The Degradation Chemistry of Farglitazar and Elucidation of the Oxidative Degradation Mechanisms.

The chemical degradation of farglitazar (1) was investigated using a series of controlled stress testing experiments. Farglitazar drug substance was stressed under acidic, natural pH, basic, and oxidative conditions in solution. In the solid state, the drug substance was stressed with heat, high humidity, and light. Farglitazar was found to be most labile toward oxidative stress. A series of mechanistic experiments are described in which the use of 18O-labelled oxygen demonstrated that oxidative degradation of farglitazar is caused primarily by singlet oxygen formed under thermal conditions. Major degradation products were isolated and fully characterized. Mechanisms for the formation of degradation products are proposed. Drug product tablets were also stressed in the solid state with heat, high humidity, and light. Stressed tablets afforded many of the same degradation products observed during drug substance stress testing, with oxidation again being the predominant degradation pathway. Evidence for the activity of singlet oxygen, formed during thermal stress testing of the solid oral dosage form, is presented. The degradation pathways observed during stress testing matched those observed during long-term stability trials of the drug product.

A retrospective study of patients' out-of-pocket costs for granulocyte colony-stimulating factors.

OBJECTIVE: With rising healthcare costs, there is an increasing concern with the burden of out-of-pocket costs on cancer patients. This study examined patients' out-of-pocket expenditures for granulocyte colony-stimulating factors, pegfilgrastim and filgrastim, which are given to cancer patients receiving myelosuppressive chemotherapy and have been shown to decrease the incidence of febrile neutropenia. METHODS: Adult patients who received chemotherapy and granulocyte colony-stimulating factors in the outpatient setting in the United States between January 2007 and June 2010 were evaluated using medical and pharmacy claims data from two healthcare data sources, the MarketScan(®) Commercial and Medicare Supplemental Databases and the HealthCore Integrated Research Database(SM). The distribution of out-of-pocket costs for granulocyte colony-stimulating factors per patient and per administration was described for each quarter. Longitudinal analyses of out-of-pocket costs for granulocyte colony-stimulating factors were also performed for patients with continuous health plan eligibility during each calendar year from 2007 to 2009. RESULTS: The pattern of out-of-pocket expenditures for pegfilgrastim and filgrastim was generally consistent between the databases and over time. On average, about 65%-75% of patients had zero quarterly out-of-pocket costs for granulocyte colony-stimulating factors. Across the years, the mean quarterly out-of-pocket costs per patient were $100-$150 and $50-$80 for pegfilgrastim and filgrastim, respectively. The mean quarterly out-of-pocket costs for granulocyte colony-stimulating factors per administration were $40-$70 and $8-$10, respectively. CONCLUSION: In this retrospective analysis of medical and pharmacy claims data, most patients who received chemotherapy and granulocyte colony-stimulating factors in 2007 to 2010 had incurred no quarterly out-of-pocket costs associated with G-CSF use.

Systematic review on infusion reactions associated with chemotherapies and monoclonal antibodies for metastatic colorectal cancer.

OBJECTIVE: The objective of this systematic review is to summarize the literature to date on the rates of infusion reactions (IR) associated with chemotherapies and monoclonal antibody (mAb) drug therapies used for the treatment of metastatic colorectal cancer (mCRC) and the associated clinical and economic impact. METHODS: This study searched Medline, Medline (R) In-Process, Embase and Cochrane Library databases for studies on IRs associated with chemotherapy and mAbs in mCRC patients from 2000-2011. RESULTS: For chemotherapy, the incidence of IRs ranged from 0-71% for all grades and 0-15% for grade 3-4. Rates of all grade IRs associated with cetuximab ranged from 7.6-33% and grade 3-4 IR rates were 0-22%. Rates of all grade IRs associated with panitumumab ranged from 0-4% and rates of grade 3-4 IRs ranged from 0-1%. The overall rate of IRs associated with bevacizumab ranged from 1.6-11%, with a rate of 0-4% for grade 3-4 IRs. A range of 50-100% of patients with grade 3-4 IRs terminated chemotherapy, and 34-100% of cetuximab patients with grade 3-4 IRs discontinued cetuximab therapy. No data were reported for bevacizumab or panitumumab. Only one study evaluated the economic impact of IRs. The study compared cetuximab administrations without an IR to those with an IR requiring resource utilization and found that mean costs were $9308 and $1725 higher for those with an IR requiring an emergency room visit or hospitalization and for those with an IR requiring outpatient treatment, respectively. CONCLUSIONS: The incidence of IRs varies among different mAbs; and IRs may cause treatment disruption and require costly medical interventions.

