Publications

The tartrate-resistant acid phosphatase (TRAP) is present in multiple tissues, including kidney, liver, lung, spleen, and bone. Recent study of (TRAP) gene expression has provided evidence for distinct promoters within the (TRAP) gene, suggesting that the gene has alternative, tissue-preferred mRNA transcripts. Examination of endogenous (TRAP) exon 1B and 1C mRNA transcripts revealed tissue-preferred transcript abundance with increased exon 1B transcripts detected in liver and kidney and increased exon 1C transcripts detected in bone and spleen. In this investigation, we have made transgenic mice that express a marker gene driven by two candidate promoters, designated BC and C, within the (TRAP) gene. The BC and C promoters are 2.2 and 1.6 kb, respectively, measured from the translation initiation site. Evaluation of BC transgenic lines demonstrated robust expression in multiple tissues. In contrast, significant transgene expression was not detected in C transgenic lines. Evaluation of transgene mRNAs in BC transgenic lines revealed that virtually all expression was in the form of B transcripts, suggesting that the tissue-preferred pattern of endogenous (TRAP) was not replicated in the BC transgenic line. Likewise, osteoclastogenic cultures from BC, but not C, transgenic bone marrow cells expressed the transgene following receptor activator of NFkappaB ligand/macrophage colony-stimulating factor stimulation. In conclusion, when compared with the 2.2-kb BC portion of the (TRAP) promoter region, the 1.6-kb C portion does not account for significant gene expression in vivo or in vitro; production of the bone- and spleen-preferred (TRAP) C transcript must depend on regulatory elements outside of the 2.2-kb promoter. As the majority of currently investigated transcription factors that influence transcriptional regulation of osteoclast gene expression bind within the 1.6-kb C portion of the (TRAP) promoter, it is likely that transcription binding sites outside of the 2.2-kb region will have profound effects on regulation of the gene in vivo and in vitro.

We observed four cases of therapeutic failures while patients were simultaneously taking medications that contained divalent cations and oral fluoroquinolones. Patients improved after conversion to the intravenous formulation of the same antibiotics, proper spacing of the divalent cation, or conversion to a different antibiotic class. Patients prescribed oral fluoroquinolones should receive instructions on proper separations of these antibiotics with divalent cations. Health care professionals should be cognizant of these interactions and educated on their potential deleterious effect.

BACKGROUND: To explore the incidence and severity of potential interactions between prescription medications and dietary supplements.

METHODS: A survey was conducted on dietary supplement use in 458 veteran outpatients currently taking prescription medications. Self-reported dietary supplement use was cross-referenced with each patient's prescription medication list, and potential interactions were identified from several tertiary sources and medical literature searches.

RESULTS: One hundred ninety-seven patients (43%) were currently taking at least 1 dietary supplement with prescription medication(s). The most common products included vitamins and minerals, garlic, Ginkgo biloba, saw palmetto, and ginseng. Among these, 89 (45%) had a potential for drug-dietary supplement interactions of any significance. Most of these interactions (n = 84 [94%]) were not serious based on limited available evidence, giving an incidence of 6% (5/89) of potentially severe interactions among patients taking interacting drugs and dietary supplements and 3% (5/197) among patients taking coincident dietary supplements and medications.

CONCLUSIONS: Although the use of dietary supplements appears to be very common among patients who also take prescription medications, most potential drug-dietary supplement interactions found were not serious. However, literature support was sparse at best. Health care providers should continue to inquire about dietary supplement use and consider the potential for interactions, regardless of their severity.

OBJECTIVE: To assess physician satisfaction with Department of Veterans Affairs (VA) formulary policies and to examine the correlation between physician satisfaction and perceived access to formulary and nonformulary medications.

STUDY DESIGN: Cross-sectional survey with specific questions on access to formulary and nonformulary medications. Statistical analyses included assessment of associations between physician satisfaction and various measures of access.

PARTICIPANTS AND METHODS: Initial sample of 4015 staff physicians working in VA healthcare facilities. Responses were received from 1812 (49%) of the 3682 physicians in the final eligible sample population.

RESULTS: Most clinicians (72%) reported that their local formulary covered more than 90% of the medications they wanted to prescribe. Most (73%) agreed that drug restrictions were important to contain costs, and 86% agreed that it was important for VA to choose "best-value" drugs. Respondents reported an 89% approval rate for nonformulary drugs, though 31% indicated that approvals routinely took 3 or more days. We found strong associations between physician satisfaction and self-reported approval rates for nonformulary drugs (P = .001), timely approval of nonformulary requests (P < .001), and percentage of nonformulary prescriptions as a proportion of overall prescriptions at a regional level (P< .01). There was no significant correlation between physician satisfaction and number of medications added to regional formularies or with drug costs per unique patient.

