Previous kinetic studies have identified a high-affinity (S)-warfarin 7-hydroxylase present in human liver microsomes which appears to be responsible for the termination of warfarin's biological activity. Inhibition of the formation of (S)-7-hydroxywarfarin, the inactive, major metabolite of racemic warfarin in humans, is known to be the cause of several of the drug interactions experienced clinically upon coadministration of warfarin with other therapeutic agents. In order to identify the specific form(s) of human liver cytochrome P-450 involved in this particular toxicity, we have determined the metabolic profiles of 11 human cytochrome P-450 forms expressed in HepG2 cells toward both (R)- and (S)-warfarin. Of the 11 forms examined only 2C9 displayed the regioselectivity and stereoselectivity appropriate for the high-affinity human liver microsomal (S)-7-hydroxylase. We further compared Michaelis-Menten and sulfaphenazole inhibition constants for (S)-warfarin 7-hydroxylation catalyzed by cDNA-expressed 2C9 and by human liver microsomes. Similar kinetic constants were obtained for each enzyme source. It is concluded that 2C9 is likely to be a principal form of human liver P-450 which modulates the in vivo anticoagulant activity of the drug. It is further concluded that those drug interactions with warfarin that arise as a result of decreased clearance of the biologically more potent S-enantiomer may have as their common basis the inhibition of P-450 2C9.

A model was proposed to assess the premise that functional limitations are an intermediary stage between risk factors (e.g., sex and frequency of walking a mile), pathology/impairments (e.g., musculoskeletal problems), and the onset and course of Instrumental Activities of Daily Living (IADL) disability. Analyses were based on two random subsamples (each with n = 524) of Longitudinal Study of Aging respondents who were nondisabled at baseline (1984) and reinterviewed in 1988 and 1990. The model's central premise was supported in two ways. The main influence of age, frequency of walking, and musculoskeletal problems was on the onset of functional limitations, rather than the onset of IADL disability. And, onset of lower body functional limitations influenced future disability (1990) through its relationship with disability in 1988 and functional limitations in 1990. The results underscore the value of clinical trials which focus on minimizing functional limitations as a strategy for preventing disability.

This study examined whether relationship quality mediates, moderates, or both mediates and moderates the associations between caregiving stressors (e.g., disability and behavioral problems) and negative consequences associated with caregiver well-being (overload, role captivity, and depression). Data on family (spouses and children) caregivers (n = 118) came from a longitudinal study of a representative sample of disabled older people and their primary caregivers. Relationship quality mediated the linkages between the presence of problem behaviors and the outcomes of role captivity and depression. That is, when problem behaviors were present, they related to higher levels of captivity and depression because quality of the relationship suffered. Relationship quality moderated the linkage between disability and overload. Specifically, for those with a higher quality of relationship, increased disability was related to higher levels of perceived overload.

Fewer older patients preferred CPR or life-prolonging treatments. Although older patients' goals for aggressive treatment were related to care, this was not so for middle-aged patients. Aggressive care was not related to prolonged life in either group.