"All eyes are on you": anorexia nervosa patient perspectives of in-patient mealtimes.

The aim of this qualitative study was to investigate in-patient perceptions of mealtimes on eating disorders units. Individual interviews were conducted with 12 women with anorexia nervosa. Using thematic analysis, three themes emerged as important: 1) Mealtime delivery (logistical factors influencing meals); 2) Individual outcomes (cognitions, emotions, behaviours and physical sensations during meals); and 3) Mealtime characteristics (including disengagement, perceived battlegrounds, and a desire for involvement in mealtimes). Future research should focus on areas of treatment delivery identified as important by patients. Recommendations are made regarding mealtime protocols based on patients' views, with increased recognition of behavioural, cognitive, physical and emotional aspects.

Mealtimes on eating disorder wards: a two-study investigation.

OBJECTIVE: This research had two aims. First, to assess the current mealtime practices within UK eating disorders units. Second, to investigate staff perspectives of these mealtimes, including their involvement and understanding of patients' experience. METHOD: Study 1 involved a survey to assess mealtime protocols across 22 eating disorders units. In Study 2, sixteen semistructured interviews were conducted with staff at three eating disorders units. RESULTS: Between and within-unit variation exist regarding the implementation of mealtimes. Thematic analysis revealed that staff perceived their provision of mealtimes to be influenced by their own interpersonal difficulties created by the meals. Additionally, they perceived that these issues could be aided by forward planning, successful teamwork, and focused staff training. DISCUSSION: There is a need for specialized mealtime implementation training. Furthermore, research is required to evaluate current mealtime practices from patient perspectives and to determine the impact of modified mealtime approaches on treatment outcome.

Effects of distraction and focused attention on actual and perceived food intake in females with non-clinical eating psychopathology.

The aim of this study was to determine the effects of distraction and focused attention on both food intake and accuracy of perceived intake in women with non-clinical levels of disordered eating. In a laboratory study, twenty-seven young women consumed three identical pasta meals once a week for three consecutive weeks. Meals were eaten ad libitum during a control and two test conditions, in which attention was either diverted away from (distraction condition) or directed towards food-related stimuli (focused attention condition). They also completed the drive for thinness, bulimia and body dissatisfaction subscales of the Eating Disorders Inventory-2. Intake was significantly higher in the distraction than in the control or focused attention conditions, but was not related to eating psychopathology. A measure of accuracy of perceived intake indicated that drive for thinness was associated with overestimation of food intake in the focused attention condition. This study suggests that distraction could promote food intake in all non-clinical consumers, irrespective of individual differences in eating behaviours. Furthermore, it suggests that those with a high drive for thinness may overestimate intake when required to focus on their food. These findings could have implications for mealtime interventions in the treatment of eating disorders.

Treatment patterns and metastasectomy among mCRC patients receiving chemotherapy and biologics.