CONCLUSIONS: VA physicians were generally supportive of VA formulary policies including choosing best-value drugs to control pharmaceutical expenditures. Nevertheless, access to nonformulary drugs and timely approval of requests for nonformulary medications were strong predictors of clinician satisfaction and support for cost-containment measures.

OBJECTIVES: We sought to examine the impact of direct-to-consumer advertising (DTCA) and pharmaceutical promotion to physicians on the likelihood that (1) an individual diagnosed with depression received antidepressant medication and that (2) antidepressant medication was used for the appropriate duration.

RESEARCH DESIGN AND SUBJECTS: A quasiexperimental design was used to examine treatment patterns of 30,621 depressed individuals whose insurance claims were included in the MarketScan database from 1997 through 2000. The main explanatory variables were spending on DTCA, detailing to physicians, and free samples for 6 antidepressant medications.

RESULTS: Individuals diagnosed with depression during periods when class-level antidepressant DTCA spending was highest (cumulative spending more than US 18.5 million dollars) had 32% higher relative odds of initiating medication therapy compared with those diagnosed during periods when DTCA spending was lowest (P < 0.0001). Free samples of medications dispensed to physicians had no effect on odds of initiating antidepressant use. Class-level DTCA spending on antidepressants had a small positive effect on the duration of antidepressant use, whereas DTCA spending for the specific medication taken by an individual had no effect on treatment duration. Detailing spending at the class or product level had no significant effect on duration of treatment with an antidepressant medication.

CONCLUSIONS: Our results suggest that DTCA of antidepressants was associated with an increase in the number of people diagnosed with depression who initiated medication therapy. DTCA was associated with a small increase in the number of individuals treated with antidepressants who received the appropriate duration of therapy. Promotion to physicians was not associated with either the initiation of treatment with an antidepressant or with the duration of therapy.

OBJECTIVE: To determine the incidence of clinically relevant potential drug-drug interactions (DDIs) in a large population of ambulatory patients utilizing a computerized, retrospective drug utilization review (DUR) program followed by clinical pharmacist audit.

METHODS: The drug claims database included approximately 2.9 million patients with more than 30 million prescriptions dispensed in the 12-month period from September 2001 through August 2002. Cases were identified by a computerized, retrospective DUR program with embedded triggers to detect 69 prespecified potentially serious DDIs, with "serious" defined as an interaction that would likely require a change in therapy or use of additional clinical or laboratory monitoring. Two types of automated, computerized assessments were conducted: the first simply detected coprescribed drug pairs, and the second assessment used more sophisticated filters to reduce false positive alerts for coprescribed drug pairs. Clinical pharmacist audit then determined the final incidence of clinically relevant warnings; in this audit, coprescribed drug pairs were defined as clinically relevant if they could cause potentially serious DDIs.

RESULTS: Eighteen drug pairs had insufficient cases for inclusion, leaving 51 drug pairs for evaluation. A total of 244,703 cases of potential DDIs were identified (0.8% of total prescription claims) by simple automated screens. More sophisticated DDI filters reduced the 244,703 potential DDIs by 70.8%, to a total of 65,544 pairs (0.2% of total prescription claims). Clinical pharmacist review reduced the number of potential DDIs by an additional 80.6%, to 12,722 drug pairs (0.04% of total prescription claims) deemed clinically relevant. The combination of sophisticated DDI filters and clinical pharmacist review reduced the incidence of potentially serious DDIs by 94.3%.

CONCLUSION: The incidence of potentially serious DDIs is relatively low (less than 1%) among ambulatory patients; however, the incidence depends on the method of case finding. Retrospective DUR programs, especially those with additional automated filters or that utilize additional pharmacist review, appear to be important screening tools in determining true rates of coprescribed drug pairs that can lead to potentially serious DDIs.

BACKGROUND: Choice of antibiotic therapy for acute exacerbations of chronic bronchitis (AECB) is important because of cost and concerns about development of resistance.

METHODS: A retrospective cohort study was conducted in outpatients with chronic obstructive pulmonary disease and documented AECB treated with antibiotics.

RESULTS: We compared outcomes and costs of AECB treated with first-line antibiotics having partial coverage against organisms associated with AECB (eg, amoxicillin), first-line antibiotics with full coverage against organisms associated with AECB (eg, sulfamethoxazole-trimethoprim), and newer broad-spectrum antibiotics (eg, azithromycin). There were no significant differences among the three antibiotic groups in failure rate, hospitalization rate, or time until subsequent AECB. Pharmacy costs were significantly less with first-line antibiotics (3.18 dollars +/- 0.64, 3.00 dollars +/- 0.48, and 36.70 dollars +/- 16.29, respectively; P < 0.0001), but there was no significant difference among all three groups with regard to total costs.

