No abstract

This study examines the possible role of estrogen in regulating the expression of the human CYP3A subfamily: CYP3A4, CYP3A5, CYP3A7, and CYP3A43. To accomplish this goal, mRNA was quantified from human livers and endometrial samples, and total CYP3A protein levels were evaluated by Western immunoblot analysis of the liver samples. The human endometrial samples were from premenopausal and postmenopausal women. The premenopausal endometrium was either in the proliferative or secretory phase, whereas for the postmenopausal endometrium samples, the women had been treated with either a placebo or estropipate, an estrogen substitute.After analyses, CYP3A4 mRNA was shown to have lower hepatic expression in females than in males. In the endometrium, CYP3A4 and CYP3A43 are down-regulated by estrogen, whereas CYP3A5 is expressed at higher levels during the secretory phase. CYP3A7 was not detected in the endometrium. In addition, the CYP3A subfamily showed increased mRNA expression in the liver as age increased. The expression levels of total CYP3A protein and total CYP3A mRNA showed good correlation. Despite apparent regulation of CYP3A4 mRNA expression by estrogen, the effects of estrogen may be overshadowed by additional regulators of gene expression.It is known that men and women do not respond equally to certain drugs administered for therapeutic relief (Harris et al., 1995); however, the reasons have yet to be fully identified and appear to be multifaceted. A variety of possibilities may contribute to therapeutic discordance, but a probable explanation is that estrogen directly or indirectly regulates a gene or genes responsible for the differences in response. Of the genes that could cause variations in drug response, a metabolizing enzyme would be a likely candidate. In particular, the cytochrome P450 (P450) superfamily is known for metabolizing a diverse set of substrates with the cytochrome P450 3A (CYP3A) subfamily metabolizing the most diverse range of substrates (Guengerich, 1999). It is possible that an estrogen-regulated P450 of the CYP3A subfamily contributes to the gender dimorphism exhibited in the drug response between women and men.

High inter-and intra-laboratory variability exists for the single-breath diffusing capacity of the lung for carbon monoxide (DL,CO) test. To detect small changes in diffusing capacity in multicentre clinical trials, accurate measurements are essential. The present study assessed whether regular DL,CO simulator testing maintained or improved instrument accuracy and reduced variability in multicentre trials.The 125 pulmonary function testing laboratories that participated in clinical trials for AIR1 Inhaled Insulin validated and monitored the accuracy of their DL,CO measuring devices using a DL,CO simulator, which creates known target values for any device. Devices measuring a simulated DL,CO different from target by .3 mL?min-1?mmHg -1 failed testing and were serviced.Device accuracy was assessed over time and with respect to differences in several variables. Initially, 31 (25%) laboratories had a DL,CO device that failed simulator testing. After fixing or replacing devices, 124 (99%) laboratories had passing devices. The percentage of failed tests significantly decreased over time. Differences in geographical region, device type, breath-hold time, temperature and pressure were not associated with meaningful differences in DL,CO device accuracy.Regular diffusing capacity of the lung for carbon monoxide simulator testing allows pulmonary function testing laboratories to maintain the accuracy of their diffusing capacity measurements, leading to reduced variability across laboratories in multicentre clinical trials.

These studies demonstrated an inverse relationship between HbA(1c) and 24-h and daytime hypoglycaemia. Lispro insulin mixtures provided lower HbA(1c) and post-prandial blood glucose values than glargine, but caused more daytime hypoglycaemia. Frequency of nocturnal hypoglycaemia was similar and severe hypoglycaemia was rare with both insulin regimens.

The opportunity to choose AIR insulin did not affect overall use of insulin at end point or A1C outcomes. Regardless of group assignment, utilizing a shared decision-making approach to treatment choices (concordance model), resulted in improved treatment satisfaction and A1C values at end point. Therefore, increasing patient involvement in treatment decisions may improve outcomes.