BACKGROUND: Several long-standing chemotherapy regimens are available to treat metastatic colorectal cancer (mCRC) including: oxaliplatin plus 5-fluorouracil (5-FU) and leucovorin (FOLFOX); and irinotecan plus 5-FU and leucovorin (FOLFIRI). More recently, new biologic therapies were approved for use in mCRC. OBJECTIVES: This study examined treatment patterns and trends in metastasectomy among newly diagnosed mCRC patients after the introduction of capecitabine (CAP) in 2001 and the biologic therapies in 2004. METHODS: Using a large, US-based administrative medical claims database of a national commercially insured population, patients with newly diagnosed mCRC were identified from 2001 to 2005. At least 6 months of patient history prior to mCRC diagnosis were required to confirm patients were newly diagnosed. Patients were followed from initial mCRC diagnosis to death, disenrollment, or 12/31/2006. Chemotherapy and biologic treatments and rates of metastasectomy over time were analyzed. RESULTS: A total of 3781 mCRC patients met the study criteria. The average time from mCRC diagnosis to initiation of systemic treatment decreased from 134.4 days (SD 261.2) to 61.7 days (SD 89.3) in 2001-2005 (p < 0.001). The most common first-line regimens were FOLFIRI (40%), 5-FU/LV (31%), and capecitabine (21%) in 2001, and FOLFOX plus bevacizumab (22%), FOLFOX alone (15%), 5-FU/LV (15%), and capecitabine (15%) in 2005. Among patients with ≥1 year of follow-up, the use of biologics increased from 37.3% in 2004 to 52.0% in 2005 (p < 0.001). The percentage of patients who underwent resection after systemic treatment increased from 2.9% to 5.6% in 2001-2005 (p = 0.169). CONCLUSIONS: Over time the standard of care chemotherapy for 1st-line mCRC has changed from FOLFIRI to FOLFOX, and the use of biologics has become common. The percentage of patients who underwent resection after systemic treatment almost doubled during the study period.

The impact of methodological approach on cost findings in comparison of epoetin alfa with darbepoetin alfa.

BACKGROUND: Two erythropoiesis-stimulating agents (ESAs), epoetin alfa and darbepoetin alfa, are approved for the treatment of chemotherapy-induced anemia in patients with cancer. Randomized controlled trials indicate that the drugs are similarly efficacious, but that the duration of clinical benefit (DCB) ranges from 2 to 7 days for epoetin alfa and from 7 to 21 days for darbepoetin alfa, depending on dose. Given equivalent efficacy, payers are increasingly interested in understanding the cost differences for these 2 drugs. OBJECTIVE: To examine the impact of different methodological approaches on the cost comparison between epoetin alfa and darbepoetin alfa users, with cancer from a payer perspective. METHODS: Episodes of care (episode) were constructed for cancer patients treated with ESAs, using MarketScan claims data. Episodes started with the first ESA claim and ended on the last ESA claim or the claim before a 42-day or longer gap in ESA therapy. Each episode was augmented with an estimated DCB based on the last dose in the episode. Cost was reimbursed amount observed in the claims database. Adjusted weekly cost was estimated using generalized linear models to control for difference in clinical and demographic differences across epoetin alfa and darbepoetin alfa episodes. RESULTS: Episodes were created in 324 darbepoetin alfa and 342 epoetin alfa users. Darbepoetin alfa users tended to be younger, had more comorbidities, and had advanced cancer (all p < 0.001). After accounting for DCB, the average weekly cost of darbepoetin alfa was significantly lower than that of epoetin alfa ($619 vs $940; p < 0.001). After multivariate adjustment, darbepoetin alfa had lower costs than epoetin alfa in the base case and all alternative approaches. CONCLUSIONS: To reduce the risk of potential bias, DCB and different patient characteristics should be taken into account when using retrospective claims data to conduct cost comparisons between agents that have significant differences in dosing schedule.

Treatment of nonmuscle invading bladder cancer: do physicians in the United States practice evidence based medicine? The use and economic implications of intravesical chemotherapy after transurethral resection of bladder tumors.

BACKGROUND: Phase 3 clinical trials performed primarily outside the US demonstrate that intravesical instillation of chemotherapy immediately after transurethral resection of the bladder (TURB) decreases cancer recurrence rates. The authors sought to determine whether US urologists have adopted this practice, and its potential effect on costs of bladder cancer (BC) care. METHODS: By using 1997-2004 MEDSTAT claims data, the authors identified patients with newly diagnosed BC who underwent cystoscopic biopsy or TURB, and those who received intravesical chemotherapy within 1 day after TURB. Economic consequences of this treatment compared with TURB alone were modeled using published efficacy estimates and Medicare reimbursements. The authors used a time horizon of 3 years and assumed that this treatment was given for all newly diagnosed low-risk BC patients. RESULTS: Between 1997 and 2004, the authors identified 16,748 patients with newly diagnosed BC, of whom 14,677 underwent cystoscopic biopsy or TURB. Of these, only 49 (0.33%) received same-day intravesical instillation of chemotherapy. From 1997 through 2004, there has been little change in the use of this treatment. The authors estimated a 3-year savings of $538 to $690 (10% to 12%) per patient treated with TURB and immediate intravesical chemotherapy compared with TURB alone, reflecting a yearly national savings of $19.8 to $24.8 million. CONCLUSIONS: Instillation of intravesical chemotherapy immediately after TURB has not been embraced in the US. Adopting this policy would significantly lower the cost of BC care.

