but overexpression of type II receptor did not rescue Hfg inhibition of TGF-β-responsive promoter activity. Further, Hfg increased mRNA expression of the inhibitory Smad, Smad7 but knockdown of Smad7 did not rescue Hfg inhibition of TGF-β responsive genes. These data suggested that the effect of Hfg was not completely TGF-βdependent. We next studied the effect of Hfg on BMP signaling. Hfg reduced BMP–Smad-reporter (BRE)4 in MDA-MB-231 or PC-3 cells treated with BMP7, as well as significantly reduced phosphoSmad2/ 3 and phospho-Smad1/5/8 proteins. Further Hfg reduced ID1 mRNA, a BMP-regulated gene. These data suggest that Hfg is an effective therapy for bone metastases through both TGF-β-dependent and independent effects.

Purpose: Selecting the optimal treatment regimen for antiviral-naive patients may be difficult, given the concern about the antiviral activity, the development of drug resistance, and the increase in drug costs. This study evaluates the costs and effectiveness of using lopinavir/ritonavir (LPV/r) vs. nelfinavir (NFV), both coadministered with stavudine and lamivudine, as the first HAART regimen in treating HIV patients, based on the results from the published clinical trial M98-863. Method: A Markov model was developed using a combination of viral load (VL) and CD4 count as surrogate markers to define health states. VL and CD4 count data from the 48-week analysis of the clinical trial were used as measures of effect. The impact of resistance difference between NFV and LPWr was also examined. Results: Over the first 5 years, the model estimated that LPWr could save $3,461 per patient in total HIV care costs compared with NFV. If the resistance advantage of LPWr was taken into account, the cost savings by LPWr increased to $5,546. For longer term projection, without considering the resistance difference, the incremental cost-effectiveness ratio (CER) for LPWr vs. NFV was $6,653 per quality-adjusted life-year (QALY). This CER compares favorably to therapies for HIV disease and for common drug treatments for other conditions and is well within accepted thresholds for health policy makers. Conclusion: When treatment options are being considered, this study suggests that use of LPWr in the first antiretroviral regimen, as compared to NFV, is cost-effective based on improved efficacy and resistance.

4688 Background: Markers of osteoblastic activity, in particular bone alkaline phosphatase (BAP), increase in hormone refractory prostate cancer (HRPC) patients. BAP has been shown to be as valuable in predicting outcomes for men with HRPC as extent of bone disease, pain, or performance score. There are few data demonstrating prediction of quality of life (QOL) as a function of BAP. The relationship between BAP and QOL was explored in a study of atrasentan. Methods: Data from a randomized, double-blind, placebo-controlled phase 3 study of metastatic HRPC patients were analyzed (401 placebo, 408 atrasentan). Patients with a baseline BAP value and a baseline and final FACT-P score were analyzed and stratified according to baseline BAP value less than or equal to or greater than the median. Analysis of covariance (ANCOVA) was used to compare the mean change from baseline to final FACT-P assessment between baseline BAP stratified groups. In addition, ANCOVA was used to compare mean change from baseline to final BAP between treatment arms. Results: The median baseline BAP value was 25.2 ng/mL. Patients with baseline BAP level greater than the median experience a rapid clinically significant deterioration in disease-specific QOL compared to patients with baseline BAP level less than or equal to the median (table). The mean change from baseline to final is significantly smaller for atrasentan (13.19 ng/mL) versus placebo (33.86 ng/mL) (p=0.001). Conclusions: HRPC patients with high BAP levels experience significant rapid deterioration in disease-specific QOL. Therapies such as atrasentan, which have significant effect on lowering BAP levels, may reduce the rapid decline in the QOL of HRPC patients. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abbott Laboratories Abbott Laboratories

BACKGROUND:Prior research has indicated patient dissatisfaction with the odor, size, and taste of cyclosporine capsules, as well as the halitosis and body odor the capsules can cause. OBJECTIVES:The purposes of this investigation were to (1) compare the overall cyclosporine capsule preference (Gengraf vs Neoral) in stable, solid-organ transplant recipients, (2) assess patient preference based on specific capsule attributes, and (3) determine the reliability of the Cyclosporine Capsule SatiSfaCtion Survey (original to this study). METHODS:In this multicenter, randomized, open-label, parallel-group, preference study, patients were recruited from 144 centers in North America with established transplant programs. Solid-organ transplant recipients who had taken stable doses of cyclosporine (Neoral) for >/=2 consecutive months were randomized in a 9:1 ratio to receive another cyclosporine formulation (Gengraf) or to remain on Neoral therapy. Patients completed the Cyclosporine Capsule Satisfaction Survey prior to randomization (baseline survey) and after taking the study drug for 4 weeks (final survey). The survey consisted of multiple attribute items with high face validity in assessing patients' perceptions and preferences with regard to their overall experience, as well as specific attributes of cyclosporine capsules known to affect patient acceptance. RESULTS:The intent-to-treat population included 1906 patients (1211 men, 693 women [sex unknown in 2 patients]; mean [SD] age, 50.2 [12.4] years). A total of 1708 patients were switched to Gengraf; 198 continued on Neoral. Based on their overall experience with both capsule formulations, the majority of patients switched to Gengraf (61.9%) responded that they preferred the Gengraf capsule, compared with 13.7% who preferred the Neoral capsule and 24.4% who indicated no preference (P < 0.001). A similar preference for Gengraf was observed based on capsule odor (66.3%), ease of swallowing (51.5%), taste (57.1%), and impact on breath odor (52.5%) and body odor (48.4%) (P < 0.001 for each test). The results of internal consistency and reproducibility calculations were high for the Cyclosporine Capsule Satisfaction Survey. Internal consistency ranged from alpha = 0.84 to 0.95 for the subscales and was alpha = 0.95 for the overall score. Ranges for reproducibility in the subscales were r = 0.75 to 0.79, with an overall reproducibility of r = 0.85. Guyatt's responsiveness statistics for the subscale and overall scores were moderately high to very high, indicating that the survey is capable of measuring change in response to treatment. CONCLUSIONS:Of the transplant recipients receiving Gengraf in this study, most preferred Gengraf to Neoral based on overall experience, capsule odor, difficulty swallowing, taste, breath odor, and body odor. Among all study patients, fewer patients receiving Gengraf were bothered by capsule odor, difficulty in swallowing, taste, or the impact on breath or body odor compared with patients who continued to receive Neoral. Internal consistency, reproducibility, and responsiveness results show that the Cyclosporine Capsule Satisfaction Survey is a psychometrically valid instrument that is appropriate for use in clinical trials.