Background:This study sought to determine the safety of single agent capecitabine, a pro-drug of 5FU, in patients with metastatic non-pancreatic neuroendocrine tumours (NETs).Methods:Multicentre phase II, first-line study design. Oral capecitabine was administered on days 1–14 of 3-week cycles.Results:Treatment was safe and well tolerated. Common toxicities were diarrhoea and fatigue.Conclusion:The study provides evidence to support the use of capecitabine as a substitute for infusional 5FU in the management of NETs.

Previous studies have shown that severe neonatal asphyxia and hypoxia lead to a redistribution of cerebral blood flow (CBF) with a preferential perfusion of the brain stem. The present study shows that this mechanism is operative also in moderately hypoxic newborn lambs (oxygen saturation 32.7-65.2) with a threshold of about 25% reduction in oxygen saturation. In hypoxia, the mean increase in total CBF, brain stem and telencephalic blood flow was 44%, 68% and 43%, respectively (five lambs). We found that naloxone reverses this redistribution, and that the effects of naloxone on telencephalic perfusion and cerebral metabolic rate of oxygen (CMRO2) were proportional. In hypoxia + naloxone (1 mg/kg), a further increase in total CBF, brain stem, and telencephalic blood flow of 30%, 7% and 31% was noted. We therefore suggest that the redistribution of CBF is an important opioid-mediated homeostatic mechanism, which diminishes the metabolic requirements of the newer part of the brain in hypoxia and allows a preferential perfusion of the vital structures of the brain stem.

To further investigate the neutrophil dysfunction of newborn infants, we have measured expression of the neutrophil Fc gamma receptors FcRIII and FcRII in extremely immature preterm neonates born at 24 to 32 weeks of gestation. Fc receptor expression was measured by FACS analysis of cells stained with monoclonal antibody Leu11b for FcRIII and IV-3 for FcRII. “Well” preterm neonates displayed reduced FcRIII, 51.05 +/- 2.0 (mean fluorescence channel +/- SE) when compared with term neonates, 69.24 +/- 5.5 and adult controls, 71.83 +/- 3.0. “Stressed” preterm neonates with severe respiratory distress syndrome or septicemia had a further downregulation of FcRIII, 32.67 +/- 3.0 and 35.75 +/- 1.8, respectively, associated with grossly abnormal cellular fluorescence distribution. In well preterm neonates, expression of FcRIII improved to adult levels during the first two postnatal weeks, suggesting a postnatal maturation of function. Stressed neonates had signs of partial neutrophil activation (increased Mac-1 expression and chemotactic ability), leading us to propose that the further downregulation of FcRIII may be due to receptor shedding in vivo by partially activated cells. FcRII expression was found to be equivalent to adult levels in both well preterm and stressed neonates. Reduced neutrophil FcRIII expression may provide some explanation for the reported abnormalities of phagocytosis and bacterial killing in preterm neonates.

SummaryThe syndrome of hypoxemia-related myocardial dysfunction in the newborn is generally associated with severe intrapartum asphyxia. We investigated the changes in total and regional distribution of myocardial blood flow (MBF) that occur during asphyxia and the factors that regulate MBF, in the chronically prepared, near term, fetal lamb. Studies were done in the awake, physiologically stable state 36-72 h after surgical preparation.In utero asphyxia was produced by partial cord occlusion and blood flow to fetal organs was measured by the radioactive microsphere technique. A complete set of control measurements was made, and then an occlusion loop was inflated to partially occlude the umbilical vessels. After 30-60 min of partial occlusion, all measurements were repeated. The third set of measurements was made after release of the occlusion loop. Six animals were studied and 17 sets of measurements obtained.Partial umbilical cord constriction produced a progressive asphyxia and acidosis. Cardiac output was severely depressed, although the increase in percentage of cardiac output directed to the myocardium (%F) was very significant. Release resulted in improved cardiac output and O2 and CO 2 exchange, although the metabolic acidosis was worse. No change occurred in the intramyocardial distribution of MBF during asphyxia or recovery. Total MBF was not significantly increased during asphyxia.Multiple linear regression analysis indicated that arterial oxygen saturation (Sa02) and heart rate were statistically significant predictor variables for absolute MBF, accounting for about 45% of the variation in MBF. Further analysis determined that mean arterial blood pressure, pH, P02, and Sa02 were all statistically significant univariate predictors of MBF as %F, but only Sa02 was a statistically significant multivariate predictor, accounting for about 82% of the variation in %F.

SUMMARY Twenty neutropenic patients with various haematological disorders were randomised prospectively to receive either intravenous amphotericin B alone or amphotericin B and oral amiloride 5 mg twice a day for treatment of confirmed or suspected fungal infection. Patients receiving amiloride had a significantly higher plasma potassium (p < 0 01), a significantly lower urinary potassium loss (p < 001), and required significantly less potassium chloride supplementation to maintain their plasma potassium within the normal range (p < 0O001). Amiloride was well tolerated, had no clinically important side effects, and provided effective control of plasma potassium in patients treated with amphotericin B.Invasive fungal infections are an important cause of morbidity and mortality in neutropenic patients. Amphotericin B is the most effective drug currently available for the management of systemic fungal infections in such patients, but nephrotoxicity is a major limiting factor in its use.' The nephrotoxic effects of amphotericin B are due to combined actions on both the glomeruli and renal tubules. In particular, selective distal tubular epithelial toxicity seems to be, at least in part, responsible for the profound potassium wasting which is a major clinical side effect of treatment with amphotericin B.2" Recent studies have also shown that amphotericin B also affects sodium flux in both the distal and transverse human colon, suggesting a further site of changed sodium/potassium exchange in patients treated with this agent.5The management of potassium wasting induced by amphotericin B may be difficult, and even large intravenous doses of potassium chloride may not be fully effective in correcting the hypokalaemia. As a consequence, clinical problems, especially muscle weakness and cardiac arrhythmias, are seen in a proportion of patients.Amiloride, a pyrazine derivative, is a potassium sparing diuretic widely used in clinical practice. It increases urinary excretion of sodium and bicarbonate while decreasing urinary potassium excretion by the distal convoluted tubule.6 Amiloride also has actions outside the kidney and inhibits sodium absorption Accepted for publication 16 December 1987 from the distal colon. Furthermore, the action of amiloride on this site potentially antagonises the effects of amphotericin B.'