Characteristics of patients initiating raloxifene compared to those initiating bisphosphonates.

BACKGROUND: Both raloxifene and bisphosphonates are indicated for the prevention and treatment of postmenopausal osteoporosis, however these medications have different efficacy and safety profiles. It is plausible that physicians would prescribe these agents to optimize the benefit/risk profile for individual patients. The objective of this study was to compare demographic and clinical characteristics of patients initiating raloxifene with those of patients initiating bisphosphonates for the prevention and treatment of osteoporosis. METHODS: This study was conducted using a retrospective cohort design. Female beneficiaries (45 years and older) with at least one claim for raloxifene or a bisphosphonate in 2003 through 2005 and continuous enrollment in the previous 12 months and subsequent 6 months were identified using a collection of large national commercial, Medicare supplemental, and Medicaid administrative claims databases (MarketScan). Patients were divided into two cohorts, a combined commercial/Medicare cohort and a Medicaid cohort. Within each cohort, characteristics (demographic, clinical, and resource utilization) of patients initiating raloxifene were compared to those of patients initiating bisphosphonate therapy. Group comparisons were made using chi-square tests for proportions of categorical measures and Wilcoxon rank-sum tests for continuous variables. Logistic regression was used to simultaneously examine factors independently associated with initiation of raloxifene versus a bisphosphonate. RESULTS: Within both the commercial/Medicare and Medicaid cohorts, raloxifene patients were younger, had fewer comorbid conditions, and fewer pre-existing fractures than bisphosphonate patients. Raloxifene patients in both cohorts were less likely to have had a bone mineral density (BMD) screening in the previous year than were bisphosphonate patients, and were also more likely to have used estrogen or estrogen/progestin therapy in the previous 12 months. These differences remained statistically significant in the multivariate model. CONCLUSION: In this sample of patients enrolled in commercial, Medicare, and Medicaid plans, patients who initiated raloxifene treatment differed from those initiating bisphosphonates. Raloxifene patients were younger, had better overall health status and appeared to be less likely to have risk factors for new osteoporotic fractures than bisphosphonate patients. Differences in the clinical profiles of these agents may impact prescribing decisions. Investigators using observational data to make comparisons of treatment outcomes associated with these medications should take these important differences in patient characteristics into consideration.

Identifying patients with benign prostatic hyperplasia through a diagnosis of, or treatment for, erectile dysfunction.

OBJECTIVE: Erectile dysfunction (ED) and lower urinary tract symptoms (LUTS) associated with benign prostate hyperplasia (BPH) are highly correlated. This study examined rates of screening, diagnosis, and treatment of BPH/LUTS among men seeking care for ED. RESEARCH DESIGN AND METHODS: This was a retrospective US claims data analysis (1999-2004) evaluating men > or = 40 years old with a new diagnosis of or prescription medication for ED. Multivariate analyses were used to examine times to screening, diagnosis, and treatment. RESULTS: 81 659 men with ED were identified (mean age 57 years). The baseline prevalence of recorded BPH was 1.5%. During the follow-up period (mean 2.2 years), 7.6% had documented BPH. Time to screening was shorter among patients seeing urologists (121.1 days) compared with those seeing primary-care physicians (282.2 days). Controlling for demographic and clinical characteristics, patients who saw a urologist were more likely to be screened (OR: 2.4, p < 0.0001), diagnosed with BPH (OR: 1.8, p < 0.0001), and treated (OR: 1.3, p < 0.0001), relative to patients seeing other providers. Men aged 75 and over were 43% less likely to be screened (p < 0.0001), but 5.4 times more likely to be diagnosed with BPH (p < 0.0001) and 5.3 times more likely to be treated (p < 0.0001) compared with men aged 40-49. CONCLUSIONS: Screening for BPH appears less likely for men with ED who do not see a urologist. When screening does occur, it takes much longer with non-specialty providers. Patient age and provider specialty are key factors associated with screening, diagnosis, and treatment of BPH among men with ED.

