Revenue sources for essential services in Florida: findings and implications for organizing and funding public health.

OBJECTIVES: The Florida Public Health Practice-Based Research Network conducted the study of Florida county health departments (CHDs) to assess relationships between self-assessed performance on essential services (ESs) and sources of funding. METHODS: Primary data were collected using an online survey based on Public Health Accreditation Board standards for ES. Bivariate and multivariate analyses were conducted to assess the relationship of sources and amounts of revenue obtained from the Florida Department of Health financial system to responses to the survey of CHD capacity for ESs. RESULTS: Self-assessed CHD performance for each ES varied extensively among the CHDs and across the 10 ESs, ranging from a high of 98% CHDs completely or almost completely meeting the standards for ES 2 (Investigating Problems and Hazards) to a low of 32% completely or almost completely meeting standards for ES 10 (Research/Evidence). Medicaid revenue and fees were positively correlated with some ESs. Per capita revenue support varied extensively among the CHDs. CONCLUSIONS: Revenue for ES is decreasing and is heavily reliant on noncategorical (discretionary) revenue. This study has important implications for continued reliance on ES as an organizing construct for public health.

Prospective Randomized Trial of Docetaxel Versus Best Supportive Care in Patients With Non-Small-Cell Lung Cancer Previously Treated With Platinum-Based Chemotherapy.

PURPOSE: To evaluate whether treatment with single-agent docetaxel would result in longer survival than would best supportive care in patients with non-small-cell lung cancer who had previously been treated with platinum-based chemotherapy. Secondary end points included assessment of response (docetaxel arm only), toxicity, and quality of life.PATIENTS AND METHODS: Patients with performance statuses of 0 to 2 and stage IIIB/IV non-small-cell lung cancer with either measurable or evaluable lesions were eligible for entry onto the study if they had undergone one or more platinum-based chemotherapy regimens and if they had adequate hematology and biochemistry parameters. They were excluded if they had symptomatic brain metastases or if they had previously been treated with paclitaxel. Patients were stratified by performance status and best response to cisplatin chemotherapy and were then randomized to treatment with docetaxel 100 mg/m2 (49 patients) or 75 mg/m2 (55 patients) or best supportive care. Patients in both arms were assessed every 3 weeks. RESULTS: One hundred four patients (103 of whom were eligible for entry onto the study) were well balanced for prognostic factors. Of 84 patients with measurable lesions, six (7.1%) achieved partial responses (three patients at each dose level). Time to progression was longer for docetaxel patients than for best supportive care patients (10.6 v 6.7 weeks, respectively; P < .001), as was median survival (7.0 v 4.6 months; log-rank test, P = .047). The difference was more significant for docetaxel 75 mg/m2 patients, compared with corresponding best supportive care patients (7.5 v 4.6 months; log-rank test, P = .010; 1-year survival, 37% v 11%; χ2 test, P = .003). Febrile neutropenia occurred in 11 patients treated with docetaxel 100 mg/m2, three of whom died, and in one patient treated with docetaxel 75 mg/m2. Grade 3 or 4 nonhematologic toxicity, with the exception of diarrhea, occurred at a similar rate in both the docetaxel and best supportive care groups. CONCLUSION: Treatment with docetaxel is associated with significant prolongation of survival, and at a dose of 75 mg/m2, the benefits of docetaxel therapy outweigh the risks.

High-affinity CRF1 receptor antagonist NBI-34041: preclinical and clinical data suggest safety and efficacy in attenuating elevated stress response.

There is an extensive evidence that corticotropin releasing factor (CRF) is hypersecreted in depression and anxiety, and blockade of CRF could have therapeutic benefit. We report preclinical data and the results of a clinical Phase I study with the novel nonpeptide CRF(1) antagonist NBI-34041/SB723620. Preclinical data conducted with different cell lines expressing human CRF receptors and in Wistar and Sprague-Dawley rats indicate that NBI-34041 is effective in reducing endocrine responses to pharmacological and behavioral challenge mediated by CRF(1) receptors. These specific properties and its well-documented safety profile enabled a clinical Phase I study with 24 healthy male subjects receiving NBI-34041 (10, 50, or 100 mg) or placebo for 14 days. Regulation of the hypothalamic-pituitary-adrenocortical (HPA) axis was evaluated by intravenous stimulation with 100 microg of human CRF. Psychosocial stress response was investigated with the Trier Social Stress Test (TSST). Treatment with NBI-34041 did not impair diurnal adrenocorticotropic hormone (ACTH) and cortisol secretion or CRF evoked ACTH and cortisol responses but attenuated the neuroendocrine response to psychosocial stress. These results suggest that NBI-34041 is safe and does not impair basal regulation of the HPA system but improves resistance against psychosocial stress. NBI-34041 demonstrates that inhibition of the CRF system is a promising target for drug development against depression and anxiety disorders.

