in rats

Sandhya Ramanathan-Girish
There is compelling in-vitro evidence that the evaluation of doxorubicin or epirubicin pharmacokinetics based solely on plasma concentration may not fully elucidate the differences between the two drugs. Both compounds bind to erythrocytes and their different binding to haemoglobin may influence their disposition in the body. The purpose of the present study was to compare the pharmacokinetics and metabolism of doxorubicin and epirubicin based on the plasma concentration, amount associated with blood cells and simultaneous monitoring of biliary and urinary elimination of unchanged drug and metabolites after single- and multiple-dose injections. The level of sarcoplasmic reticulum Ca2+ ATPase in the heart was also measured as a biomarker of cardiotoxicity. Male Sprague-Dawley rats were treated in a parallel design with doxorubicin or epirubicin on a multiple-dosing basis (4 mg kg,1 per week) or as a single dose injection (20 mg kg,1). Blood, urine and bile samples were collected periodically after each dose in the multiple-dosing regimen and the single dose injection, and at the end of each experiment the hearts were removed. The concentrations of each drug in plasma, blood cells, bile and urine samples were determined, and by simultaneous curve-fitting of plasma and bile data according to compartmental analysis, the pharmacokinetic parameters and constants were estimated. The concentration of drug associated with blood cells was analysed according to non-compartmental analysis. The bile and urine samples provided the in-vivo metabolic data. The level of Ca2+ ATPase in the heart, determined by Western blotting, was used as the toxicodynamic parameter to correlate with the kinetic data. Multiple-dosing regimens reduced the total plasma clearance and increased the area under the plasma concentration-time curve of both drugs. Also, the area under the curve of doxorubicin associated with blood cells increased with the weekly doses, and the related mean residence time (MRT) and apparent volume of distribution (Vdss) were steadily reduced. In contrast to doxorubicin, the MRT and Vdss of epirubicin increased significantly. Metabolic data indicated significant differences in the level of alcohol and aglycones metabolites. Doxorubicinol and doxorubicin aglycones were significantly greater than epirubicinol and epirubicin aglycone, whereas epirubicinol aglycone was greater than doxorubicinol aglycone. The area under the blood cells concentration-time curve correlated linearly with the changes in Ca2+ ATPase net intensity. The results of this study demonstrate the importance of the kinetics of epirubicin and doxorubicin associated with blood cells. Linear correlation between the reduction of net intensity of the biomarker with the area under the curve of doxorubicin associated with blood cells confirms that the differences between the two compounds are related to their interaction with blood cells. This observation together with the observed differences in metabolism may underline a significant role for blood cells in distribution and metabolism of doxorubicin and epirubicin. [source]

The Effect of Different Dosing Schedules of UCN-01 on its Pharmacokinetics and Cardiohaemodynamics in Dogs

7-Hydroxy-staurosporine (UCN-01) is now under development as a novel anticancer drug. In clinical studies, different infusion schedules are being investigated in the USA and Japan. To examine the effect of different infusion schedules on the pharmacokinetics and cardiohaemodynamics of UCN-01, dogs were treated with UCN-01 as either a 3-h or a 24-h constant intravenous infusion. Blood pressure and heart rate, together with UCN-01 concentrations during and after infusion, were monitored. To analyse the relationship between the pharmacokinetics and cardiohaemodynamics of UCN-01, the plasma concentration of UCN-01 at the end of infusion (Cend), the area under the plasma concentration versus time curves (AUC0-,) and the mean residence time (MRT) were used. As indices of cardiohaemodynamic changes, the area under decreasing systolic blood pressure and increasing heart rate versus time curves (dAUCpressure and AUCheart rate) were calculated by the trapezoidal method. For the 3-h (0.22 and 0.65 mgkg,1) and 24-h infusion (0.81 to 6.48 mgkg,1), systolic and diastolic blood pressures fell after or during infusions, accompanied by a dose-dependent increase in heart rate for both infusions. During both infusion schedules, the plasma concentrations of UCN-01 gradually increased and Cend showed a dose-proportional increase. After that, UCN-01 was eliminated bi-exponentially with an elimination half-life of 5.14 1.12 to 8.32 1.80 h. The total clearance (CLtotal) ranged from 0.383 to 0.666 0.149L h,1kg,1. There was no significant difference in these parameters among the doses in each infusion schedule, indicating that UCN-01 has a linear pharmacokinetic profile over the dose range examined for each infusion, and there were also no significant differences between the 3-h and 24-h infusion except for MRT. The pharmacokinetic parameters of Cend, AUC0-, and slope0-3h exhibited a degree of correlation with the AUCheart rate in the 3-h infusion and correlated significantly with the dAUCpressure in the 24-h infusion. The MRT did not correlate with cardiohaemodynamic changes during either infusion. In conclusion, the pharmacokinetic profile of UCN-01 after the shorter infusion is similar to that after the longer one. However, a longer dosing period of UCN-01 increased the residence time in comparison with the shorter infusion. This may be due to the effect on the circulatory function in dogs. [source]

