Cytochrome P-450 2D6 (CYP2D6) is involved in the metabolism of many therapeutic drugs even though the enzyme represents a small proportion of the total CYP content of human liver. In vivo phenotyping with probe drug substrates such as debrisoquine and dextromethorphan showed a clear separation between poor metabolizers (PM) and extensive metabolizers (EM). This polymorphism may affect susceptibility to environmental disease, as suggested by molecular epidemiologic studies that found an association between CYP2D6 metabolizer phenotype and cancer risk; however, this association is not consistent. There are only a few examples of CYP2D6 involvement in toxicant mechanism of action, but this has not been extensively studied. Gene probe studies documented a number of genetic polymorphisms that underlie CYP2D6 metabolizer phenotypes. The EM group carries the wild-type (*1) or active (*2) variant alleles, while the PM group carries the *3, *4, *5, or *6 alleles, all of which code for a protein that has lower or null CYP2D6 activity. The current analysis characterizes (a) influence of genotype on phenotype based upon in vivo metabolism studies of probe drugs and (b) frequency of the major genotypes in different population groups is also characterized. These data were then incorporated into Monte Carlo modeling to simulate population distributions of CYP2D6 activity. This analysis reproduced the bimodal distributions commonly seen in phenotyping studies of Caucasians and found extensive population variability in enzyme activity, as indicated by the 9- to 56-fold difference between the PM modal median and the total population median CYP2D6 activity. This substantial degree of interindividual variability in CYP function indicates that assessments involving CYP2D6 substrates need to consider the full distribution of enzyme activity in refining estimates of internal dose in health assessments of xenobiotics.

Research on the ways older people use prescription medications (Rx) is a mainstay of the gerontological literature because use of Rx medications is common, and appropriate use is central to effective management of chronic disease. But older adults are also major consumers of over-the-counter (OTC) medications, which can be equally significant for self-care. Nearly half of older adults aged 75-85, for example, are regular users of an OTC product. Ensuring that consumers safely and effectively use OTC products is critical in order to minimize potential drug-drug interactions and unintentional misuse. Yet we know surprisingly little about the ways older adults select OTC medications and decide when to start or stop use, how older people actually take these medications, or how involved clinicians and family members are in older adult OTC behavior. Research in this area is critical for developing interventions to help ensure safe and appropriate OTC use. For this reason, The Gerontological Society of America (GSA), in partnership with the Consumer Healthcare Products Association (CHPA), convened a summit of experts to set an agenda for research in OTC behaviors among older adults. The panel suggested a need for research in 5 key areas: Health literacy and OTC behavior, decision making and OTC use, the role of clinicians in OTC medication behavior, older adult OTC behavior and family care, and technologies to promote optimal use of OTC medications.

A randomized controlled efficacy trial targeting older adults with hypertension (age 60 and over) provided an e-health, tailored intervention with the “next generation” of the Personal Education Program (PEP-NG). Eleven primary care practices with advanced practice registered nurse (APRN) providers participated. Participants (N=160) were randomly assigned by the PEP-NG (accessed via a wireless touchscreen tablet computer) to either control (entailing data collection and four routine APRN visits) or tailored intervention (involving PEP-NG intervention and four focused APRN visits) group. Compared to patients in the control group, patients receiving the PEP-NG e-health intervention achieved significant increases in both self-medication knowledge and self-efficacy measures, with large effect sizes. Among patients not at BP targets upon entry to the study, therapy intensification in controls (increased antihypertensive dose and/or an additional antihypertensive) was significant (p=.001) with an odds ratio of 21.27 in the control compared to the intervention group. Among patients not at BP targets on visit 1, there was a significant declining linear trend in proportion of the intervention group taking NSAIDs 21–31 days/month (p=0.008). Satisfaction with the PEP-NG and the APRN provider relationship was high in both groups. These results suggest that the PEP-NG e-health intervention in primary care practices is effective in increasing knowledge and self-efficacy, as well as improving behavior regarding adverse self-medication practices among older adults with hypertension.