Imaging the norepinephrine transporter in humans with (S,S)-[11C]O-methyl reboxetine and PET: problems and progress.

UNLABELLED: Results from human studies with the PET radiotracer (S,S)-[(11)C]O-methyl reboxetine ([(11)C](S,S)-MRB), a ligand targeting the norepinephrine transporter (NET), are reported. Quantification methods were determined from test/retest studies, and sensitivity to pharmacological blockade was tested with different doses of atomoxetine (ATX), a drug that binds to the NET with high affinity (K(i)=2-5 nM). METHODS: Twenty-four male subjects were divided into different groups for serial 90-min PET studies with [(11)C](S,S)-MRB to assess reproducibility and the effect of blocking with different doses of ATX (25, 50 and 100 mg, po). Region-of-interest uptake data and arterial plasma input were analyzed for the distribution volume (DV). Images were normalized to a template, and average parametric images for each group were formed. RESULTS: [(11)C](S,S)-MRB uptake was highest in the thalamus (THL) and the midbrain (MBR) [containing the locus coeruleus (LC)] and lowest for the caudate nucleus (CDT). The CDT, a region with low NET, showed the smallest change on ATX treatment and was used as a reference region for the DV ratio (DVR). The baseline average DVR was 1.48 for both the THL and MBR with lower values for other regions [cerebellum (CB), 1.09; cingulate gyrus (CNG) 1.07]. However, more accurate information about relative densities came from the blocking studies. MBR exhibited greater blocking than THL, indicating a transporter density approximately 40% greater than THL. No relationship was found between DVR change and plasma ATX level. Although the higher dose tended to induce a greater decrease than the lower dose for MBR (average decrease for 25 mg=24+/-7%; 100 mg=31+/-11%), these differences were not significant. The different blocking between MBR (average decrease=28+/-10%) and THL (average decrease=17+/-10%) given the same baseline DVR indicates that the CDT is not a good measure for non-NET binding in both regions. Threshold analysis of the difference between the average baseline DV image and the average blocked image showed the expected NET distribution with the MBR (LC) and hypothalamus>THL>CNG and CB, as well as a significant change in the supplementary motor area. DVR reproducibility for the different brain regions was approximately 10%, but intersubject variability was large. CONCLUSIONS: The highest density of NETs was found in the MBR where the LC is located, followed by THL, whereas the lowest density was found in basal ganglia (lowest in CDT), consistent with the regional localization of NETs in the nonhuman primate brain. While all three doses of ATX were found to block most regions, no significant differences between doses were found for any region, although the average percent change across subjects of the MBR did correlate with ATX dose. The lack of a dose effect could reflect a low signal-to-noise ratio coupled with the possibility that a sufficient number of transporters were blocked at the lowest dose and further differences could not be detected. However, since the lowest (25 mg) dose is less than the therapeutic doses used in children for the treatment of attention-deficit/hyperactivity disorder ( approximately 1.0 mg/kg/day), this would suggest that there may be additional targets for ATX's therapeutic actions.

Application of economic impact analysis to a local public health agency and its "Academic Health Department".

Public health systems are stressed by increasing demands and inadequate resources. This study was designed to demonstrate how economic impact analysis can estimate the economic value of a local public health system's infrastructure as well as the economic assets of an "Academic Health Department" model. This study involved the secondary analysis of publicly available data on health department finances and employment using proprietary software specifically designed to assess economic impacts. The health department's impact on the local community was estimated at over 100 million dollars, exceeding the economic impact of other recently studied local industries with no additional costs to local taxpayers.

The slow and long-lasting blockade of dopamine transporters in human brain induced by the new antidepressant drug radafaxine predict poor reinforcing effects.

BACKGROUND: (2S,3S)-2-(3-Chlorophenyl)-3,5,5,-trimethyl-2-morpholinol hydrochloride (radafaxine) is a new antidepressant that blocks dopamine transporters (DAT). A concern with drugs that block (DAT) is their potential reinforcing effects and abuse liability. Using positron emission tomography (PET) we have shown that for DAT-blocking drugs to produce reinforcing effects they must induce >50% DAT blockade and the blockade has to be fast (within 15 minutes). This study measures the potency and kinetics for DAT blockade by radafaxine in human brain. METHODS: PET and [11C]cocaine were used to estimate DAT blockade at 1, 4, 8, and 24 hours after radafaxine (40 mg p.o.) in 8 controls. Plasma pharmacokinetics and behavioral and cardiovascular effects were measured in parallel. RESULTS: DAT blockade by radafaxine was slow, and at 1 hour, it was 11%. Peak blockade occurred at about 4 hours and was 22%. Blockade was long lasting: at 8 hours 17%, and at 24 hours 15%. Peak plasma concentration occurred about 4 to 8 hours. No behavioral or cardiovascular effects were observed. CONCLUSIONS: The relatively low potency of radafaxine in blocking DAT and its slow blockade suggests that it is unlikely to have reinforcing effects. This is consistent with preclinical studies showing no self-administration. This is the first utilization of PET to predict abuse liability of a new antidepressant in humans based on DAT occupancy and pharmacokinetics.