SIAM-Like Phenomenon Caused by Low Doses of Alcohol

ALCOHOLISM, Issue 2010
Akiko Shimamoto
Background:, Swift increase in alcohol metabolism (SIAM) is usually evoked by a large dose of ethanol, which is often demonstrated by an abrupt increase in oxygen uptake. SIAM was induced by low doses of ethanol and evaluated by pharmacokinetic analyses of ethanol and its metabolites. Methods:, Rabbits were initially administered 1.0 g/kg of ethanol solution and the same dose was given to the bolus group 6 hours after the first injection. The infusion group was administered 0.25 g/kg/h of ethanol 2 hours after the first injection. Blood concentrations of ethanol, acetaldehyde, and acetate were then determined and comparisons were made using pharmacokinetic parameters. Results:, A significantly higher ethanol elimination rate was observed after re-administration of ethanol to the bolus group. Other pharmacokinetic parameters were unaffected. The concentration at steady state (Css) for the infusion group was stable. A significantly higher level of mean residence time (MRT) in blood acetaldehyde was observed for the bolus group, whereas no MRT changes were observed for the infusion group. A significantly higher level of blood acetate Css was observed after re-administration of ethanol to the bolus group, following the changes in area under concentration and MRT. No Css changes were observed for the infusion group. The Css of acetate at stage 2 was significantly higher for the bolus group, compared to the infusion group. Conclusion:, Low doses of ethanol enhanced alcohol metabolism in rabbits, according to a pharmacokinetic analysis of circulating ethanol concentrations. Simultaneous analyses of its metabolites followed the kinetic of ethanol. [source]

Enantioselective analysis of mirtazapine, demethylmirtazapine and 8-hydroxy mirtazapine in human urine after solid-phase microextraction

Fernando Jos Malagueo de Santana
Abstract A selective and reproducible off-line solid-phase microextraction procedure was developed for the simultaneous enantioselective determination of mirtazapine (MRT), demethylmirtazapine and 8-hydroxymirtazapine in human urine. CE was used for optimization of the extraction procedure whereas LC-MS was used for method validation and application. The influence of important factors in the solid-phase microextraction efficiency is discussed, such as the fiber coatings, extraction time, pH, ionic strength, temperature and desorption time. Before extraction, human urine samples were submitted to enzymatic hydrolysis at 37C for 16,h. Then, the enzyme was precipitated with trichloroacetic acid and the pH was adjusted to 8 with 1,mol/L pH 11 phosphate buffer solution. In the extraction, the analytes were transferred from the aqueous solution to the polydimethylsiloxane-divinylbenzene fiber coating and then desorbed in methanol. The mean recoveries were 5.4, 1.7 and 1.0% for MRT, demethylmirtazapine and 8-hydroxymirtazapine enantiomers, respectively. The method was linear over the concentration range of 62,1250,ng/mL. The within-day and between-day assay precision and accuracy were lower than 15%. The method was successfully employed in a preliminary cumulative urinary excretion study after administration of racemic MRT to a healthy volunteer. [source]

