Voriconazole pharmacokinetics in liver transplant recipients.

The objective of this study was to evaluate the pharmacokinetics of voriconazole and the potential correlations between pharmacokinetic parameters and patient variables in liver transplant patients on a fixed-dose prophylactic regimen. Multiple blood samples were collected within one dosing interval from 15 patients who were initiated on a prophylactic regimen of voriconazole at 200 mg enterally (tablets) twice daily starting immediately posttransplant. Voriconazole plasma concentrations were measured using high-pressure liquid chromatography (HPLC). Noncompartmental pharmacokinetic analysis was performed to estimate pharmacokinetic parameters. The mean apparent systemic clearance over bioavailability (CL/F), apparent steady-state volume of distribution over bioavailability (Vss/F), and half-life (t1/2) were 5.8+/-5.5 liters/h, 94.5+/-54.9 liters, and 15.7+/-7.0 h, respectively. There was a good correlation between the area under the concentration-time curve from 0 h to infinity (AUC0-infinity) and trough voriconazole plasma concentrations. t1/2, maximum drug concentration in plasma (Cmax), trough level, AUC0-infinity, area under the first moment of the concentration-time curve from 0 h to infinity (AUMC0-infinity), and mean residence time from 0 h to infinity (MRT0-infinity) were significantly correlated with postoperative time. t1/2, lambda, AUC0-infinity, and CL/F were significantly correlated with indices of liver function (aspartate transaminase [AST], total bilirubin, and international normalized ratio [INR]). The Cmax, last concentration in plasma at 12 h (Clast), AUMC0-infinity, and MRT0-infinity were significantly lower in the presence of deficient CYP2C19*2 alleles. Donor characteristics had no significant correlation with any of the pharmacokinetic parameters estimated. A fixed dosing regimen of voriconazole results in a highly variable exposure of voriconazole in liver transplant patients. Given that trough voriconazole concentration is a good measure of drug exposure (AUC), the voriconazole dose can be individualized based on trough concentration measurements in liver transplant patients.

Modified citrus pectin (MCP) increases the prostate-specific antigen doubling time in men with prostate cancer: a phase II pilot study.

This trial investigated the tolerability and effect of modified citrus pectin (Pecta-Sol) in 13 men with prostate cancer and biochemical prostate-specific antigen (PSA) failure after localized treatment, that is, radical prostatectomy, radiation, or cryosurgery. A total of 13 men were evaluated for tolerability and 10 for efficacy. Changes in the prostate-specific antigen doubling time (PSADT) of the 10 men were the primary end point in the study. We found that the PSADT increased (P-value<0.05) in seven (70%) of 10 men after taking MCP for 12 months compared to before taking MCP. This study suggests that MCP may lengthen the PSADT in men with recurrent prostate cancer.

Retrospective evaluation of intersubject brain registration.

Although numerous methods to register brains of different individuals have been proposed, no work has been done, as far as we know, to evaluate and objectively compare the performances of different nonrigid (or elastic) registration methods on the same database of subjects. In this paper, we propose an evaluation framework, based on global and local measures of the relevance of the registration. We have chosen to focus more particularly on the matching of cortical areas, since intersubject registration methods are dedicated to anatomical and functional normalization, and also because other groups have shown the relevance of such registration methods for deep brain structures. Experiments were conducted using 6 methods on a database of 18 subjects. The global measures used show that the quality of the registration is directly related to the transformation's degrees of freedom. More surprisingly, local measures based on the matching of cortical sulci did not show significant differences between rigid and non rigid methods.

Consistent landmark and intensity-based image registration.

Two new consistent image registration algorithms are presented: one is based on matching corresponding landmarks and the other is based on matching both landmark and intensity information. The consistent landmark and intensity registration algorithm produces good correspondences between images near landmark locations by matching corresponding landmarks and away from landmark locations by matching the image intensities. In contrast to similar unidirectional algorithms, these new consistent algorithms jointly estimate the forward and reverse transformation between two images while minimizing the inverse consistency error-the error between the forward (reverse) transformation and the inverse of the the reverse (forward) transformation. This reduces the ambiguous correspondence between the forward and reverse transformations associated with large inverse consistency errors. In both algorithms a thin-plate spline (TPS) model is used to regularize the estimated transformations. Two-dimensional (2-D) examples are presented that show the inverse consistency error produced by the traditional unidirectional landmark TPS algorithm can be relatively large and that this error is minimized using the consistent landmark algorithm. Results using 2-D magnetic resonance imaging data are presented that demonstrate that using landmark and intensity information together produce better correspondence between medical images than using either landmarks or intensity information alone.

Consistent image registration.

