Pharmacokinetics of S-1, an oral formulation of ftorafur,oxonic acid and 5-chloro-2,4-dihydroxypyridine (molar ratio 1:0.4:1) in patients with solid tumors

S-1 is an oral formulation of ftorafur (FT), oxonic acid and 5-chloro-2,4-dihydroxypyridine (CDHP) at a molar ratio of 1:0.4:1. FT is a 5-fluorouracil (5-FU) prodrug, CDHP is a dihydropyrimidine dehydrogenase (DPD) inhibitor and oxonic acid is an inhibitor of 5-FU phosphoribosylation in the gastrointestinal mucosa and was included to prevent gastrointestinal toxicity. We determined the pharmacokinetics of S-1 in 28 patients at doses of 25, 35, 40 and 45 mg/m(2). The plasma C(max) values of FT, 5-FU, oxonic acid and CDHP increased dose-dependently and after 1-2 h were in the ranges 5.8-13 microM, 0.4-2.4 microM, 0.026-1.337 microM, and 1.1-3.6 microM, respectively. Uracil levels, indicative of DPD inhibition, also increased dose-dependently from basal levels of 0.03-0.25 microM to 3.6-9.4 microM after 2-4 h, and 0.09-0.9 microM was still present after 24 h. The pharmacokinetics of CDHP and uracil were linear over the dose range. The areas under the plasma concentration curves (AUC) for CDHP and uracil were in the ranges 418-1735 and 2281-8627 micromol x min/l, respectively. The t(1/2) values were in the ranges 213-692 and 216-354 min, respectively. Cumulative urinary excretion of FT was predominantly as 5-FU and was 2.2-11.9%; the urinary excretion of both fluoro-beta-alanine and uracil was generally maximal between 6 and 18 h. During 28-day courses with twice-daily S-1 administration, 5-FU and uracil generally increased. Before each intake of S-1, 5-FU varied between 0.5 and 1 microM and uracil was in the micromolar range (up to 7 microM), indicating that effective DPD inhibition was maintained during the course. In a biopsy of an esophageal adenocarcinoma metastasis that had regressed, thymidylate synthase, the target of 5-FU, was inhibited 50%, but increased four- to tenfold after relapse in subsequent biopsies. In conclusion, oral S-1 administration resulted in prolonged exposure to micromolar 5-FU concentrations due to DPD inhibition, and the decrease in uracil levels after 6 h followed the pattern of CDHP and indicates reversible DPD inhibition.     

Substantial sick-leave costs savings due to a graded activity intervention for workers with non-specific sub-acute low back pain

The objective of this study is to compare the costs and benefits of a graded activity (GA) intervention to usual care (UC) for sick-listed workers with non-specific low back pain (LBP). The study is a single-blind, randomized controlled trial with 3-year follow-up. A total of 134 (126 men and 8 women) predominantly blue-collar workers, sick-listed due to LBP were recruited and randomly assigned to either GA (N = 67; mean age 39 ± 9 years) or to UC (N = 67; mean age 37 ± 8 years). The main outcome measures were the costs of health care utilization during the first follow-up year and the costs of productivity loss during the second and the third follow-up year. At the end of the first follow-up year an average investment for the GA intervention of €475 per worker, only €83 more than health care utilization costs in UC group, yielded an average savings of at least €999 (95% CI: −1,073; 3,115) due to a reduction in productivity loss. The potential cumulative savings were an average of €1,661 (95% CI: −4,154; 6,913) per worker over a 3-year follow-up period. It may be concluded that the GA intervention for non-specific LBP is a cost-beneficial return-to-work intervention.     

MR diagnosis of pancreatic transplant rejection

To determine the role of MR imaging in the assessment of pancreatic transplant rejection, we prospectively obtained 13 MR scans in nine transplant patients. The presence of rejection was verified pathologically by pancreatic transplant biopsies in five patients. In two additional patients, rejection was proved by concordant renal transplant biopsy as well as by compatible clinical and laboratory data. In the remaining two patients, in whom no biopsy was done, clinical and laboratory data showed no evidence of rejection. The mean T2 of the seven pancreata undergoing rejection was significantly elevated (86 msec) compared with the mean T2 of the two transplants not undergoing rejection (59 msec) (p less than .002). These preliminary results suggest that MR may be useful in the noninvasive diagnosis of pancreatic rejection.     

Effectiveness of a return-to-work intervention for subacute low-back pain

The effectiveness of return-to-work intervention for subacute low-back pain on work absenteeism, pain severity, and functional status was examined by means of a systematic review of randomized controlled trials. Publications in English that met the selection criteria were identified in a computer-aided search and assessed for methodological quality. A best-evidence synthesis was performed instead of statistical data pooling, because of the heterogeneity of the interventions and study populations. Five of nine studies comparing return-to-work intervention with usual care were identified as methodologically high-quality studies. Strong evidence was found for the effectiveness of return to work intervention on the return-to-work rate after 6 months and for the effectiveness of return-to-work intervention on the reduction of days of absence from work after > or = 12 months. It can be concluded that return-to-work interventions are equal or more effective regarding absence from work due to subacute low-back pain than usual care is.