Publications

alpha-Particles are suitable to treat cancer micrometastases because of their short range and very high linear energy transfer. alpha-Particle emitter (213)Bi-based radioimmunotherapy has shown efficacy in a variety of metastatic animal cancer models, such as breast, ovarian, and prostate cancers. Its clinical implementation, however, is challenging due to the limited supply of (225)Ac, high technical requirement to prepare radioimmunoconjugate with very short half-life (T(1/2) = 45.6 min) on site, and prohibitive cost. In this study, we investigated the efficacy of the alpha-particle emitter (225)Ac, parent of (213)Bi, in a mouse model of breast cancer metastases. A single administration of (225)Ac (400 nCi)-labeled anti-rat HER-2/neu monoclonal antibody (7.16.4) completely eradicated breast cancer lung micrometastases in approximately 67% of HER-2/neu transgenic mice and led to long-term survival of these mice for up to 1 year. Treatment with (225)Ac-7.16.4 is significantly more effective than (213)Bi-7.16.4 (120 microCi; median survival, 61 days; P = 0.001) and (90)Y-7.16.4 (120 microCi; median survival, 50 days; P < 0.001) as well as untreated control (median survival, 41 days; P < 0.0001). Dosimetric analysis showed that (225)Ac-treated metastases received a total dose of 9.6 Gy, significantly higher than 2.0 Gy from (213)Bi and 2.4 Gy from (90)Y. Biodistribution studies revealed that (225)Ac daughters, (221)Fr and (213)Bi, accumulated in kidneys and probably contributed to the long-term renal toxicity observed in surviving mice. These data suggest (225)Ac-labeled anti-HER-2/neu monoclonal antibody could significantly prolong survival in HER-2/neu-positive metastatic breast cancer patients.

The expanding clinical challenge of respiratory tract infections due to resistant bacteria necessitates the development of new forms of therapy. The development of a compound composed of silver coupled to a methylated caffeine carrier (silver carbene complex 1 [SCC1]) that demonstrated in vitro efficacy against bacteria, including drug-resistant organisms, isolated from patients with respiratory tract infections was described previously. The findings of current in vitro studies now suggest that bactericidal concentrations of SCC1 are not toxic to airway epithelial cells in primary culture. Thus, it was hypothesized that SCC1 could be administered by the aerosolized route to concentrate delivery to the lung while minimizing systemic toxicity. In vivo, aerosolized SCC1 delivered to mice resulted in mild aversion behavior, but it was otherwise well tolerated and did not cause lung inflammation following administration over a 5-day period. The therapeutic efficacy of SCC1 compared to that of water was shown in a 3-day prophylaxis protocol, in which mice infected with a clinical strain of Pseudomonas aeruginosa had increased survival, decreased amounts of bacteria in the lung, and a lower prevalence of bacteremia. Similarly, by using an airway infection model in which bacteria were impacted in the airways by agarose beads, the administration of SCC1 was significantly superior to water in decreasing the lung bacterial burden and the levels of bacteremia and markers of airway inflammation. These observations indicate that aerosolized SCC1, a novel antimicrobial agent, warrants further study as a potential therapy for bacterial respiratory tract infections.

OBJECTIVE: To examine racial differences in medication use by older long-stay Veterans Affairs Nursing Home Care Unit (NHCU) patients.

DESIGN: Longitudinal study.

SETTINGS: 133 Veterans Affairs NHCUs.

PARTICIPANTS: Three thousand four hundred eighty veterans 65 years of age or older admitted between January 1, 2004, and June 30, 2005, for 90 days or more.

MAIN OUTCOMES MEASURES: Prevalence of those taking nine or more medications (i.e., polypharmacy) and medications from specific therapeutic medication classes. Racial differences were determined using 0.05 level chi-squared tests.

