Publications

Biopharmaceutics Classification System and Biopharmaceutics Drug Distribution Classification System are complimentary, not competing, classification systems that aim to improve, simplify, and speed drug development. Although both systems are based on classifying drugs and new molecular entities into four categories using the same solubility criteria, they differ in the criterion for permeability and have different purposes. Here, the details and applications of both systems are reviewed with particular emphasis of their role in drug development.

BACKGROUND

In the last 6 months of life, many older adults will experience a hospitalization, followed by a transfer to a skilled nursing facility (SNF) for additional care. We sought to examine patterns of Medicare posthospitalization SNF use in the last 6 months of life.

METHODS

We used data from the Health and Retirement Study, a longitudinal survey of older adults, linked to Medicare claims (January 1994 through December 2007). We determined the number of individuals 65 years or older at death who had used the SNF benefit in the last 6 months of life. We report demographic, social, and clinical correlates of SNF use. We examined the relationship between place of death and hospice use for those residing in nursing homes and the community before the last 6 months of life.

RESULTS

The mean age at death among 5163 individuals was 82.8 years; 54.5% of the cohort were female, and 23.2% had resided in a nursing home. In total, 30.5% had used the SNF benefit in the last 6 months of life, and 9.2% had died while enrolled in the SNF benefit. The use of the SNF benefit was greater among patients who were 85 years or older, had at least a high school education, did not have cancer, resided in a nursing home, used home health services, and were expected to die soon (P < .01 for all). Of community dwellers who had used the SNF benefit, 42.5% died in a nursing home, 10.7% died at home, 38.8% died in the hospital, and 8.0% died elsewhere. In contrast, of community dwellers who did not use the SNF benefit, 5.3% died in a nursing home, 40.6% died at home, 44.3% died in the hospital, and 9.8% died elsewhere.

CONCLUSIONS

Almost one-third of older adults receive care in a SNF in the last 6 months of life under the Medicare posthospitalization benefit, and 1 in 11 elders will die while enrolled in the SNF benefit. Palliative care services should be incorporated into SNF-level care.

Multidrug-resistant Escherichia coli strains belonging to a single lineage frequently account for a large proportion of extraintestinal E. coli infections in many parts of the world. However, limited information exists on the community prevalence and clonal composition of drug-susceptible E. coli strains. Between July 2007 and September 2010, we analyzed all consecutively collected Gram-negative bacterial isolates from patients with bloodstream infection (BSI) admitted to a public hospital in San Francisco for drug susceptibility and associated drug resistance genes. The E. coli isolates were genotyped for fimH single nucleotide polymorphisms (SNPs) and multilocus sequence types (MLSTs). Among 539 isolates, E. coli accounted for 249 (46%); 74 (30%) of them were susceptible to all tested drugs, and 129 (52%) were multidrug resistant (MDR). Only five MLST genotypes accounted for two-thirds of the E. coli isolates; the most common were ST131 (23%) and ST95 (18%). Forty-seven (92%) of 51 ST131 isolates, as opposed to only 8 (20%) of 40 ST95 isolates, were MDR (P < 0.0001). The Simpson's diversity index for drug-susceptible ST genotypes was 87%, while the index for MDR ST genotypes was 81%. ST95 strains were comprised of four fimH types, and one of these (f-6) accounted for 67% of the 21 susceptible isolates (P < 0.003). A large proportion (>70%) of both MDR and susceptible E. coli BSI isolates represented community-onset infections. These observations show that factors other than the selective pressures of antimicrobial agents used in hospitals contribute to community-onset extraintestinal infections caused by clonal groups of E. coli regardless of their drug resistance.

