Cisapride may improve feeding tolerance of preterm infants: a randomized placebo-controlled trial.

To evaluate the efficacy of cisapride in improving tolerance of enteral feeding, 59 premature infants were randomized into a blinded placebo-controlled study. Treatment was initiated with the introduction of enteral feeding and continued until 150 ml/kg/day of milk were tolerated. Only in extremely low birth weight (ELBW) infants, was the time to tolerate full enteral feeding shorter in the treatment group, whereas ECG recordings showed a significantly prolonged QTc interval during treatment. Two children developed cardiac rhythm disturbances. In conclusion premature infants may not benefit from routine use of the drug to improve enteral feeding, and seem to be more vulnerable to its side effects.

CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes.

Azathioprine and its metabolite 6-mercaptopurine (6-MP) are immunosuppressive drugs that are used in organ transplantation and autoimmune and chronic inflammatory diseases such as Crohn disease. However, their molecular mechanism of action is unknown. In the present study, we have identified a unique and unexpected role for azathioprine and its metabolites in the control of T cell apoptosis by modulation of Rac1 activation upon CD28 costimulation. We found that azathioprine and its metabolites induced apoptosis of T cells from patients with Crohn disease and control patients. Apoptosis induction required costimulation with CD28 and was mediated by specific blockade of Rac1 activation through binding of azathioprine-generated 6-thioguanine triphosphate (6-Thio-GTP) to Rac1 instead of GTP. The activation of Rac1 target genes such as mitogen-activated protein kinase kinase (MEK), NF-kappaB, and bcl-x(L) was suppressed by azathioprine, leading to a mitochondrial pathway of apoptosis. Azathioprine thus converts a costimulatory signal into an apoptotic signal by modulating Rac1 activity. These findings explain the immunosuppressive effects of azathioprine and suggest that 6-Thio-GTP derivates may be useful as potent immunosuppressive agents in autoimmune diseases and organ transplantation.

The effect of midazolam on stress levels during simulated emergency medical service transport: a placebo-controlled, dose-response study.

UNLABELLED: Patients in the emergency medical service (EMS) may have increased endogenous catecholamines because of pain or fear and may benefit from sedation similar to premedication in the hospital. During a simulated EMS scene call, 72 healthy male volunteers were either transported by paramedics from a third-floor apartment through a staircase with subsequent EMS transport with sirens (three stress groups of n = 12; total, n = 36) or asked to sit on a chair for 5 min and lie down on a stretcher for 15 min (three control groups of n = 12; total, n = 36). Catecholamine plasma samples were measured in the respective stress and control groups at baseline and after placebo IV (n = 12) or 25 (n = 12) or 50 (n = 12) microg/kg of midazolam IV throughout the experiment, respectively. Statistical analysis was performed with analysis of variance; P < 0.05 was considered significant. The Placebo Stress versus Control group, but not the 50 microg/kg Stress Midazolam group, had both significantly increased epinephrine (73 +/- 5 pg/mL versus 45 +/- 5 pg/mL; P < 0.001) and norepinephrine (398 +/- 34 pg/mL versus 278 +/- 23 pg/mL; P < 0.01) plasma levels after staircase transport. After EMS transport, the Placebo Stress versus Control group had significantly increased epinephrine (51 +/- 4 pg/mL versus 37 +/- 4 pg/mL; P < 0.05) but not norepinephrine (216 +/- 24 pg/mL versus 237 +/- 18 pg/mL) plasma levels, whereas no significant differences in catecholamine plasma levels occurred between groups after either 25 or 50 microg/kg of midazolam. In conclusion, simulated EMS patients may be subject to more stress during staircase transport than during transport in an EMS vehicle. Titrating sedation with 25 microg/kg of midazolam significantly reduced endogenous catecholamines but not heart rate. IMPLICATIONS: Simulated emergency medical service patients were more likely to be stressed when being transported by paramedics through a staircase than in an ambulance. Accordingly, it may be beneficial to inject sedative drugs before initiating transport to ensure patient comfort and safety.

Pharmacokinetics of levofloxacin during continuous venovenous hemodiafiltration and continuous venovenous hemofiltration in critically ill patients.

STUDY OBJECTIVE: To assess the pharmacokinetics of levofloxacin during continuous venovenous hemodiafiltration (CVVHDF) and continuous venovenous hemofiltration (CVVH). DESIGN: Nonrandomized pharmacokinetic evaluation. SETTING: University surgical intensive care unit. PATIENTS: Six critically ill patients. INTERVENTION: Five patients received levofloxacin 500 mg/day and one patient received levofloxacin 125 mg/day All patients received continuous renal replacement therapy: CVVHDF on day 1 and CVVH on day 2, using an acrylonitrile hollow-fiber 0.9-m2 filter, constant blood flow rate of 90 ml/minute, substitution flow rate of 1 L/hour predilution, and dialysate flow rate of 1 L/hour (CVVHDF). MEASUREMENTS AND MAIN RESULTS: Serum, ultrafiltrate, and dialysate concentrations of levofloxacin were determined by high-performance liquid chromatography. Extracorporeal clearance was 26.05 +/- 4.66 ml/hour during CVVHDF and 15.71 +/- 2.73 ml/hour during CVVH (p<0.05). Elimination half-life was 28.08 +/- 4.5 hours and 45.9 +/- 17.7 hours, and distribution volume was 1.51 +/- 0.52 L/kg and 1.42 +/- 0.42 L/kg for CVVHDF and CVVH, respectively. Saturation was 0.76 +/- 0.13 for CVVHDF versus a sieving coefficient of 0.77 +/- 0.16 for CVVH. CONCLUSION: Marked extracorporeal elimination of levofloxacin occurs, requiring a dosage adjustment that can be calculated from the characteristics of CVVH and CVVHDF.