In vivo activity of bupropion at the human dopamine transporter as measured by positron emission tomography.

BACKGROUND: Converging lines of evidence are consistent with an inhibitory effect of the antidepressant and smoking-cessation aid bupropion on dopamine and norepinephrine reuptake, but the in vivo effects of the drug at the human dopamine transporter (DAT) have not been studied to date. This study employed positron emission tomography (PET) to assess the extent and duration of DAT receptor occupancy by bupropion and its metabolites under conditions of steady-state oral dosing with bupropion sustained-release (SR) in healthy volunteers. METHODS: Six healthy male volunteers received bupropion SR 150 mg daily on days 1 through 3 and 150 mg every 12 hours on day 4 through the morning of day 11. PET investigations were performed between 1 and 7 days before initiation of bupropion SR dosing, as well as 3, 12, and 24 hours after the last dose of bupropion SR on day 11. RESULTS: Bupropion and its metabolites inhibited striatal uptake of the selective DAT-binding radioligand (11)C-betaCIT-FE in vivo. Three hours after the last dose of bupropion SR, average DAT occupancy by bupropion and its metabolites was 26%-a level that was maintained through the last PET assessment at 24 hours after dosing. CONCLUSIONS: Bupropion and its metabolites induced a low occupancy of the striatal DAT over 24 hours under conditions of steady-state oral dosing with therapeutic doses of bupropion SR. These data are consistent with the hypothesis that dopamine reuptake inhibition may be responsible in part for the therapeutic effects of the drug.

Estimation of the effect of food on the disposition of oral 5-fluorouracil in combination with eniluracil.

AIMS: To determine the effect of food on the pharmacokinetics of 5-fluoruracil (5-FU) taken orally with eniluracil and to compare the performance of different pharmacokinetic analysis methods in the detection a potential food-drug interaction. METHODS: In a randomized, open-label, two-way crossover study, 12 patients received eniluracil (50 mg, orally) on days 1 and 2 and 5-FU (20 mg/m(2), orally) on day 2 following either a 2-h fast or 20 min after a standard meal. Treatments were separated by 7 days. Timed blood samples were collected during the first two treatment periods and 5-FU concentrations determined by GC/MS. Data were analyzed and pharmacokinetic parameter estimates were obtained using a noncompartmental, two-stage and population analysis methods. RESULTS: In fasted individuals, the clearance/bioavailability of 5-FU was estimated to be 5.6 l/h. The mean absorption lag-time was 0.24 h and was followed by rapid absorption of 5-FU. Administration of 5-FU and eniluracil with food resulted in a decrease in the 5-FU absorption rate constant by 90%. As a result, the peak plasma concentration (C(max)) of 5-FU was decreased by 21% and the time to C(max) was increased 2.9-fold. Clearance of 5-FU, relative bioavailability, and area under the plasma concentration vs time curve (AUC) remained unchanged with coadministration of food. Similar results were obtained using all three data analysis methods. CONCLUSIONS: Administration of food with oral 5-FU and eniluracil slowed absorption of 5-FU and decreased 5-FU C(max), but did not effect AUC. Further investigation of the incorporation of population pharmacokinetic approaches in food effect studies is warranted.

A Review of the Neuropharmacology of Bupropion, a Dual Norepinephrine and Dopamine Reuptake Inhibitor.