This paper presents a new method for image registration based on jointly estimating the forward and reverse transformations between two images while constraining these transforms to be inverses of one another. This approach produces a consistent set of transformations that have less pairwise registration error, i.e., better correspondence, than traditional methods that estimate the forward and reverse transformations independently. The transformations are estimated iteratively and are restricted to preserve topology by constraining them to obey the laws of continuum mechanics. The transformations are parameterized by a Fourier series to diagonalize the covariance structure imposed by the continuum mechanics constraints and to provide a computationally efficient numerical implementation. Results using a linear elastic material constraint are presented using both magnetic resonance and X-ray computed tomography image data. The results show that the joint estimation of a consistent set of forward and reverse transformations constrained by linear-elasticity give better registration results than using either constraint alone or none at all.

The pharmacokinetics of a single oral dose of mycophenolate mofetil in patients with varying degrees of renal function.

BACKGROUND: The purpose of this study was to determine the effect of renal function on the elimination and disposition of mycophenolic acid and its glucuronide metabolite (MPAG) after oral administration of the pro-drug mycophenolate mofetil. In addition, this study sought to examine hemodialysis removal of mycophenolic acid and its MPAG. METHODS: Subjects were stratified into five groups on the basis of iohexol clearance. After an overnight fast, all subjects received a single 1 gm dose of mycophenolate mofetil. Plasma concentrations of mycophenolic acid and MPAG were measured from 0 to 96 hours after administration. Mycophenolic acid and MPAG maximum plasma concentration (Cmax) and the time to reach Cmax (tmax) for each group were determined from the mean plasma concentration-time profiles. Area under the plasma concentration-time curve values for mycophenolic acid and MPAG were calculated by the trapezoidal rule. The half-lives of mycophenolic acid and MPAG were calculated from the terminal portions of the concentration-time profiles. RESULTS: Mycophenolic acid clearance was not associated with changes in glomerular filtration rate (GFR). Cmax tended to increase as GFR declined. MPAG clearance correlated well with GFR (r2 = 0.905). Clearance of mycophenolic acid and MPAG were unaffected by hemodialysis. CONCLUSIONS: Clearance of mycophenolic acid after a single 1 gm oral dose of mycophenolate mofetil is unaffected by renal function. Clearance of mycophenolic acid is unaffected by hemodialysis. Diminished renal function should not require preemptive adjustment of 1 gm doses of mycophenolate mofetil; however dosage adjustment may be warranted on the basis of adverse effects or toxicity in individual patients. Mycophenolate mofetil can be administered irrespective of hemodialysis session without effect on mycophenolic acid exposure.

A randomized trial comparing cyclosporine induction with sequential therapy in renal transplant recipients.

Calcium antagonists may reduce the nephrotoxicity of cyclosporine (CsA), allowing CsA to be introduced immediately after renal transplantation and thereby obviating the need for sequential induction therapy with a monoclonal or polyclonal antibody. To test this hypothesis, in a pilot feasibility trial 100 cadaveric or one-haplotype-mismatched living-related renal transplant recipients were randomized to either (1) sequential therapy with anti-thymocyte globulin (ATG) (ATGAM; Upjohn, Kalamazoo, MI) 20 mg/kg/d for 7 to 14 days until renal function was established and CsA (Sandimmune; Sandoz, East Hanover, NJ) was started, or (2) CsA 8 mg/kg/d begun immediately before surgery with diltiazem (Cardizem; Marion Merrell Dow, Kansas City, MO) 60 mg sustained release twice daily. Acute rejection episodes during the first 90 days were not different with ATG versus CsA induction (42% v 28%; P = 0.142 by chi-square analysis). Graft failures (10% v 16%; P = 0.372) and the incidence of delayed graft function (28% v 34%; P = 0.516) were also similar with ATG compared with CsA. ATG caused lower platelet counts (138 +/- 59 x 10(3) v 197 +/- 75 x 10(3) at 7 days; P < 0.001) and lower white blood cell counts (9.6 +/- 4.6 x 10(3) v 12.3 +/- 4.9 x 10(3) at 7 days; P = 0.003). Diltiazem reduced the dose of CsA required to maintain target blood levels (479 +/- 189 mg/d v 576 +/- 178 mg/d at 14 days; P = 0.015). There were no statistically significant differences between the groups in serum creatinine levels at days 1, 3, 5, 7, 14, 28, 60, or 90. The results of this pilot feasibility trial suggest that prophylactic treatment with CsA and diltiazem may be equally effective and less toxic than ATG induction after renal transplantation.

Characterization of epiphycan, a small proteoglycan with a leucine-rich repeat core protein.