RESULTS: The sample consisted of 14.3% who were black. Blacks compared with whites (all comparisons P < 0.05 except where noted) were younger (13.6% vs. 17.4%, older than 85 years of age), had less depression (22.24 vs. 29.79%), less allergies (9.82% vs. 20.36%), and a similar rate of moderate-to severe pain (22.65% vs. 24.05; P = 0.49). The percent of polypharmacy was similar by race (blacks 74.35% vs. whites 71.18%; P = 0.62), as was the prevalence of medication class use with the exceptions that blacks were less likely than whites to take central nervous system (CNS) medications (75.75% vs. 80.14%; P = 0.02) and antihistamines (13.03% vs. 16.8%; P = 0.04). Specifically, blacks were less likely than whites to receive a selective serotonin-reuptake inhibitor (SSRI) antidepressant (20.84% vs. 27.17%; P < 0.01) or a second-generation antihistamine (3.41% vs. 6.51%; P < 0.01), but more likely than whites to receive opioids (14.63% vs. 11.27%; P = 0.03).

CONCLUSION: There appears to be racial differences in the overall use of antihistamines and CNS medications and some of their subclasses.

OBJECTIVE: The objective of the study was to identify patient and provider factors associated with prescribing antibiotics for outpatients with acute respiratory tract infections of likely nonbacterial etiology.

METHODS: We identified outpatients who were diagnosed in the emergency department with nonspecific upper respiratory tract infections (URIs) and acute bronchitis at the VA Pittsburgh Healthcare System from June 15, 2003, to June 14, 2004, and the Philadelphia VA Medical Center from November 30, 2003, to March 31, 2004. Stepwise logistic regression was used to identify factors independently associated with antibiotic prescribing.

RESULTS: Overall, 26% of the 667 eligible patients with URIs and/or acute bronchitis received antibiotics. Antibiotics were prescribed significantly more frequently for acute bronchitis at one site (97% vs 65%, P < .001). Using multivariable analysis, the following factors were independently associated with antibiotic prescribing (odds ratio, 95% confidence interval): presence of 1 or more comorbidities (2.1, 1.2-3.5), fever (2.5, 1.4-4.4), purulent sputum (2.5, 1.5-4.4), shortness of breath (2.8, 1.4-5.4), altered breath sounds (4.6, 2.4-8.6), diagnosis of acute bronchitis (15.9, 8.0-31.8), provider age > or = 30 years (2.6, 1.1-6.3), and noninternal medicine specialty (2.7, 1.2-6.0).

CONCLUSIONS: Antibiotic use was high and varied substantially for URIs and acute bronchitis. Specific signs and symptoms, a diagnosis of acute bronchitis, and provider age and specialty were associated with antibiotic prescribing. Interventions to decrease inappropriate prescribing should address the perceived utility of antibiotics in acute bronchitis and the accuracy of signs and symptoms in diagnosing a bacterial respiratory infection.

OBJECTIVES: To establish consensus oral dosing guidelines for primarily renally cleared medications prescribed for older adults.

DESIGN: Literature search followed by a two-round modified Delphi survey.

SETTING: A nationally representative survey of experts in geriatric clinical pharmacy.

PARTICIPANTS: Eleven geriatric clinical pharmacists.

MEASUREMENTS: After a comprehensive literature search and review by an investigative group of six physicians (2 general internal medicine, 2 nephrology, 2 geriatrics), 43 dosing recommendations for 30 medications at various levels of renal function were created. The expert panel rated its agreement with each of these 43 dosing recommendations using a 5-point Likert scale (1=strongly disagree to 5=strongly agree). Recommendation-specific means and 95% confidence intervals were estimated. Consensus was defined as a lower 95% confidence limit of greater than 4.0 for the recommendation-specific mean score.

RESULTS: The response rate was 81.8% (9/11) for the first round. All respondents who completed the first round also completed the second round. The expert panel reached consensus on 26 recommendations involving 18 (60%) medications. For 10 medications (chlorpropamide, colchicine, cotrimoxazole, glyburide, meperidine, nitrofurantoin, probenecid, propoxyphene, spironolactone, and triamterene), the consensus recommendation was not to use the medication in older adults below a specified level of renal function (e.g., creatinine clearance <30 mL/min). For the remaining eight medications (acyclovir, amantadine, ciprofloxacin, gabapentin, memantine, ranitidine, rimantadine, and valacyclovir), specific recommendations for dose reduction or interval extension were made.