BACKGROUND: The neurochemical and biological effects of antidepressant medications have become better defined over the last decade. When the anti-depressant bupropion was introduced in the United States in 1989, the specific pharmacologic basis of its clinical effects was uncertain. Research conducted over the past decade has significantly advanced the understanding of the neuropharmacology of bupropion and has demonstrated a novel mechanism of antidepressant activity. This article discusses the mechanism of action of bupropion and relates the drug's neuropharmacologic effects to its clinical efficacy and tolerability profiles. DATA SOURCES: Data were obtained via the MEDLINE database in an English-language search spanning the period 1965 to May 2002 and using the search terms bupropion, bupropion SR, and antidepressants, as well as from the manufacturer's bupropion databases. CONCLUSIONS: The preclinical and clinical data show that bupropion acts via dual inhibition of norepinephrine and dopamine reuptake and is devoid of clinically significant serotonergic effects or direct effects on postsynaptic receptors. Dual norepinephrine and dopamine reuptake inhibition is associated with a unique clinical profile. Bupropion has demonstrated efficacy comparable to that of other antidepressants. However, because bupropion is a selective norepinephrine and dopamine reuptake inhibitor with no serotonergic activity, common antidepressant-associated side effects, such as sexual dysfunction, weight gain, and sedation, are not associated with bupropion therapy.

Brief strengths-based case management promotes entry into HIV medical care: results of the antiretroviral treatment access study-II.

OBJECTIVE: The Antiretroviral Treatment Access Study-II (ARTAS-II) evaluated a brief case management intervention delivered in health departments and community-based organizations (CBOs) to link recently diagnosed HIV-infected persons to medical care rapidly. METHODS: Recently diagnosed HIV-infected persons were recruited from 10 study sites across the United States during 2005 to 2006. The intervention consisted of up to 5 sessions with an ARTAS linkage case manager over a 90-day period. The outcome measure was whether or not the participant had seen an HIV medical care provider at least once within 6 months of enrollment. Multivariate logistic regression was used to identify significant predictors of receiving HIV medical care. RESULTS: Seventy-nine percent (497 of 626) of participants visited an HIV clinician at least once within the first 6 months. Participants who were older than 25 years of age, Hispanic, and stably housed; had not recently used noninjection drugs; had attended 2 or more sessions with the case manager; and were recruited at a study site that had HIV medical care colocated on its premises were all significantly more likely to have received HIV care. CONCLUSIONS: The ARTAS linkage case management intervention provides a model that health departments and CBOs can use to ensure that recently diagnosed HIV-infected persons attend an initial HIV care encounter.

Low doses of pamidronate to treat osteopenia in children with severe cerebral palsy: a pilot study.

The aim of this study was to test the efficacy of low doses of pamidronate in increasing bone mineral density (BMD) in non-ambulatory children and adolescents with cerebral palsy (CP). Twenty-three non-ambulatory children and adolescents (12 females, 11 males; mean age 10y [SD 5y], range 4y 1 mo-17 y 11 mo) with severe spastic quadriplegic CP and low BMD were recruited from a multidisciplinary clinic. Severity of CP was graded at Level IV (n=10) and Level V (n=13) using the Gross Motor Function Classification System. Patients received intravenous pamidronate (4.12 mg/kg/y, maximum 45 mg/d) every 4 months. Lumbar spine and femoral neck BMD were measured at baseline and after 4 and 12 months. Twelve months after the first dose of pamidronate there was a significant increase in lumbar spine and femoral neck BMD (p<0.01 for both sites) and z scores compared with baseline values (p<0.01 for both sites). Mean BMD z scores increased 1.6 points for femoral neck and 1.9 points for lumbar spine after 12 months of pamidronate treatment. Serum intact parathyroid hormone increased significantly and cross-linked N-teleopeptide of type I collagen decreased significantly at 12 months. No significant side effect was noted. Low doses of pamidronate are well tolerated and significantly increase BMD in non-ambulatory children and adolescents with CP.

Screening adherence in BRCA1/2 families is associated with primary physicians' behavior.

This study provides an assessment of long-term breast and ovarian cancer screening behaviors and the variables associated with adherence with screening among women with or at 50% for having a BRCA1/2 mutation. Participants in the study included 112 women (33 mutation carriers and 79 at 50% risk). Data was collected through a mailed questionnaire, which included items to assess screening behaviors in the last 2 years, risk perception, cancer specific distress, adherence determinants, specific barriers, and cancer history. Statistical analysis included descriptive statistics and non-parametric tests to describe bivariate associations and regression analysis. Adherence rates were 72% for annual mammography, 21% for semi-annual clinical breast exam (CBE), 29% for monthly breast self-exam (BSE), and 19% for annual transvaginal ultrasound (US). Only one participant was adherent with semi-annual CA125. Variables that had a significant association (P < 0.05) with at least one screening modality included: a lack of time, marital status, education, cancer history, provider concern, perceived screening utility, confidence in ability to overcome barriers, cancer specific distress, and risk perception. Primary physician behavior, either in terms of screening recommendations or screening performance in the case of CBE, had significant independent association with adherence to mammography, CBE, and US screening recommendations. The results of this study highlight the essential role that primary physicians play in supporting their very high-risk patients' adherence.