UNLABELLED

While it is generally accepted that women have lower pain thresholds for diverse forms of noxious stimuli, the mechanistic basis for this sexual dimorphism in nociceptive pain remains to be elucidated. We confirmed, in the rat, that females have lower cutaneous mechanical nociceptive thresholds and established a similar sexual dimorphism in muscle. To determine if a peripheral mechanism underlies this sexual dimorphism in pain threshold, we compared biophysical properties of cultured dorsal root ganglion (DRG) neurons that innervated the gastrocnemius muscle in female and male rats. DRG neurons from female rats, which innervated the gastrocnemius muscle, had a more hyperpolarized resting membrane potential. To determine if this was associated with a higher mechanical nociceptive threshold, in contradiction to our working hypothesis, we compared the function, in vivo, of nociceptive afferents innervating the gastrocnemius muscle in male and female rats. C-fiber nociceptors innervating muscle in female rats had higher mechanical thresholds than those in males. Other response characteristics of these nociceptors were not significantly different. Thus, both in vitro and in vivo electrophysiology experiments support the idea that lower mechanical nociceptive threshold in females may be due to sexual dimorphism in central nervous system mechanisms, a difference large enough to overcome an opposing difference in peripheral pain mechanisms.

PERSPECTIVE

This article unifies in vivo and in vitro electrophysiology with behavioral data examining the differences in mechanical nociceptive threshold between male and female rats. The data provide a novel perspective on the peripheral and behavioral outcomes of noxious mechanical stimulation.

BACKGROUND

IgE is both a marker and mediator of allergic inflammation. Despite reported differences in serum total IgE levels by race-ethnicity, African American and Latino subjects have not been well represented in genetic studies of total IgE.

OBJECTIVE

We sought to identify the genetic predictors of serum total IgE levels.

METHODS

We used genome-wide association data from 4292 subjects (2469 African Americans, 1564 European Americans, and 259 Latinos) in the EVE Asthma Genetics Consortium. Tests for association were performed within each cohort by race-ethnic group (ie, African American, Latino, and European American) and asthma status. The resulting P values were meta-analyzed, accounting for sample size and direction of effect. Top single nucleotide polymorphism associations from the meta-analysis were reassessed in 6 additional cohorts comprising 5767 subjects.

RESULTS

We identified 10 unique regions in which the combined association statistic was associated with total serum IgE levels (P<5.0×10(-6)) and the minor allele frequency was 5% or greater in 2 or more population groups. Variant rs9469220, corresponding to HLA-DQB1, was the single nucleotide polymorphism most significantly associated with serum total IgE levels when assessed in both the replication cohorts and the discovery and replication sets combined (P=.007 and 2.45×10(-7), respectively). In addition, findings from earlier genome-wide association studies were also validated in the current meta-analysis.

CONCLUSION

This meta-analysis independently identified a variant near HLA-DQB1 as a predictor of total serum IgE levels in multiple race-ethnic groups. This study also extends and confirms the findings of earlier genome-wide association analyses in African American and Latino subjects.

INTRODUCTION

Anxiety sensitivity (i.e., AS; the degree to which one believes that anxiety and its related sensations are harmful) is a stable trait that is associated with habitual smoking. Yet, the mechanisms linking AS and smoking are unclear. A promising hypothesis is that high-AS individuals are more sensitive to the acute subjective reinforcing effects of smoking and are, therefore, more prone to tobacco dependence. This study examined trait AS as a predictor of several subjective effects of cigarette smoking.

METHODS

Adult non-treatment-seeking smokers (N = 87; 10+ cigarettes/day) completed a measure of AS during a baseline session. Prior to a subsequent experimental session, participants were asked to smoke normally before their appointment. At the outset of that visit, each participant smoked a single cigarette of their preferred brand in the laboratory. Self-report measures of affect and cigarette craving were completed before and after smoking, and post-cigarette subjective effect ratings were provided.

RESULTS

AS predicted greater increases in positive affect from pre- to post-cigarette (β = .30, p = .006) as well as greater smoking satisfaction and psychological reward (β = .23 to .48, ps < .03). Each of these effects remained statistically significant after adjusting for anxiety symptom severity. AS did not predict the degree of negative affect and craving suppression or post-cigarette aversive effects.

CONCLUSIONS

These findings suggest that positive reinforcement mechanisms may be particularly salient etiological processes that maintain smoking in high-AS individuals.