Enantiotropically-related polymorphs of {4-(4-chloro-3-fluorophenyl)-2-[4-(methyloxy)phenyl]-1,3-thiazol-5-yl} acetic acid: crystal structures and multinuclear solid-state NMR.

Single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), and solid-state NMR (SSNMR) techniques are used to analyze the structures of two nonsolvated polymorphs of {4-(4-chloro-3-fluorophenyl)-2-[4-(methyloxy)phenyl]-1,3-thiazol-5-yl} acetic acid. These polymorphs are enantiotropically-related with a thermodynamic transition temperature of 35 +/- 3 degrees C. The crystal structure of Form 1, which is thermodynamically more stable at lower temperatures, was determined by SCXRD. The crystal structure of Form 2 was determined using PXRD structure solution methods that were assisted using two types of SSNMR experiments, dipolar connectivity experiments and chemical shift measurements. These experiments determined certain aspects of local conformation and intermolecular packing in Form 2 in comparison to Form 1, and provided qualitative knowledge that assisted in obtaining the best possible powder structure solution from the X-ray data. NMR chemical shifts for 1H, 13C, 15N, and 19F nuclei in Forms 1 and 2 are sensitive to hydrogen-bonding behavior, molecular conformation, and aromatic pi-stacking interactions. Density functional theory (DFT) geometry optimizations were used in tandem with Rietveld refinement and NMR chemical shielding calculations to improve and verify the Form 2 structure. The energy balance of the system and other properties relevant to drug development are predicted and discussed.

The Longitudinal Examination of Arthritis Pain (LEAP) study: relationships between weekly fluctuations in patient-rated joint pain and other health outcomes.

OBJECTIVE: To examine relationships between weekly fluctuations in self-rated joint pain and other health outcomes among adults with osteoarthritis (OA). METHODS: In this observational study, 287 adults (aged > or = 50 yrs) with hip or knee OA were recruited from 16 medical practices across the United States. Patients were telephoned weekly for 12 weeks to assess pain/stiffness, daily activities/function, productivity, emotional well-being, quality of life, and healthcare utilization. Associations between changes in joint pain levels and other health outcomes were evaluated using a generalized estimating equation model. RESULTS: The mean (SD) pain score at Week 1 was 4.2 (2.1) on the Western Ontario and McMaster Universities OA index (WOMAC) pain subscale (0 = no pain, 10 = extreme pain); during the study, 49% of patients reported a between-week fluctuation of > or = 2 points. A 2-point decrease in WOMAC pain subscale score was associated with a 22% decrease in number of days of limited activity/week (beta = -0.107; 95% confidence interval -0.163, -0.051); a 48% decrease in number of days of missed work/week (beta = -0.217; 95% CI -0.395, -0.039); a 14% decrease in number of nights with pain-related sleep interference/week (beta = -0.068; 95% CI -0.109, -0.027). Patients were 1.6 times more likely to contact a healthcare provider when their pain changed from "acceptable" to "unacceptable." CONCLUSION: Weekly fluctuations in pain levels and other health outcomes were identified among adults with OA. Decreases in patient-reported pain were associated with improvements in daily activities/functioning and decreases in work absenteeism, sleep interference, and healthcare resource use.

Assessment of the clinical management of fragility fractures and implications for the new HEDIS osteoporosis measure.