The disposition of free and niosomally encapsulated Rac-flurbiprofen in dairy bovines

Confalonieri, E. O., Soraci, A. L., Becaluba, M., Denzoin, L., Rodriguez, E., Riccio, B., Tapia, O. The disposition of free and niosomally encapsulated Rac-flurbiprofen in dairy bovines. J. vet. Pharmacol. Therap. 33, 9,14. Pharmacokinetic parameters were established for flurbiprofen (FBP) after intravenous (i.v.) administration (0.5 mg/kg) of niosomal and nonniosomal formulations in dairy cattle. Niosomes of FBP showed a drug loading of 92.0 0.7% and the intravenous administration of the FBP niosomes to dairy cattle did not produce any immunological reaction associated to niosomal components. Niosomal FBP was slowly eliminated from plasma and mean residual time (MRT) and AUC0,t and t 1/2 values were significantly higher than those for non niosomal FBP formulations. The results presented in this study indicate that the long circulation of FBP niosomes offers a potential application for improving the pharmacokinetic parameters of short half-life drugs for clinical use. Niosomes offer new promising perspectives of drug delivery modules in bovine therapeutics. [source]

Kinetics and residues after intraperitoneal procaine penicillin G administration in lactating dairy cows

This paper describes the pharmacokinetic profile of procaine penicillin G after intraperitoneal (IP) administration in eight lactating dairy cows. Procaine pencillin G (PPG, 21 000 IU/kg) was deposited into the abdominal cavity of each cow following an incision in the right paralumbar fossa. Blood and milk samples were taken over the following 10 days, at which point the cows were euthanized. Plasma, milk, muscle, liver, and kidney penicillin concentrations were determined by HPLC, with a limit of quantification of 5 ng/mL for plasma and milk and 40 ng/g for tissue samples. A noncompartmental method was used to analyze plasma kinetics. The mean pharmacokinetic parameters (SD) were: Cmax, 5.5 2.6 ,g/mL; Tmax, 0.75 0.27 h; AUC0-,, 10.8 4.9 ,gh/mL; MRT, 2.2 0.9 h. All milk from treated cows contained detectable penicillin residues for a minimum of three milkings (31 h) and maximum of five milkings (52 h) after administration. Concentrations of penicillin in all muscle, liver, and kidney samples taken 10 days postadministration were below the limit of quantification. Necropsy examinations revealed foci of hemorrhage on the rumenal omentum of most cows but peritonitis was not observed. Systemic inflammation as determined by change in leukogram or plasma fibrinogen was noted in one cow. The results of this study demonstrate that IP PPG is absorbed and eliminated rapidly in lactating dairy cows. [source]

Preclinical pharmacology of robenacoxib: a novel selective inhibitor of cyclooxygenase-2

This manuscript reports the results of preclinical studies in the rat with robenacoxib, a novel selective cyclooxygenase (COX)-2 inhibitor. Robenacoxib selectively inhibited COX-2 in vitro as evidenced from COX-1:COX-2 IC50 ratios of 27:1 in purified enzyme preparations and >967:1 in isolated cell assays. Binding to COX-1 was rapid and readily reversible (dissociation t1/2 << 1 min), whilst COX-2 binding was slowly reversible (t1/2 = 25 min). In vivo, robenacoxib inhibited PGE2 production (an index of COX-2 inhibition) in lipopolysaccharide (LPS)-stimulated air pouches (ID50 0.3 mg/kg) and for at least 24 h in zymosan-induced inflammatory exudate (at 2 mg/kg). Robenacoxib was COX-1 sparing, as it inhibited serum TxB2 synthesis ex vivo (an index of COX-1 inhibition) only at very high doses (100 mg/kg but not at 2,30 mg/kg). Robenacoxib inhibited carrageenan-induced paw oedema (ID50 0.40,0.48 mg/kg), LPS-induced fever (ID50 1.1 mg/kg) and Randall,Selitto pain (10 mg/kg). Robenacoxib was highly bound to plasma protein (99.9% at 50 ng/mL in vitro). After intravenous dosing, clearance was 2.4 mL/min/kg and volume of distribution at steady-state was 306 mL/kg. Robenacoxib was preferentially distributed into inflammatory exudate; the AUC for exudate was 2.9 times higher than for blood and the MRT in exudate (15.9 h) was three times longer than in blood (5.3 h). Robenacoxib produced significantly less gastric ulceration and intestinal permeability as compared with the reference nonsteroidal anti-inflammatory drug (NSAID), diclofenac, and did not inhibit PGE2 or 6-keto PGF1, concentrations in the stomach and ileum at 30 mg/kg. Robenacoxib also had no relevant effects on kidney function at 30 mg/kg. In summary, results of preclinical studies in rats studies suggest that robenacoxib has an attractive pharmacological profile for potential use in the intended target species, cats and dogs. [source]

