No abstract

Most reverse transcriptase and protease inhibitors used in highly active antiretroviral therapy for treating human immunodeficiency virus (HIV) infections exhibit poor penetration into the brain, raising the concern that the brain may be a sanctuary site for the development of resistant HIV variants. This study explores the relationship between the dose and plasma and brain concentrations of zosuquidar and the effect of this selective P-glycoprotein inhibitor on central nervous system penetration of the HIV protease inhibitor nelfinavir maintained at steady state by intravenous infusions in rats. Nelfinavir was infused (10 mg/kg/h) for up to 10 h with or without concurrent administration of an intravenous bolus dose of 2, 6, or 20 mg/kg zosuquidar given at 4 h. Brain tissue and plasma were analyzed for both drug concentrations. Brain tissue/plasma nelfinavir concentration ratios (uncorrected for the vascular contribution) increased nonlinearly with zosuquidar dose from 0.06 +/- 0.03 in the absence of zosuquidar and 0.09 +/- 0.02 between 2 and 6 h after 2 mg/kg zosuquidar to 0.85 +/- 0.19 after 6 mg/kg and 1.58 +/- 0.67 after 20 mg/kg zosuquidar. Zosuquidar brain tissue/plasma concentration ratios exhibited a similar abrupt increase from 2.8 +/- 0.3 after a 2 mg/kg dose to approximately 15 after the 6 and 20 mg/kg doses. The apparent threshold in the plasma concentration of zosuquidar necessary to produce significant enhancement in brain uptake of nelfinavir appears to be close to the plasma concentrations associated with the maximum tolerated dose reported in the literature after repeated dosing of zosuquidar in patients.

A prospective multicentre study was performed to identify patients with fetal choroid plexus cysts and examine the association between choroid plexus cysts and chromosome abnormalities in the context of variables such as maternal age, serum triple-screen results, race, other prenatally-identified fetal anomalies and cyst characteristics. A total of 18 437 scans were performed in 5 centres and 257 fetuses were identified with choroid plexus cysts. Outcome was available on 250 patients, and of these, chromosomal abnormalities were detected in a total of 13 (5.2 per cent) fetuses. 26 patients in the group had additional ultrasound abnormalities, and 8 of these had fetal chromosome abnormalities. Among the 224 patients with isolated choroid plexus cysts, 5 (2.2 per cent) were found to have chromosomal abnormalities. All cases with identified chromosomal abnormalities were associated with an additional risk factor, such as other ultrasound findings, advanced maternal age or abnormal maternal serum triple-screen results.

A new generation of ONLINE assays has been developed that offers improved performance and enhanced ease of use. This family of assays is being applied to both the COBAS INTEGRA and Roche/Hitachi line of analyzers. The four ONLINE DAT II assays that were evaluated included cocaine (benzoylecgonine) (BE), methadone (MDN), opiates (OP), and tetrahydrocannabinol (THC). The BE assay has a dual cutoff (150/300 ng/mL) with a dynamic range from 0 to 5000 ng/mL. The MDN assay has a cutoff of 300 ng/mL with a dynamic range from 0 to 2000 ng/mL. The opiates assay has a 300 ng/mL cutoff with a 0 to 2000 ng/mL range and a 2000 ng/mL cutoff with a 0 to 8000 ng/mL range. The THC assay has 20, 50, and 100 ng/mL cutoffs with 0 to 100, 0 to 300, and 0 to 300 ng/mL dynamic ranges, respectively. The ranges of the intra-assay precision (coefficients of variation for n = 20) run in the semiquantitative mode are 2.3-7.5% for BE, 2.0-3.8% for MDN, 1.9-4.2% for OP, and 3.9-5.2% for THC. The intra-assay qualitative precision for all of the assays as calculated from absorbance values is generally higher than that of the intra-assay semiquantitative precision at the cutoff. The qualitative precision ranges between 0.4% and 3.1%. The standard curve stability defined for the COBAS INTEGRA systems for these reagents ranges from 35 to 68 days. The clinical sensitivity and specificity were compared to the OnLine generation I and CEDIA immunoassays, as well as gas chromatography-mass spectrometry (GC-MS). The results indicate that for each assay, the sensitivity and specificity were the same or greater when compared to the other two immunoassay technologies. The results of each assay also correlated very well (> 99%) when compared with GC-MS.

No abstract