BACKGROUND: Rates of screening for and treatment of osteoporosis have been low, even among those with fractures who are at greatest risk for new fractures. OBJECTIVE: The objective of this study was to examine trends in the clinical management of patients with fragility fractures to provide baseline data for future assessments of the impact of the new Health Plan Employer Data and Information Set (HEDIS) measure. RESEARCH DESIGN: The MarketScan Medicare Supplemental and Coordination of Benefits (COB) database was used to examine adherence to the 2004 HEDIS guidelines by measuring the percent of women age 67 and older who were screened and/or treated after a fracture from 2000 through 2005. Clinical, demographic, and provider characteristics were assessed to determine the correlates of being screened and treated. RESULTS: The overall unadjusted percent of women screened and treated remains low, with just 10.2% screened and 12.9% treated in 2005. Multivariate analyses, which controlled for fracture location, patient characteristics, physician specialty, and region indicated small, albeit statistically significant, increases in treatment and screening over time. Women fracturing in 2005 were 27% more likely to be screened and 15% more likely to receive treatment relative to those fracturing in the year 2000. CONCLUSIONS: Although our study found some improvements in the screening for and treatment of osteoporosis among Medicare beneficiaries with a fragility fracture from 2000 through 2005, the overall percent of women screened and/or treated remained low. These data provide a baseline for assessing the impact of the new HEDIS measure in the coming years.

Health care cost associated with prostate cancer, androgen deprivation therapy and bone complications.

PURPOSE: We ascertained the health care costs of androgen deprivation therapy and related skeletal events. MATERIALS AND METHODS: Using data from the MarketScan Medicare Supplemental and Coordination of Benefits Database, we identified cases with International Classification of Disease, 9th Revision codes indicating a diagnosis of prostate cancer who initiated androgen deprivation therapy between 1999 and 2002. The control group consisted of patients with prostate cancer with no androgen deprivation therapy use, matched by age, geographic region, insurance plan and index year. All had followup data for at least 36 months. The occurrence and cost of osteoporosis and any bone fracture were assessed using a propensity score matched sample. RESULTS: Of the 8,577 eligible men with prostate cancer, 3,055 initiated androgen deprivation therapy and 5,522 did not. At the time of androgen deprivation therapy initiation those on androgen deprivation therapy had more severe comorbidity (3.1 vs 2.6, p <0.001) and proportionally more bone metastases (2.8% vs less than 0.6%, p <0.001) but no difference in fracture rate. After 3 years of followup the androgen deprivation therapy group experienced significantly more fractures (18.7% vs 14.6%, p <0.001). The mean unadjusted total cost of health care during the 36-month period was $48,350 per person for cases and $26,097 for controls. CONCLUSIONS: Among men with prostate cancer, those on androgen deprivation therapy cost the health care system almost twice as much as those not on androgen deprivation therapy. After controlling for differences in health status, the majority of the excess cost is attributable to androgen deprivation therapy and then to a lesser extent, the fractures. These results suggest that the bone complications of osteoporosis and fractures in men on androgen deprivation therapy have important economic consequences.

Economic burden of osteoporosis-related fractures in Medicaid.

OBJECTIVE: There are limited studies concerning the economic burden of osteoporosis in the Medicaid population. This study estimated the direct cost of osteoporosis-related fractures (OPFx) to state Medicaid budgets. METHODS: This retrospective analysis utilized Medicaid claims databases from three states, which included approximately 8 million Medicaid recipients. The study sample had at least one claim for an osteoporosis diagnosis (733.0x) between January 1, 2000 and December 31, 2001. Beneficiaries with a fracture and a diagnosis of osteoporosis were assigned to the case cohort. A propensity score-based matching method was used to select a cohort of controls with osteoporosis but without a fracture. An exponential conditional mean model was used to estimate the incremental annual cost associated with fractures. RESULTS: The study cohort (n = 7626) and a 1:1 matched control group were identified. The study cohort was 85.8% female, had an average age of 65 years, were 53.2% white, and 48.9% were eligible for Medicare. There were significant increases (all P < 0.05) from the preperiod to study period for this cohort in the proportion that had at least one hospital admission (14.0% vs. 26.5%), nursing home admission (9.2% vs. 17.2%), home health (39.1% vs. 49.3%), or emergency room visit (21.3% vs. 31.9%). In contrast, the control cohort had very little increase in utilization. The regression-adjusted incremental cost for osteoporosis-related expenses in the year after fracture was estimated at $4007 per patient. The estimated incremental cost was $5370 for the subset of patients who were eligible for Medicare. CONCLUSION: The economic burden of osteoporosis-related fractures on state Medicaid budgets is substantial.