Pharmacokinetics of erythromycin after the administration of intravenous and various oral dosage forms to dogs

The purpose of this study was to describe and compare the pharmacokinetic properties of different formulations of erythromycin in dogs. Erythromycin was administered as lactobionate (10 mg/kg, IV), estolate tablets (25 mg/kg p.o.) and ethylsuccinate tablets or suspension (20 mg/kg p.o.). After intravenous (i.v.) administration, the principal pharmacokinetic parameters were (mean SD): AUC(0,,) 4.20 1.66 ,gh/mL; Cmax 6.64 1.38 ,g/mL; Vz 4.80 0.91 L/kg; Clt 2.64 0.84 L/hkg; t, 1.35 0.40 h and MRT 1.50 0.47 h. After the administration of estolate tablets and ethylsuccinate suspension, the principal pharmacokinetic parameters were (mean SD): Cmax, 0.30 0.17 and 0.17 0.09 ,g/mL; tmax, 1.75 0.76 and 0.69 0.30 h; t,, 2.92 0.79 and 1.53 1.28 h and MRT, 5.10 1.12 and 2.56 1.77 h, respectively. The administration of erythromycin ethylsuccinate tablets did not produce measurable serum concentrations. Only the i.v. administration rendered serum concentrations above MIC90 = 0.5 ,g/mL for 2 h. However, these results should be cautiously interpreted as tissue erythromycin concentrations have not been measured in this study and, it is recognized that they can reach much higher concentrations than in blood, correlating better with clinical efficacy. [source]

Pharmacokinetics of oxytetracycline in the American horseshoe crab, Limulus polyphemus

The American horseshoe crab, Limulus polyphemus, is regularly cultured and maintained in research laboratories and public aquaria. Rising concerns over the health of these captive animals makes the diagnosis and treatment of pathological conditions in L. polyphemus essential. This study investigated the kinetics of oxytetracyline following either intravascular or oral dosing. Oxytetracylcine is a broad-spectrum antibiotic used in the treatment of various bacterial diseases of aquatic animals. A noncompartmental model was developed to describe the pharmacokinetics of oxytetracycline (OTC) in the horseshoe crab. The following parameters were determined for a single intravascular bolus of 25 mg/kg OTC: AUC = 9524.60 ,gh/mL, MRT = 443.65 h, Clb = 0.044 mL/min/kg, Vd(ss) = 1.164 L/kg, t1/2 = 128.3 h, Cmax = 55.90 ,g/mL, Cave = 27.39 ,g/mL. Following a single oral bolus of 25 mg/kg, these parameters were calculated: AUC = 5861.81 ,gh/mL, MRT = 395.89 h, Clb = 0.071 mL/min/kg, Vd(ss) = 1.688 L/kg, t1/2 = 210.0 h, Cmax = 7.83 ,g/mL, Cave = 2.89 ,g/mL, F = 61.56%. [source]

