Prenatal exposure to cigarette smoke is associated with an increased risk of sudden infant death syndrome. The effect of maternal smoking on apnea and arousal patterns in preterm infants is currently unknown. Multichannel polysomnographic studies were performed in preterm infants. Thirty infants were enrolled into the study: 16 exposed prenatally to cigarette smoke (S) and 14 control infants (C). There was no difference in the gestational and postconceptional ages at the time of study. Maternal smoking was associated with a significant increase in the apneic index in these infants (28.6 +/- 6.4/hour [S] vs. 13.2 +/- 3.9 [C]; p<0.05), and the difference was noted for obstructive events and only during active sleep. The arousal index was significantly decreased in the maternal smoking group (34.5 +/- 2.3/hour [S] vs. 46.3 +/- 5.6/hour [C]; p<0.05), with a specific decrease in percentage of arousal after respiratory events (10.7 +/- 2.1% [S] vs. 29.4 +/- 5.4% [C]; p<0.05). In conclusion, preterm infants exposed prenatally to cigarette smoke have increased respiratory events during active sleep, predominantly due to obstructive apnea, and possibly a higher arousal threshold during apneic events. These alterations in respiratory and arousal patterns in preterm infants born to smoking mothers may lead to significant vulnerability in this population.
The cholesteryl ester transfer protein (CETP) inhibitor anacetrapib exhibits a long terminal half-life (t ½ ) in humans; however, the dispositional mechanisms that lead to this long t ½ are still being elucidated. As it is hypothesized that disposition into adipose tissue and binding to CETP might play a role, we sought to delineate the relative importance of these factors using a preclinical animal model. A multiple-dose pharmacokinetic study was conducted in C57BL6 wild-type (WT) lean, WT diet-induced obese (DIO), natural flanking region (NFR) CETP-transgenic lean, and NFR-DIO mice. Mice were dosed orally with 10 mg/kg anacetrapib daily for 42 days. Drug concentrations in blood, brown and white adipose tissue, liver, and brain were measured up to 35 weeks postdose. During dosing, a 3-to 9-fold accumulation in 72-hour postdose blood concentrations of anacetrapib was observed. Drug concentrations in white adipose tissue accumulated ∼20-to 40-fold, whereas 10-to 17-fold accumulation occurred in brown adipose and approximately 4-fold in liver. Brain levels were very low (<0.1 mM), and a trend of accumulation was not seen. The presence of CETP as well as adiposity seems to play a role in determining the blood concentrations of anacetrapib. The highest blood concentrations were observed in NFR DIO mice, whereas the lowest concentrations were seen in WT lean mice. In adipose and liver tissue, higher concentrations were seen in DIO mice, irrespective of the presence of CETP. This finding suggests that white adipose tissue serves as a potential depot and that disposition into adipose tissue governs the long-term kinetics of anacetrapib in vivo.
A high-performance liquid chromatographic (HPLC) method for the determination of granisetron (GRN) in guinea pig plasma has been developed. Guinea pig plasma spiked with GRN was microfiltered, and the recovered filtrate was directly injected onto the column without any further cleanup procedures. Separation was achieved on a spherical silica column and GRN was detected at 305 nm. Approximately 800-900 injections were made without any evidence of column deterioration. For the standard curves, correlation coefficients ranged from 0.9978-0.9999, and the percent standard deviation (%SD) from the mean area under the curve (AUC) was calculated to be less than 10% for all concentrations, except for the lowest concentration (0.325 ng/microL, 11.3%). Between-day and within-day coefficients of variation (%CV) ranged from 4.9 to 9.5% and 3.6 to 7.6%, respectively. Percent errors for within-day test plasma samples were not greater than 8.2% of the expected concentration for all samples except for 1.125 ng/microL (-14.6%). The limit of sensitivity was found to be 0.019 ng/microL. Estimated recovery of GRN in the microfiltrate was calculated to be 58-59% and 78-81% in plasma and water, respectively. Stability studies indicated that repeated refrigeration and warming (for six days) of microfiltered GRN plasma samples produced no changes in GRN concentrations from day to day. However, microfiltered GRN plasma samples that were repeatedly frozen and thawed demonstrated erratic concentration changes from day to day. The precision, accuracy, and small sample requirements of this method indicate its utility for pharmacokinetic studies in small animals where sample volume may be restrictive.
Advances in technology have led to a shift for peptide quantification from traditional ligand-binding assays to LC-MS/MS-based analysis, which presents challenges, in other assay sensitivity, specificity and ruggedness, in addition to lacking of regulatory guidance, especially for the hybrid assay format. Methodology & results: This report communicates a strategy that has been employed in our laboratories for method development and assay validation, and exemplified in a case study of MK-2640, a glucose-responsive insulin, in multiple matrices. Intact MK-2640 was monitored, while immunoaffinity purification and SPE were used to support the rat/dog GLP and clinical studies, respectively. The rationale and considerations behind our approach, as well as the acceptance criteria applied to the assay validation are discussed.
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