The aims of our trial were to study the pharmacokinetics of tacrolimus in paediatric kidney transplant recipients. The study comprised 25 patients (median age 13 years, range 2-20 years) followed for 12 months; five pharmacokinetics profiles (within the first and second week and after 1 month, 6 months and 12 months) were obtained. Patients were divided into two groups: six children<6 years old and 19 older children. Tacrolimus was given at an initial dose of 0.15 mg/kg twice a day. Blood samples were drawn before and 1 h, 2 h, 3 h, 4 h, 6 h, 9 h and 12 h after drug administration. Patient and kidney survival rates were 100% at 1 year. At 6 months and 12 months creatinine clearance was 68.5+/-16.3 ml/min per 1.73 m2 and 64.0+/-15.2 ml/min per 1.73 m2 body surface area, respectively. Tacrolimus trough levels were 7.8+/-1.9 ng/ml and 7.3+/-2.5 ng/ml. The area under the concentration-time curve for 0 h to 12 h (AUC0-12) normalised to a dose of 0.15 mg/kg, increased with time from the kidney transplantation and stabilised after the 6th month post-transplantation. During the first month after transplantation the normalised tacrolimus concentration-time profiles were significantly greater in the older children (P<0.05); the actual doses were significantly greater in the younger children (P<0.05). In conclusion, initial doses of 0.15 mg/kg twice a day orally are safe and guarantee a satisfactory degree of immunosuppression, with our therapeutic regimen. Children<6 years old need to start with a 50% higher tacrolimus dose to achieve the same pharmacokinetic and immunosuppressive results.

In this study we assessed whether conditioned media from a human pancreatic cancer cell line (MIA PaCa 2) can interfere with some intracellular pathways involved in glucose metabolism in isolated rat hepatocytes. The hepatocytes. isolated from Male Wistar rats, were incubated with MIA PaCa 2-conditioned or nonconditioned media. Conditioned and nonconditioned hepatocytes were run for 120 min in the presence or absence of insulin (100 m M ) and were sampled at fixed time intervals. Supernatant glucose levels decreased to a similar extent over time in both conditioned and nonconditioned hepatocytes, while lactate levels significantlly increased in nonconditioned hepatocytes with respect to conditioned hepatocytes. A pyruvate kinase activity increase was observed only in nonconditioned hepatocytcs and was biphasic in nature, since this increased activity was dctccted both after a few and after 30 min following insulin stimulation. The cyclic A M P level increase was significantly higher in conditioned than in nonconditioned hepatocytes. It appears that MIA PaCa 2 cells produce a factor(s) that may interfere with one of the insulin-mediated intracellular pathways of glucose metabolism, namely, glycolysis. This detrimental effect on glycolysis is supported by the blunted rise in lactate concentration in the medium after the glucose challenge. This substance(s) probably transfers its signal inside the target cells, activating the adenylate cyclase pathway. These results support the hypothesis that pancreatic cancer is the cause rather than the consequence of diabetes mellitus. Key Words: Pancreatic cancer-Diabetes mellitus-MIA PaCa 2.Severall literature studies demonstrate a link between paincreatic cancer and altered glucose homeostasis (1-11). Overt diabetes mellitus and/or a reduced glucose tolerance are found in -80% of patients with pancreatic cancer (2,5,7). Several in vivo and in viiro studies attempted to identify the pathophysiological mechanism(s) responsible for the association between pancreatic cancer and diabetes mellitus. It hlas been shown that pancreatic cancerassociated diabetes does not depend on the destruction of pancreatic p cells (5,7,9) but, rather, on the Manuscript Address corrcspondence and reprint requcsts to Dott. M. Plebani.

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