Pharmacokinetics and bioavailability of imidocarb dipropionate in swine

A two-way crossover study was performed in eight healthy young pigs to determine the pharmacokinetics of imidocarb dipropionate (IMDP) following intravenous (2 mg/kg b.w.) and intramuscular (2 mg/kg b.w.) administrations. Each animal received one intravenous and one intramuscular injection with a 30-day washout period between the two-treatments. Plasma concentrations were measured by high-performance liquid chromatography (HPLC) assay with UV detector at regular intervals for up to 24 h post-injection. Intravenous plasma concentration profiles best fit a three-compartmental model yielding a mean system clearance (Cl(s)) of 558 mL/kgh and a mean half-life of 13.91 h. Mean imidocarb AUC(0,,) (,gh/mL), Vc (L/kg), Vd(area)(L/kg) and MRT(0-t) (h) values were 3.58, 0.11, 14.36 and 1.46, respectively. Compartmental modeling of imidocarb, after intramuscular administration produced best fit for two-compartmental model yielding mean K, (h,1), Cmax (,g/mL), tmax (h), and bioavailability (%) of 3.89, 2.02, 0.54, and 86.57 for the 2 mg/kg dose level. The present studies showed that IMDP was rapidly absorbed, widely distributed, and slowly eliminated. No adverse effects were observed in any of the pigs after i.v. and i.m. administrations of IMDP. The favorable PK behavior, such as the long half-life, acceptable bioavailability indicated that it is likely to be effective in pigs. [source]

Pharmacokinetic and pharmacodynamic properties of metomidate in turbot (Scophthalmus maximus) and halibut (Hippoglossus hippoglossus)

M. K. Hansen
Metomidate was administered to halibut (Hippoglossus hippoglossus) and turbot (Scophthalmus maximus) intravenously at a dose of 3 mg/kg bodyweight, as a bath treatment at a dose of 9 mg/L water for 5 min to study the disposition of metomidate, and as bath treatment (9 mg/L) for 10 min to study the absorption and effect of metomidate on respiration and balance/motor control. Additionally, turbot were given metomidate orally at a dose of 7 mg/kg. The studies were performed in seawater at a temperature of 10.3 0.4 C (halibut) and 18.0 0.3 C (turbot). Pharmacokinetic modeling of the data showed that metomidate had shorter elimination half-life and higher plasma concentrations in turbot compared with halibut, both species displaying a rapid uptake, distribution and excretion. Following intravenous administration, the volumes of distribution at steady state (Vd(ss)) were 0.21 L/kg (halibut) and 0.44 L/kg (turbot). Plasma clearances (Cl) were 0.099 L/hkg in halibut and 0.26 L/hkg in turbot and the elimination half-lives (t,z) were calculated to be 5.8 h and 2.2 h in halibut and turbot, respectively. Mean residence times (MRT) were 2.2 h in halibut and 1.7 h in turbot. Following oral administration, the t,z was 3.5 h in turbot. The maximum plasma concentration (Cmax) was 7.8 mg/L in turbot 1 h after administration. The oral bioavailability (F) was calculated to 100% in turbot. Following 5 min bath the maximum plasma concentrations (Cmax), which were observed immediately after end of the bath, were 9.5 mg/L and 13.3 mg/L in halibut and turbot, respectively. Metomidate rapidly immobilized the fish, with respiratory depression, reduced heart rate, and loss of balance/motor control within 1 min (mean). Recovery was slow, with resumed balance/motor control after 26.4 min. Opercular respiration movements were resumed more rapidly with a recorded mean of 1.7 min. Oral administration was demonstrated to be a way of immobilizing fish, for example in large aquariums, without exposing them to unwanted stress. [source]

