Alpha 2U-globulin: measurement in rat kidney and relationship to hyaline droplets

The concentration of renal alpha 2U-globulin increased in a dose-dependent manner in adult male but not female rats which received a single dose of 2,2,4-trimethylpentane (TMP). After administration of a single dose of 12 mmol TMP/kg to adult male rats, the renal concentration of alpha 2U-globulin reached a peak at 48 hours and returned to near background level after 7 days. These changes in renal alpha 2U-globulin concentration were closely paralleled by changes in renal hyaline droplet formation. Renal alpha 2U-globulin and hyaline droplets were absent in normal pre-puberty male rats, and neither could be stimulated by a single dose of TMP. alpha 2U-Globulin was localised in the renal cortex of adult male rats, in particular the S2 segment of the proximal tubule. A greater staining intensity due to alpha 2U-globulin was seen in the S2 and adjacent segments after a single dose of TMP. A strong association is suggested between the presence of renal hyaline droplets and the occurrence of alpha 2U-globulin.     

Temporal variation in triazolam pharmacokinetics and pharmacodynamics after oral administration

The effect of time of day of drug administration on triazolam pharmacokinetics was studied in ten healthy men. In a randomized, two-way, crossover investigation, each subject received one 0.5 mg triazolam tablet either in the morning (7 AM) or evening (10 PM). Blood samples were obtained immediately before dosing and at selected times up to 12 hours after dosing. Triazolam plasma concentrations were determined by gas chromatography with electron capture detection. Psychomotor performance tests, including digit symbol substitution, card sorting by suits, and card sorting by fours, were administered, and the subjects' sedation was rated before drug and at two, ten, and 12 hours after drug administration. In addition, anterograde amnesia was assessed by showing objects to subjects two hours after dosing and testing aided and unaided recall at ten hours following administration. Triazolam's apparent elimination half-life after evening administration was significantly longer than after daytime ingestion (3.77 hr vs. 2.94 hr, P less than .05). There was no difference between times of dosing in total oral clearance or apparent volume of distribution. The absorption of triazolam was slower after evening administration, with an absorption half-life of 21.9 vs 13.3 minutes after daytime dosing. Performance decrements were significantly greater two hours after dosing in evening than in the daytime, but anterograde amnesia was more pronounced after daytime dosing. There was no effect on psychomotor performance at ten or 12 hours after administration in daytime or evening. These results indicate temporal variation in triazolam absorption and elimination.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of simplifying choice tasks on estimates of taste heterogeneity in stated-choice surveys

Researchers usually employ orthogonal arrays or D-optimal designs with little or no attribute overlap in stated-choice surveys. The challenge is to balance statistical efficiency and respondent burden to minimize the overall error in the survey responses. This study examined whether simplifying the choice task, by using a design with more overlap, provides advantages over standard minimum-overlap methods. We administered two designs for eliciting HIV test preferences to split samples. Surveys were undertaken at four HIV testing locations in San Francisco, California. Personal characteristics had different effects on willingness to pay for the two treatments, and gains in statistical efficiency in the minimal-overlap version more than compensated for possible imprecision from increased measurement error.     

Reduced blood clearance and increased urinary excretion of N-nitrosodimethylamine in patas monkeys exposed to ethanol or isopropyl alcohol.

Low concentrations of N-nitrosodimethylamine are metabolized in rodent and human liver by cytochrome P450IIE1, an activity competitively inhibitable by ethanol. In rodents coadministration of ethanol with N-nitrosodimethylamine results in increased tumorigenicity in extrahepatic organs, probably as a result of reduced hepatic clearance. To test this concept in a primate, the effects of ethanol cotreatment on the pharmacokinetics of N-nitrosodimethylamine were measured in male patas monkeys. Ethanol, 1.2 g/kg given p.o. before i.v. N-nitrosodimethylamine (1 mg/kg) or concurrently with an intragastric dose resulted in a 10-50-fold increase in the area under the blood concentration versus time curves and a 4-13-fold increase in mean residence times for N-nitrosodimethylamine. Isopropyl alcohol, 3.2 g/kg 24 h before N-nitrosodimethylamine, also increased these parameters 7-10-fold; this effect was associated with persistence of isopropyl alcohol and its metabolic product acetone, both IIE1 inhibitors, in the blood. While no N-nitrosodimethylamine was detected in expired air, trace amounts were found in urine. Ethanol and isopropyl alcohol pretreatment increased the maximum urinary N-nitrosodimethylamine concentration 15-50-fold and the percentage of the dose excreted in the urine by 100-800-fold. Thus ethanol and isopropyl alcohol greatly increase systemic exposure of extrahepatic organs to N-nitrosodimethylamine in a primate.