Utilization and cost of health care services associated with primary malignant brain tumors in the United States.

OBJECTIVES: To evaluate the economic burden of primary malignant brain tumors in a commercially insured population in the United States, and to identify the primary drivers of health care resource use and cost. PATIENTS AND METHODS: A retrospective cohort analysis was performed using a 1998-2000 database containing inpatient, outpatient, and pharmacy claims for employees, their dependents, and early retirees of over 50 large US employers with wide geographic distribution. Patients were followed from first brain tumor diagnosis until death, termination of health benefits coverage, or study end. Controls without any cancer diagnosis were matched at a 3:1 ratio by demographic characteristics and length of follow-up. RESULTS: Patients with malignant brain tumors (n = 653) had significantly greater health service utilization and costs for hospitalizations, emergency room visits, outpatient office visits, laboratory tests, radiology services, and pharmacy-dispensed drugs (all P < 0.05) than did controls (n = 1959). Regression-adjusted mean monthly costs were $6364 for brain tumor patients, compared with $277 for controls (P < 0.0001). The primary cost driver was inpatient care ($4502 per month). Total costs during the study period were $49,242 for those with brain tumors and $2790 for controls (P < 0.0001). CONCLUSION: Patients with malignant brain tumors accrued health care costs that were 20 times greater than demographically matched control subjects without cancer. The costs for inpatient services were the primary drivers of total health resource use. Despite their low incidence, primary malignant brain tumors produce a substantial burden on the US health care system. There is a marked need for improved and new approaches to treatment to reduce the resource use and to offset health care costs associated with this disease.

Acyclic, orally bioavailable ketone-based cathepsin K inhibitors.

Starting from a potent ketone-based inhibitor with poor drug properties, incorporation of P(2)-P(3) elements from a ketoamide-based inhibitor led to the identification of a hybrid series of ketone-based cathepsin K inhibitors with better oral bioavailability than the starting ketone.

Medical costs associated with non-Hodgkin's lymphoma in the United States during the first two years of treatment.

OBJECTIVES: To determine the direct costs of medical care associated with aggressive and indolent non-Hodgkin's lymphoma (NHL) in the United States; to show how costs for aggressive NHL change over time by examining costs related to initial, secondary and palliative treatment phases; and to evaluate the economic consequences of treatment failure in aggressive NHL. PATIENTS AND METHODS: A retrospective cohort analysis of 1999 - 2000 direct costs in newly diagnosed NHL patients and controls (subjects without any cancer) was conducted using the MarketScan medical and drug claims database of large employers across the United States. Treatment failure analysis was conducted for aggressive NHL patients, and was defined by the need for secondary treatment or palliative care after initial therapy. Cost of treatment failure was calculated as difference in regression-adjusted costs between patients with initial therapy only and patients experiencing initial treatment failure. RESULTS: Patients with aggressive (n = 356) and indolent (n = 698) NHL had significantly greater health service utilization and associated costs (all P < 05) than controls (n = 1068 for aggressive, n = 2094 for indolent). Mean monthly costs were 5871 dollars for aggressive NHL vs. 355 dollars for controls (P < 0001) and 3833 dollars for indolent NHL vs. 289 dollars for controls (P < 0001). The primary cost drivers were hospitalization (aggressive NHL = 44% of total costs, indolent NHL = 50%) and outpatient office visits (aggressive NHL = 39%, indolent NHL = 34%). For aggressive NHL, mean monthly initial treatment phase costs (10,970 dollars) and palliative care costs (9836 dollars) were higher than costs incurred during secondary phase (3302 dollars). The mean cost of treatment failure in aggressive NHL was 14,174 dollars per month, and 85,934 dollars over the study period. CONCLUSION: The treatment of NHL was associated with substantial health care costs. Patients with aggressive lymphomas tended to accrue higher costs, compared with those with indolent lymphomas. These costs varied over time, with the highest costs occurring during the initial treatment and palliative care phases. Treatment failure was the most expensive treatment pattern. New strategies to prevent or delay treatment failure in aggressive NHL could help reduce the economic burden of NHL.