The epiphysis of developing bones is a cartilaginous structure that is eventually replaced by bone during skeletal maturation. We have separated a dermatan sulfate proteoglycan, epiphycan, from decorin and biglycan by using dissociative extraction of bovine fetal epiphyseal cartilage, followed by sequential ion-exchange, gel permeation, hydrophobic, and Zn2+ chelate chromatographic steps. Epiphycan is a member of the small leucine-rich proteoglycan family, contains seven leucine-rich repeats (LRRs), is related to osteoglycin (osteoinductive factor) (Bentz, H., Nathan, R. M., Rosen, D. M., Armstrong, R. M., Thompson, A. Y., Segarini, P. R., Mathews, M. C., Dasch, J., Piez, K. A., and Seyedin, S. M. (1989) J. Biol. Chem. 264, 20805-20810), and appears to be the bovine equivalent of the chick proteoglycan PG-Lb (Shinomura, T., and Kimata, K. (1992) J. Biol. Chem. 267, 1265-1270). The intact proteoglycan had a median size of approximately 133 kDa. The core protein was 46 kDa by electrophoretic analysis, had a calculated size of 34,271 Da, and had two approximately equimolar N termini (APTLES ... and ETYDAT ... ) separated by 11 amino acids. There were at least three O-linked oligosaccharides in the N-terminal region of the protein, based on blank cycles in Edman degradation and corresponding serine or threonine residues in the translated cDNA sequence. The glycosaminoglycans ranged in size from 23 to 34 kDa were more heterogeneous than those in other dermatan sulfate small leucine-rich proteoglycans and were found in the acidic N-terminal region of the protein core, N-terminal to the LRRs. A four-cysteine cluster was present at the N terminus of the LRRs, and a disulfide-bonded cysteine pair was present at the C terminus of the protein core. The seventh LRR and an N-linked oligosaccharide were between the two C-terminal cysteines. An additional potential N-glycosylation site near the C terminus did not appear to be substituted at a significant level.

A psychophysiological assessment battery.

This research project was the first step in the development of a psychophysiological assessment battery. The battery consisted of eight tasks that have a history of use within the field of psychophysiology. These tasks were examined on a nonpathological, physically healthy sample. This sample was administered the assessment battery three times over the course of 16 weeks. The response systems of HR, SC, RR, TPA, and FPA were examined. Two major research questions were then examined. The first question was whether a subject would display a stable physiological profile on the assessment battery across the three administrations. The second question was whether there would be individual differences in physiological profiles on the assessment battery. These differences were examined in terms of individual response stereotypy (IRS) and stimulus response specificity (SRS). Depending on the task, from 30 to 100% of the subjects displayed stable physiological profiles across administrations. Twenty-five subjects displayed a high degree of SRS. Five subjects displayed a high degree of IRS.

Biocompatibility test procedures for materials evaluation in vitro. II. Objective methods of toxicity assessment.

Methods of assessing the biocompatibility of materials for use in medical devices were evaluated. Ten materials were tested using quantitative, objectively graded in vitro biochemical and functional assays employing four cell lines (CCL 1, 74, 76, and 131) used in previous work and five primary cell types (human lymphocytes, polymorphonuclear leukocytes, and mixed leukocytes, mouse macrophages, and mouse embryo). The biochemical methods (DNA synthesis, protein synthesis, and ATP activity) demonstrated good agreement in toxicity ranking of the materials, regardless of which cell culture was used and, also, the cell cultures responded similarly for each method. Methods that measured functional characteristics of cells (adhesion and phagocytosis) were highly sensitive but had low toxicity ranking agreement and reproducibility. Assays (defined as method and cell culture combinations) using cell lines were more reproducible than assays using primary cell types. Significant differences in sensitivity were noted among the assay systems for particular material types. The in vitro assays were more sensitive to differences in material composition than was a 90-day assay by subcutaneous implantation in rats.

Biocompatibility test procedures for materials evaluation in vitro. I. Comparative test system sensitivity.

Relative sensitivity of in vitro biocompatibility test systems was explored. Cellular responses of 12 standardized cell lines to 20 materials representing a range of toxicity were measured. Each cell line and material combination was tested in duplicate using four different culture methods, and each culture plate was examined by two graders. Results of the tissue culture assays were compared to those obtained for the same materials in vivo using a 5-day rabbit intramuscular implant assay. Methods involving measurement of cellular growth (colony counts or percent of confluence) in serum-fortified media extracts of test samples were generally more sensitive and discriminating than those in which test materials were placed directly in cell cultures (measurement of zone of growth inhibition). There was good agreement between graders for all test methods. Antibiotics were not used in the test program. Based upon sensitivity, reproducibility, ability to discriminate materials, and grader agreement, 4 of the 12 cell lines and 2 of the 4 test methods appeared most suitable for screening and evaluation of materials. Agreement of results using these four cell lines with intramuscular implantation tests for the 30 materials ranged from 60 to 90%.