CONCLUSION: An expert panel of geriatric clinical pharmacists was able to reach consensus agreement on a number of oral medications that are primarily renally cleared.

OBJECTIVE: To compare users and nonusers of Veterans Affairs (VA) pharmacy services by age group.

STUDY DESIGN: Cross-sectional.

METHODS: We used data on sociodemographics, health status, and medical conditions from the Medical Expenditure Panel Survey (MEPS) to compare users and nonusers of VA pharmacies for medications. Data were pooled for 2003-2005 to ensure adequate sample sizes. Student t tests were used to compare the means for each variable, and all analyses were adjusted for the complex sample design of the MEPS.

RESULTS: Among both nonelderly (18-64 years) and elderly (>or=65 years) veterans, a higher proportion who used VA pharmacy services versus those who did not use VA pharmacy services (1) were black (nonelderly: 17.7 % vs 7.4%, P <.001; elderly: 9.4% vs 4.7%, P <.001); (2) had no alternative insurance (nonelderly: 27.2% vs 4.8%, P <.001; elderly: 36.3% vs 19.9%, P <.001); (3) had lower incomes (nonelderly: 32.4% vs 11.5%, P <.001; elderly: 32.4% vs 25.4%, P = .01); (4) had less than a high school education (nonelderly: 13.0% vs 6.5%, P <.001; elderly: 27.5% vs 17.6%, P <.001); (5) were disabled; and (6) reported poorer health. A higher percentage of nonelderly users reported a mental health condition (31.6% vs 19.4%, P <.001).

CONCLUSIONS: Veterans who use VA pharmacy services appear to be more ill than those who do not use VA pharmacy services. In addition, the VA appears to be a safety net for uninsured veterans who have mental health problems.

BACKGROUND: Although gatifloxacin is no longer available, other fluoroquinolones may significantly interfere with glucose homeostasis. The objective of the present study was to compare the risk of severe hypo- and hyperglycemia in a cohort of patients treated with gatifloxacin, levofloxacin, ciprofloxacin, or azithromycin.

METHODS: This was a retrospective inception cohort study of outpatients with a new prescription for gatifloxacin, levofloxacin, ciprofloxacin, or azithromycin from 1 October 2000 through 30 September 2005 in the Veterans Affairs health care system. For patients who received one of these antibiotics, we identified outcomes of hospitalization with a primary diagnosis of hypo- or hyperglycemia. Multivariable logistic regression was used to determine the odds of hypo- and hyperglycemia with the individual fluoroquinolones versus azithromycin.

RESULTS: The crude incidence rates for severe hypo- and hyperglycemia among those who received gatifloxacin, levofloxacin, ciprofloxacin, and azithromycin were 0.35 and 0.45, 0.19 and 0.18, 0.10 and 0.12, and 0.07 and 0.10 cases per 1000 patients, respectively. Among patients with diabetes, the odds ratios for hypoglycemia compared with azithromycin were 4.3 (95% confidence interval [CI], 2.7-6.6) for gatifloxacin, 2.1 (95% CI, 1.4-3.3) for levofloxacin, and 1.1 (95% CI, 0.6-2.0) for ciprofloxacin. The odds ratios for hyperglycemia were 4.5 (95% CI, 3.0-6.9) for gatifloxacin, 1.8 (95% CI, 1.2-2.7) for levofloxacin, and 1.0 (95% CI, 0.6-1.8) for ciprofloxacin.

CONCLUSIONS: The odds of severe hypo- and hyperglycemia were significantly greater with gatifloxacin and levofloxacin, but not ciprofloxacin, than with azithromycin. Thus, the risk of a clinically relevant dysglycemic event appears to vary among the fluoroquinolones.