An interactive computer program (Personal Education Program [PEP]) designed for the learning styles and psychomotor skills of older adults was used to teach older adults about potential drug interactions that can result from self-medication with over-the-counter (OTC) agents and alcohol. Subjects used the PEP on notebook computers equipped with infrared sensitive touchscreens. Subjects were recruited from senior centers. Those who met age, vision, literacy, independence, and medication use criteria were randomly assigned to one of three groups: (1) PEP plus information booklet; (2) information booklet only; or (3) control. A repeated measures (three time periods 2 weeks apart), three-group design was used. Users of PEP had significantly greater knowledge and self-efficacy scores than both the conventional and control groups at all three time points. The PEP group reported fewer adverse self-medication behaviors over time. Reported self-medication behaviors did not change over time for either the conventional or control groups. Subjects indicated a high degree of satisfaction with the PEP and reported their intent to make specific changes in self-medication behaviors.

A touch screen–enabled “Personal Education Program” was modified to the “next generation” to capture self-medication behaviors of older adults with hypertension and assess related knowledge and self-efficacy. The program analyzes patient-entered information and delivers interactive educational content tailored to the reported behaviors. Summaries of self-reported symptoms, medication use (including frequency/time), drug interactions, and corrective strategies with an illustration of the drug interaction are printed to inform the provider before the primary care visit and for the patient to take home for self-study. After formative research during development and formal diagnostic and verification usability studies with advanced practice nurses and older adults, a beta test was conducted with older adults with hypertension over a 3-month period. Findings from the beta test suggest that older adult user satisfaction was high. Blood pressure declined over the four visits for 82% of the participants. The next generation of the Personal Education Program had a large effect size in increasing knowledge and self-efficacy for avoiding adverse self-medication behaviors. Behavior risk score did not change significantly but was significantly correlated with systolic blood pressure on the fourth visit. The positive results found in this small sample suggest that the next generation of the Personal Education Program could play a central role in facilitating patient-provider communication and medication adherence.

Paraoxonase-1 (PON1) is a serum esterase that hydrolyzes the activated oxon form of several organophosphates. The central role of PON1 in detoxification of organophosphate (OP) pesticides was demonstrated in knockout mouse studies, suggesting that human variability in PON1 needs to be considered in health risk assessments involving exposure to these pesticides. The current analysis focused on two genetic loci in which polymorphisms demonstrated to affect PON1 activity. Detailed kinetic studies and population studies found that the *192Q (wild type) allele is more active toward some substrates (such as sarin, soman, and diazoxon) and less active toward others (such as paraoxon or chlorpyrifos) relative to the variant *192R allele. Another allele that affects activity is *55M; PON1 enzyme quantity, rather than specific activity or substrate preference, is altered. The *192R variant occurs commonly with a frequency of 25-64% across the populations analyzed. The *55M allele is less common, occurring in 5-40% of individuals depending upon the ethnic group studied. These activity and allele frequency data were incorporated into Monte Carlo simulations in which the frequency of both variant alleles was simultaneously modeled in Caucasian, African American, and Japanese populations. The resulting Monte Carlo activity distributions were bimodal for the substrate paraoxon with approximately fourfold differences between low- and high-activity modal medians. Differences in activity between total population median and 1st percentile were five- to sixfold. When sarin metabolic variability was simulated, the population distributions were unimodal. However, there was an even greater degree of interindividual variability (median to 1st percentile difference >20-fold). These results show that the combined effects of two PON1 allelic variants yielded a population distribution that is associated with a considerable degree of interindividual variability in enzyme activity. This indicates that assessments involving PON1 substrates need to evaluate polymorphism-related variability in enzyme activity to display the distribution of internal doses and adverse responses. This may best be achieved via physiologically based pharmacokinetic (PBPK) models that input PON1 activity distributions, such as those generated in this analysis, to simulate the range of oxon internal doses possible across the population.

No abstract

Preventing Drug Interactions in Active Older Adults is an educational intervention to prevent prescription and over-the-counter (OTC) drug and alcohol interactions in active, community-living older adults. The objectives of the program are to increase older adults' knowledge of potential interactions of prescription medications with OTC drugs and alcohol and to increase their confidence (self-efficacy) about how to avoid such interactions. An interactive multimedia computer software program (Personal Education Program or PEP) was designed for the learning styles and psychomotor skills of older adults. Focus groups of older adults evaluated PEP components in a formative manner during development. The program content dealing with antacids, calcium supplements, and acid reducers was pilot tested with 60 older adults recruited from local senior centers. Participants used the PEP on notebook computers equipped with infrared-sensitive touchscreens. Users of PEP had greater knowledge and self-efficacy scores than controls. Participants indicated a high degree of satisfaction with the PEP and reported their intent to make specific changes in self-medication behaviors.