Relative oral bioavailability of microgranulated amoxicillin in pigs

P. Anfossi
A new microgranulated formulation of amoxicillin trihydrate for in-feed medication was developed using a lipogelled matrix. Its relative bioavailability was compared with powdered drug in pigs and an assessment was made to determine whether therapeutic concentrations were achieved. Microgranules containing 10% (MICR10) and 30% (MICR30) amoxicillin and free amoxicillin trihydrate powder (reference, AMX) were administered at dosages of 50 mg of amoxicillin/kg b.w. using a three-way-crossover design. Amoxicillin analysis in serum was performed by a sensitive high performance liquid chromatography (HPLC) method with fluorometric detection, using an extraction procedure already described for edible tissues of fish and adapted and validated for pig serum. The oral bioavailability of both microgranulated formulations was higher than that of the reference formulation [relative bioavailability (F): 153.9 58.2% for MICR10; 126.2 70.5% for MICR30] and the area under the concentration,time curve (AUC) values of MICR10 and AMX formulations were significantly different (P < 0.05). Differences between the mean maximum concentration (Cmax), time of Cmax (tmax) and mean residence time (MRT) of the drug formulations were not significant. Microgranulated amoxicillin is suitable for in-feed administration to pigs and, because of its higher oral bioavailability compared with the powdered compound, it may be more effective for the treatment of susceptible infections. [source]

Plasma achiral and chiral pharmacokinetic behaviour of intravenous oxfendazole co-administered with piperonyl butoxide in sheep

Co-administration of piperonyl butoxide (PB) potentiates fenbendazole (FBZ) in small ruminants. The resultant increase in bioavailability of FBZ and its metabolite oxfendazole (OFZ) has important implications for the efficacy of these drugs against benzimidazole (BZD)-resistant strains of Teladorsagia circumcincta. This study evaluated the racemic (achiral) and enantiomeric (chiral) plasma disposition kinetics of OFZ and its metabolites after the co-administration of PB and OFZ in sheep. Six 6,8-month-old, parasite-free, female Dorset sheep (30,40 kg) were used in a two-phase crossover experiment. In phase I, three sheep received 30 mg/kg PB orally, followed by a single intravenous (i.v.) injection of OFZ at 5 mg/kg. The other three animals were treated similarly except that 5 mL of water replaced PB. In phase 2, treatments for the two groups were reversed and were given 14 days after the initiation of phase I. Three analytes OFZ, FBZ and fenbendazole sulphone (FBZSO2) were recovered in plasma up to 48 h post-treatment in both experimental groups. Achiral and chiral pharmacokinetic (PK) profiles for OFZ, after the co-administration of PB, were characterized by a significantly greater area under the concentration,time curve (AUC) and a longer mean residence time (MRT). Chiral OFZ distribution ratios were comparable in both treatment groups. Piperonyl butoxide treatment markedly influenced the plasma PK profiles for FBZ and FBZSO2 following OFZ administration. Production of FBZ was enhanced as reflected by increased (> 60%) AUC, delayed Tmax and a significantly delayed (> 45%) elimination (tel). Although AUC values for FBZSO2 were not significantly different between groups, this metabolite was depleted more slowly from plasma (tel > 60% and MRT > 42%) following PB treatment. This study demonstrated that PB co-administration is associated with an inhibition of OFZ biotransformation, as evidenced by the significantly higher plasma concentrations of OFZ and FBZ, and this could have important implications in terms of antiparasite therapy against BZD-resistant parasite strains. [source]

Pharmacokinetics of sarafloxacin in pigs and broilers following intravenous, intramuscular, and oral single-dose applications