We aimed to elucidate the clinical significance of borderline troponin I (TnI) increases and see if such increases are of similar significance across different assays. Markedly increased TnI is a strong predictor of adverse cardiac events. It is not clear if borderline increases with different commercially available TnI assays provide similar prognostic information. From January 2001 to February 2004, 3 different TnI assays (Beckman Access TnI, Beckman Access AccuTnI, and Vitros ECI Troponin) were used to evaluate the peak TnI value in 1,152 consecutive patients admitted with suspected acute coronary syndrome/non-ST-elevation myocardial infarction (MI). Recommended cutoffs were used to differentiate borderline from marked increases reported as consistent with MI. Clinical data and 30-day death/new MIs were determined by chart abstraction. Demographics and cardiac risk factors were similar for the 3 groups. Frequency of borderline TnI ranged widely among assays (18.7% to 42.1%) but was significantly less with the Vitros ECI Troponin assay (p <0.0001). Prognostic significance of borderline increased TnI values also varied greatly by assay, with borderline Beckman Access AccuTnI increases being predictive of adverse 30-day outcomes (odds ratio 4.0, 95% confidence interval 1.46 to 10.97, p = 0.007), but not with the other 2 assays. Borderline increases were significantly associated with chronic renal insufficiency (CRI; serum creatine >1.5); the relation to adverse 30-day outcomes and borderline increases persisted after correcting for CRI in a multivariate logistic regression model. In conclusion, although borderline increased TnI levels are common and significantly associated with CRI, they do not all portend the same clinical prognosis. This study highlights the need for standardization of TnI levels across different assays.

BACKGROUND: Cost-related nonadherence to medieations is common among older adults, yet physician-patient communication about medication cost concerns is infrequent. One factor affecting communication and adherence may be older adults' confidence in the information about prescription drugs provided by physicians and other sources.

OBJECTIVES: This study was conducted to identify which source older adults most trust to provide information on drugs and to examine the relationship between older patients' trust in physicians to provide price information and the occurrence of cost-related nonadherence.

METHODS: We conducted a cross-sectional national telephone survey of individuals aged > or =50 years who were taking at least 1 prescription medication. Respondents were asked how much they would trust various sources (physician, pharmacist, nurse, insurance plan, the Internet, consumer groups, friends and family) to provide helpful information on "the price of the prescription medicine compared to others like it" and on "how well the prescription medicine will work for you compared to other medicines like it." The response options were a lot, somewhat, and not at all. Other measures of interest were respondents' beliefs concerning physicians' ability to lower drug costs and patient activation. We also evaluated the potential association between trust in physicians to deliver drug price information and cost-related medication nonadherence.

RESULTS: Compared with the other sources of information studied, doctors and pharmacists were the sources that respondents were most likely to trust "a lot" to provide information on drug prices (55.6% and 61.7%, respectively) and to provide information on drug effectiveness (79.9% and 66.4%). Less than half (42.3%) of respondents who said that they trusted their doctor to provide drug price information "somewhat" or "not at all" agreed that there are ways doctors could lower drug costs (P = 0.01 vs those who trusted their doctor "a lot"). Adults aged > or =65 years were more likely than those aged 50 to 64 years to trust their doctors "a lot" to provide information on drug prices (odds ratio [OR] = 1.44; 95% CI, 1.08-1.92); the same was true of members of minority groups compared with white respondents (OR = 1.72; 95%) CT, 1.1 3-2.61 ). Among individuals with high drug spending, those who placed "a lot" of trust in their doctors to provide price information were less likely than those who trusted their doctor "somewhat" or "not at all" to have cost-related nonadhcrence (OR = 0.40; 95% CI, 0.20-0.78).

CONCLUSIONS: In this survey, older adults trusted physicians and pharmacists more than the other sources studied to provide information on prescription drugs. Trust in physicians to provide price information was an important moderator of the effect of high drug spending on cost-related nonadhcrence. Efforts to provide patients and their providers with comparative data on drug prices and effectiveness may reduce cost-related nonadhcrence.