Pharmacokinetic interrelationships of irinotecan (CPT-11) and its three major plasma metabolites in patients enrolled in phase I/II trials

Irinotecan (CPT-11) is an analogue of 20(S)-camptothecin with promising activity against several tumor types. In patients, CPT-11 is metabolized to 7-ethyl-10-hydroxy-camptothecin (SN-38) and to the β-glucuronide of SN-38. Recently, we identified an additional metabolite of CPT11, 7-ethyl-10-[4.N- (5-aminopentanoic acid)-1-piperidino] carbonyloxycamptothecin (APC; L. P. Rivory et al., Cancer Res., 56: 3689-3694, 1996). The aim of this study was to investigate the interrelationships of all four compounds to identify factors that might be responsible for the large interpatient variability in CPT-11 and SN-38 kinetics. The plasma kinetics of CPT-11, SN-38, the β- glucuronide of SN-38, and APC were studied in 19 patients for a total of 33 cycles (115-600 mg/m). Although the area under the concentration curves (AUCs) of all compounds studied increased with dose, there was considerable variability. Ratios of the AUCs of the appropriate compounds were used as estimates of the major routes of metabolism (conversion of CPT-11 to SN-38, metabolism of CPT-11 to APC, and glucuronidation of SN-38). Each ratio varied more than 10-fold across the patient population, and the apparent extent of conversion of CPT-11 to SN-38 was highest at the 115 mg/m dose level. Interestingly, AUC(SN-38) was greater in patients with both high AUC(CPT-11) and AUC(APC). We conclude that the variability of the pharmacokinetics of CPT-11 and SN-38 is likely to be due to extensive interpatient differences in the pathways implicated in the metabolism of CPT-11

Endoscopic submucosal dissection with early multitraction placed before circumferential incision allows excellent exposure but with a risk of catching the muscularis propria

International audienc

Les changements précoces de poids et de pression artérielle sont associés à la mortalité chez les patients en dialyse

International audienc

Plasma osteoprotegerin is associated with mortality in hemodialysis patients.

Expression of bone proteins resulting from transdifferentiation of vascular smooth muscle cells into osteoblasts suggests that vascular calcifications are a bioactive process. Regulating molecules such as osteoprotegerin (OPG) and receptor activator of NF-kappaB ligand (RANKL) could play a key role in bone-vascular calcification imbalance. This study investigated the contribution of these proteins as well as mineral metabolism disorders in hemodialysis (HD) patient outcome. A total of 185 HD patients were followed up prospectively for 2 yr. In addition to clinical characteristics, mineral metabolism markers as well as OPG and soluble RANKL (sRANKL) were measured at baseline. After 2 yr, survival rates were described with Kaplan-Meier and compared with Cox regression analyses; 50 patients died (27 from cardiovascular diseases). Calcium, phosphate, and calcium x phosphate product were not associated with mortality. Both hyperparathyroidism (parathyroid hormone > or =300 pg/ml) and hypoparathyroidism (parathyroid hormone or =12.52 mg/L. In this condition, both highest (RR 5.68; 95% CI 1.48 to 22.73; P = 0.01) and lowest tertiles (RR 5.37; 95% CI 147 to 1968; P = 0.01) significantly predicted poor outcome. These results show that regulating-bone molecules, especially OPG, are strong predictors of mortality in HD patients, suggesting that OPG is a vascular risk factor, in particular in patients who have high C-reactive protein levels. OPG determination therefore should be added to the biologic follow-up of these patients

Association of aminothiols with the clinical outcome in hemodialysis patients: comparison of chromatography and immunoassay for homocysteine determination: aminothiols as predictive factors of hemodialysis outcome

Background: Controversial results about hyperhomocysteinemia and cardiovascular (CV) risk in hemodialysis (HD) could be due in part to the methodology used for homocysteine (Hcy) determination. Objective: To compare the influence of the method used for Hcy determination (chromatography or immunoassay), in regard to the association of Hcy with CV mortality rate in HD patients in a 3 year prospective study. Methods: One hundred sixty-two patients undergoing HD were included in a cohort study. Baseline Hcy levels were measured by high performance liquid chromatography (HPLC) and fluorescence polarization immunoassay (FPIA). Cysteine and cysteinylglycine were determined simultaneously to Hcy measure by HPLC. Results: Hcy levels obtained with both methods were highly correlated (r2=0.927, p<0.0001). An increased relative risk (RR) for CV mortality (n=31) was found between the highest against lowest tertile of Hcy both with HPLC: 2.74 [1.07-7.02, confidence interval 95% (CI)] (p<0.05) and with FPIA: 2.76 [0.99-7.70, CI 95%] (p=0.05). Interestingly, increased cysteine (≥452 µmol/L) and cysteinylglycine (≥36.6 µmol/L) levels were associated with decreased RR of non-CV death (n=26) (RR: 0.27 [0.09-0.79, CI 95%], p=0.02) for cysteine and RR: 0.28 [0.09-0.90, CI 95%], p=0.03 for cysteinylglycine when compared versus first tertile. Conclusion: This study demonstrated an increased risk of CV mortality in HD patients with Hcy values in the third tertile, independently to the method used. HPLC offers the advantage of simultaneously determination of other aminothiols that appear associated with non-CV mortality