H. Z. Ding
Pharmacokinetics of sarafloxacin, a fluoroquinolone antibiotic, was determined in pigs and broilers after intravenous (i.v.), intramuscular (i.m.), or oral (p.o.) administration at a single dose of 5 (pigs) or 10 mg/kg (broilers). Plasma concentration profiles were analysed by a noncompartmental pharmacokinetic method. Following i.v., i.m. and p.o. doses, the elimination half-lives (t1/2,) were 3.37 0.46, 4.66 1.34, 7.20 1.92 (pigs) and 2.53 0.82, 6.81 2.04, 3.89 1.19 h (broilers), respectively. After i.m. and p.o. doses, bioavailabilities (F) were 81.8 9.8 and 42.6 8.2% (pigs) and 72.1 8.1 and 59.6 13.8% (broilers), respectively. Steady-state distribution volumes (Vd(ss)) of 1.92 0.27 and 3.40 1.26 L/kg and total body clearances (ClB) of 0.51 0.03 and 1.20 0.20 L/kg/h were determined in pigs and broilers, respectively. Areas under the curve (AUC), mean residence times (MRT), and mean absorption times (MAT) were also determined. Sarafloxacin was demonstrated to be more rapidly absorbed, more extensively distributed, and more quickly eliminated in broilers than in pigs. Based on the single-dose pharmacokinetic parameters determined, multiple dosage regimens were recommended as: a dosage of 10 mg/kg given intramuscularly every 12 h in pigs, or administered orally every 8 h in broilers, can maintain effective plasma concentrations with bacteria infections, in which MIC90 are <0.25 ,g/mL. [source]

Plasma pharmacokinetics of warfarin enantiomers in cats

The purpose of this study was to determine the dispositions of S-warfarin and R-warfarin in normal cats following intravenous and oral administrations of racemic warfarin. Citrated blood samples were collected from 10 cats prior to and at times 5, 15, and 30 min, 1, 2, 3, 4, 5, 6, 12, 24, 36, 48, 72, 96, and 120 h following a single intravenous bolus of 0.5 mg/kg of racemic warfarin. After a 21-day washout period, samples were then similarly collected in three groups of four cats for 120 h following oral administration of 0.1, 0.25, and 0.5 mg/kg racemic warfarin. S-warfarin and R-warfarin were detected using a high-performance liquid chromatography assay validated for cat plasma. Drug concentration,time curves were subjected to non-compartmental analysis. Median pharmacokinetic parameters associated with the intravenous administration of 0.5 mg/kg racemic warfarin were as follows: t1/2 (S:28.2, R:18.3 h), area under the plasma concentration,time curve (AUC; S:33.0, R:24.6 h*,g/mL), area under the moment curve (AUMC; S:1889, R:527.8 h*h*,g/mL), and mean residence time (MRT; S:38.7, R:20.9 h). For each parameter, S-warfarin was significantly different from R-warfarin (P<0.05). Warfarin was absorbed rapidly after oral administration, and the dosage did not affect the time to maximum concentration (S:0.87, R:0.75 h). Oral dosage significantly influenced maximum plasma concentration (ng/mL, S:1267, R:1355 at 0.5 mg/kg; S:614.9, R:679.4 at 0.25 mg/kg; S:250.5, R:367.6 at 0.1 mg/kg), AUC (h*,g/mL, S:45.12, R:30.91 at 0.5 mg/kg; S:22.98:, R:18.99 at 0.25 mg/kg; S:3.922, R:3.570 at 0.1 mg/kg) and AUMC (h*h*,g/mL, S:2135, R:1062 at 0.5 mg/kg; S:943.1, R:599.9 at 0.25 mg/kg; S:132.2, R:59.03 at 0.1 mg/kg), but not t1/2 (S:23.5, R:11.6 h) nor MRT (S:26.3, R:13.5 h). Both warfarin enantiomers were highly (>96.5%) protein-bound. Quantitation of the warfarin content in commercially available tablets indicated an unequal distribution of the drug throughout the tablet. [source]

An automated method for nonparametric kinetic analysis of clinical DCE-MRI data: Application to glioblastoma treated with bevacizumab