CONCLUSION: We found no difference in outcome between older traditional antibiotics with adequate coverage against organisms associated with AECB and newer broad-spectrum antibiotics.

OBJECTIVE: To identify the documented indications for long-term therapy with lansoprazole 30 mg twice daily at the Veterans Affairs Pittsburgh Healthcare System, assess compliance with appropriate use criteria, evaluate patients eligible for step-down therapy, and recommend appropriate step-down therapy in order to improve patient care, decrease overprescribing, and reduce medication costs.

STUDY DESIGN: Prospective intervention.

METHODS: The records of all patients with prescriptions for lansoprazole 30 mg twice daily as of June 2000 were reviewed. Patients were interviewed to assess medication compliance and symptom control and to provide education on lifestyle modifications. Interventions with the providers were completed to encourage step-down therapy in appropriate patients.

RESULTS: Two hundred forty-eight patients with active prescriptions for twice-daily lansoprazole were reviewed. Of these patients, 66% (n = 163) did not have an indication compliant with the medical center's guidelines for use of lansoprazole 30 mg twice daily. Of these, 88% (n = 143) had no documented attempt at step-down therapy and 49% (n = 80) had no documented gastrointestinal workup. Interventions for step-down therapy were recommended for 48% (n = 120) of the 248 patients. Forty-six percent (n = 60) of recommendations were accepted, resulting in a cost savings of dollars 85000 per year.

CONCLUSIONS: A high rate of clinician noncompliance with the guidelines for appropriate use of lansoprazole 30 mg twice daily was found. These prescribing patterns resulted in significant cost concerns. Our review and interventions led to step-down therapy for almost half of the patients receiving twice-daily lansoprazole. This review of patient records and intervention with primary care providers resulted in cost reduction and offered an opportunity to educate patients on beneficial lifestyle modifications.

OBJECTIVE: To determine whether there are racial differences in adherence to cardiac medications.

DESIGN: Retrospective analysis.

PATIENTS: African-American and white male veterans aged 45 years or older who had received any of four groups of drugs: angiotensin-converting enzyme inhibitors (ACEIs), beta-blockers (BBs), calcium channel blockers (CCBs,) or HMG CoA (hydroxymethyl glutaryl coenzyme A) reductase inhibitors (statins).

DATA: Administrative records were used to identify eligible veterans and their demographic characteristics, medical diagnoses, and medication use. We used a standard measure of adherence to medications based on whether the veteran obtained enough drug to take it as prescribed on 80% of the days.

RESULTS: We identified 833 eligible African-American and 4436 eligible white veterans. In univariable analysis, African Americans were less likely to be adherent to medications than whites for ACEIs (81.4% versus 87.6%, P = 0.004), CCBs (75.3% versus 81.7%, P = 0.003), and statins (59.9% versus 74.1%, P < 0.001) but not BBs (84.8% versus 83.5%, P = 0.6). In multivariable analysis, racial differences in adherence to medications were found primarily among veterans younger than 55 years old.

CONCLUSIONS: Younger African Americans were less adherent to medications than whites in a setting where financial barriers are minimized. Although the reason for this finding is unclear, it may contribute to high cardiovascular morbidity among African Americans.

In elongating pollen tubes of the conifer Picea abies (Norway spruce), microtubules form a radial array beneath the plasma membrane only at the elongating tip and an array parallel with elongation throughout the tube. Tips specifically swell following microtubule disruption. Here we test whether these radial microtubules coordinate cell wall deposition and maintain tip integrity as tubes elongate. Control pollen tubes contain cellulose throughout the walls, including the tip. Pollen tubes grown in the presence of isoxaben, which disrupts cellulose synthesis, are significantly shorter with a decrease in cellulose throughout the walls. Isoxaben also significantly increases the frequency of tip swelling, with no effect on tube width outside of the swollen tip. The decrease in cellulose is more pronounced in pollen tubes with swollen tips. The effects of isoxaben are reversible. Following isoxaben treatment, the radial array of microtubules persists beneath the plasma membrane of nonswollen tips, while this array is specifically disrupted in swollen tips. Microtubules instead form a random network throughout the tip. Growth in these pollen tubes is turgor driven, but the morphological changes due to isoxaben are not just the result of weakened cell walls since pollen tubes grown in hypoosmotic media are not significantly shorter but do have swollen tips and tubes are wider along their entire length. We conclude that the radial microtubules in the tip do maintain tip integrity and that the specific inhibition of cellulose microfibril deposition leads to the disorganization of these microtubules. This supports the emerging model that there is bidirectional communication across the plasma membrane between cortical microtubules and cellulose microfibrils.