The levels of plasma cholesterol in the human fetus throughout gestation.

The present study was undertaken to define the umbilical cord plasma concentrations of cholesterol throughout human gestation. Mixed arterial and venous cord plasma samples obtained from abortuses of women undergoing elective abortion or from infants of women who underwent spontaneous premature vaginal delivery, and from infants of women who delivered vaginally at term were assayed for cholesterol by a micro-enzymatic method. No cases that involved any maternal or fetal complications (other than prematurity) were included in this study. Early in gestation (10-16 weeks post-conception), the total cholesterol level in cord plasma was 85.4 +/- 30.7 mg/dl (mean +/- SD), N = 68, with the cholesterol levels in some samples falling within the range of those of adults. Between 16.5 and 20 weeks post-conception, the umbilical cord plasma cholesterol level declined to 39.9 +/- 21.0 mg/dl, n = 19 (P less than 0.001). The cholesterol concentration in umbilical cord plasma then rose to 67.8 +/- 24.0 mg/dl, n = 17 (P less than 0.01) between 26.5 and 32 weeks of gestation. Thereafter, a second decline in the umbilical cord plasma cholesterol level occurred, with the values at 32.5-36 weeks being 58.4 +/- 13.6 mg/dl (n = 16), and at 36.5 to 40 weeks post-conception (term) being 51.4 +/- 11.5 mg/dl, n = 44 (P less than 0.01 vs. 26.5-32 wks). We suggest that the observed changes in fetal cholesterol levels could be related to alterations during development in the rates of lipoprotein-cholesterol biosynthesis and subsequent clearance from plasma by the fetal adrenals wherein cholesterol is used as substrate for steroid biosynthesis.

Validation of a radioimmunoassay procedure for N,N'-diacetylbenzidine, a metabolite of the chemical carcinogen benzidine, in urine.

The biaryl amine benzidine has been reported to produce tumors of the bladder in both man and animals. We have developed and validated a radioimmunoassay (RIA) procedure for monitoring potential human exposure to benzidine through detection in urine samples of one of its known urinary metabolites. The antibody used in the assay was produced in rabbits and is specific for N,N'-diacetylbenzidine (N,N'-DAB). At a 1/15000 initial dilution, this antiserum bound 50% of an iodinated tracer [125I]-N4'-[4-hydroxyphenethylaminohemisuccinyl]-4-acetamido-4-aminobiphenyl. One hundred pg (0.373 pmol) of N,N'-DAB displaced 50% of the tracer initially bound to the antiserum. The validity of the RIA procedure was established by the parallelism exhibited between the standard curve and aliquots of spiked human urine samples. The RIA has good spiked human urine samples. The RIA has good sensitivity (average minimal detectable dose less than 10 pg) and reproducibility (within-and between-assay coefficients of variation at midrange of the standard curve were 3.94 and 12.48, respectively). A series of 109 randomly selected human urine control samples were analyzed and a nonspecific interference of 0.52 +/- 0.04 ng of N,N'-DAB/mL urine was found.

Development of a radioimmunoassay procedure for 4-acetamidobiphenyl, a metabolite of the chemical carcinogen 4-aminobiphenyl, in urine.

The synthetic chemical 4-aminobiphenyl (4-ABP) has been shown to be a bladder carcinogen in both man and animals. A valid radioimmunoassay for a metabolite of 4-ABP has been developed as a means to monitor potential human exposure to 4-ABP. The antibody was produced by the immunization of two female New Zealand White rabbits and was found to be highly specific for 4-acetamidobiphenyl (4-AABP), the acetylated metabolite of 4-ABP. At an initial dilution of 1/5000, the antisera bound 45% of the [125I]-labeled derivative of 4-ABP. This derivative was prepared by coupling 4-hemisuccinamidobiphenyl (4-HSBP) with tyramine, and then radioiodinating this compound using the enzymatic lactoperoxidase method. The dose of 4-acetamidobiphenyl which would displace 50% of the labeled hapten initially bound to the antiserum, was about 1 ng (4.8 pmol). Scatchard analysis of the standard curve binding data indicated the presence of at least two populations of binding sites. The equilibrium association constant for the higher binding affinity component was 2.8 x 10(8) Liters/mole. A series of 210 randomly selected human urine control samples were analyzed and a nonspecific background contribution of 1.67 +/- 0.07 ng (mean + S.E.) of "4-acetamidobiphenyl"/mL urine was found.