Gregory Z. Ferl
Abstract Here, we describe an automated nonparametric method for evaluating gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA) kinetics, based on dynamic contrast-enhanced,MRI scans of glioblastoma patients taken before and after treatment with bevacizumab; no specific model or equation structure is assumed or used. Tumor and venous blood concentration-time profiles are smoothed, using a robust algorithm that removes artifacts due to patient motion, and then deconvolved, yielding an impulse response function. In addition to smoothing, robustness of the deconvolution operation is assured by excluding data that occur prior to the plasma peak; an exhaustive analysis was performed to demonstrate that exclusion of the prepeak plasma data does not significantly affect results. All analysis steps are executed by a single R script that requires blood and tumor curves as the sole input. Statistical moment analysis of the Impulse response function yields the area under the curve (AUC) and mean residence time (MRT). Comparison of deconvolution results to fitted Tofts model parameters suggests that and AUC of the Impulse response function closely approximate fractional clearance from plasma to tissue (Ktrans) and fractional interstitial volume (ve) . Intervisit variability is shown to be comparable when using the deconvolution method (11% [] and 13%[AUC]) compared to the Tofts model (14%[Ktrans] and 24%[ve]). AUC and both exhibit a statistically significant decrease (P < 0.005) 1 day after administration of bevacizumab. Magn Reson Med 63:1366,1375, 2010. 2010 Wiley-Liss, Inc. [source]

Dynamic contrast-enhanced MRI using Gd-DTPA: Interindividual variability of the arterial input function and consequences for the assessment of kinetics in tumors ,

Ruediger E. Port
Abstract Gd-DTPA kinetics in arterial blood was investigated by dynamic MRI in 47 patients with malignant and benign mammary tumors. Signal enhancement was monitored for 10 min after the beginning of a 1-min infusion of 0.1 mmol/kg Gd-DTPA. Kinetics in blood was biexponential with median half-lives of 21 sec and 11.1 min, respectively. Peak signal enhancement and the area under the signal enhancement,time curve varied 2.5- and 3.7-fold between patients. The shortest mean residence time in one of up to three tumor compartments, MRT*, was estimated using either the individual (reference) or a mean population (surrogate) arterial input function (AIF). MRT* (reference estimate) was 1.0 (0,1.5), 1.9 (1.5,2.3), and 2.5 (2.3,2.8) min in carcinomas, fibroadenomas, and mastopathies, respectively (median and interquartile distance). Surrogate estimates were unbiased but differed from the reference estimates 1.5-fold or more in 23% of cases. AIFs should be monitored individually if accurate estimates of individual MRT* are desired. Magn Reson Med 45:1030,1038, 2001. 2001 Wiley-Liss, Inc. [source]

Extrarenal rhabdoid tumors of soft tissue: Clinicopathological and molecular genetic review and distinction from other soft-tissue sarcomas with rhabdoid features

Yoshinao Oda
Malignant rhabdoid tumor (MRT) of the soft tissue is a rare and highly aggressive tumor that occurs in infancy or childhood. It predominantly involves a deep axial location such as the neck or paraspinal region. Microscopically, the tumor is composed of a diffuse proliferation of rounded or polygonal cells with eccentric nuclei, prominent nucleoli and glassy eosinophilic cytoplasm containing hyaline-like inclusion bodies, arranged in sheets and nests. These characteristic ,rhabdoid cells' are also present in certain soft-tissue sarcomas such as synovial sarcoma, extraskeletal myxoid chondrosarcoma and leiomyosarcoma. The existence of rhabdoid cells in these other sarcomas is correlated with a worse prognosis for the patients. Cytogenetic and molecular analyses have shown abnormalities in the long arm of chromosome 22 and alteration of the hSNF5/INI1 (SMARCB1) gene in renal, extrarenal and intracranial MRT. This gene alteration has been considered to be a specific molecular event in MRT, but a recent study has also demonstrated frequent alteration of this gene in proximal-type epithelioid sarcoma (ES). Both MRT of soft tissue and proximal-type ES show immunoreactivity for vimentin, cytokeratin and epithelial membrane antigen. The tumor cells of proximal-type ES are also occasionally positive for CD34 and ,-catenin, whereas MRT of soft tissue has no immunoreaction for these markers. Detailed clinicopathological and immunohistochemical evaluations are necessary to distinguish MRT of soft tissue from proximal-type ES, because these tumors demonstrated a similar morphology and the same gene alteration. [source]