Lipids in Children and Links to Adult Vascular Disease.

Atherosclerosis often begins in childhood or adolescence. Post-mortem studies in children have shown the presence of coronary atheroma, and there are hereditary conditions associated with hyperlipidaemia in childhood which lead to premature cardiovascular disease. Detection of hyperlipidaemia early in life can be crucial in the prevention of premature death from atherosclerosis. The circulating lipoproteins are in a constant state of flux, with passage of apolipoproteins and lipids between the various particles. Genetic variants of apolipoproteins can cause both hypercholesterolaemia and hypertriglyceridaemia. Elevated concentrations of lipoprotein(a) predispose to coronary artery disease. Another important molecule in lipid metabolism, proprotein convertase subtilisin/kexin type 9 (PCSK9), plays a crucial role in the removal of low-density lipoprotein (LDL) receptors. Reference intervals for the various lipid subfractions are now available for children, and there are guidelines regarding when to take action regarding paediatric hyperlipidaemia. The most important genetic condition in children which may lead to premature death from coronary heart disease is familial hypercholesterolaemia (FH). FH is best diagnosed and treated early in life. Most cases are due to defects in the LDL receptor. Pharmacotherapy for FH usually involves the statin group of drugs, although newer medications are now available, especially for the treatment of homozygous FH. Statin therapy has been demonstrated to be successful in preventing cardiac events in FH. Secondary dyslipidaemia in childhood can be associated with numerous diseases including diabetes, lifestyle disorders such as obesity, and drugs. Treatment of the underlying condition usually resolves the hyperlipidaemia.

Alpha-fetoprotein-a potential biomarker of intestinal regeneration in the infant.

We hypothesise that the human infant, whether born prematurely or at term, may have special capacities when mounting a healing response to severe post-natal gastrointestinal injury consequent upon stem cells of endodermal origin, located in the infant gut, persisting beyond the intrauterine period. Should such endodermal stem cells persist beyond birth, and should they survive any gastro-intestinal injury, there would be a possibility for them to be re-activated, and then to differentiate into progeny cells appropriate to replacement of the destroyed intestinal cell type(s). We therefore postulate that in infants who survive significant intestinal necrosis requiring surgical excision in the perinatal period, a component of the recovery process may include some degree of intestinal regeneration. Evidence for the regeneration of intestine would be evinced by measurement of a biomarker in the plasma of recovering infants--alpha-fetoprotein (AFP)--as this protein would be produced by early generations of these putative replacement progeny intestinal cells. We would anticipate an initial significant rise in the plasma AFP, prior to a plateau in levels, and then a subsequent fall in plasma AFP values. This would indicate the activity, then subsequent cessation, of any intestinal cell regenerative process. We have recently published a previously undescribed pattern of anomalous serial plasma concentrations of AFP in several infants who survived following significant intestinal necrosis and subsequent surgical resection. We consider this novel hypothesis, and our associated observation of another cause of rising AFP in the post-natal period, to support our contention regarding the presence and potential of intestinal stem cells, and a regenerative process within the infant gastro-intestinal system. This hypothesis has important implications for the understanding of the physiologic responses following gut cell necrosis in the human newborn as well as future approaches to research directions, clinical support and potential treatment modalities, during their recovery phase. Further studies are needed to confirm our hypothesis.

Population pharmacokinetics of mycophenolic acid in children and young people undergoing blood or marrow and solid organ transplantation.

AIMS: To characterize the population pharmacokinetics of mycophenolic acid (MPA) and evaluate dose regimens using a simulation approach and accepted therapeutic drug monitoring targets in children and young people undergoing blood or marrow, kidney and liver transplantation. METHODS: MPA concentration-time data were collected using an age specific sampling protocol over 12h. Some patients provided randomly timed but accurately recorded blood samples. Total and unbound MPA were measured by HPLC. NONMEM was employed to analyze MPA pharmacokinetic data. Simulations (n= 1000) were conducted to assess the suitability of the MPA dose regimens to maintain total MPA AUC(0,12h) within the range 30 and 60mg l(-1) h associated with optimal outcome. RESULTS: A two-compartment pharmacokinetic model with first-order elimination best described MPA concentration-time data. Population mean estimates of MPA clearance, inter-compartmental clearance, volumes of distribution in the central and peripheral compartments, absorption rate constant and bioavailability were 6.42 l h(-1) , 3.74 l h(-1) , 7.24 l, 16.8l, 0.39h(-1) and 0.48, respectively. Inclusion of bodyweight and concomitant ciclosporin reduced the inter-individual variability in CL from 54.3% to 31.6%. Children with a bodyweight of 10kg receiving standard MPA dose regimens achieve an MPA AUC below the target range suggesting they may be at a greater risk of acute rejection. CONCLUSIONS: The population pharmacokinetic model for MPA can be used to explore dosing guidelines for safe and effective immunotherapy in children and young people undergoing transplantation.

Amphotericin B dose optimization in children with malignant diseases.

In this study, rational dosing guidelines for amphotericin B-deoxycholate (AmB) are proposed for children. AmB steady-state trough concentrations (C(ss,trough)) and plasma creatinine concentrations (C(creat)) were measured in 83 children (age: 10 months to 18 years) receiving prophylactic AmB therapy (1 mg/kg/day). Maximum tolerable AmB C(ss,trough) were identified by determining the probability of large (>24%, 75th percentile) increases in C(creat) after 6 days of AmB for a series of C(ss,trough) ranges. Dose requirements were determined using a concentration-targeting approach. The 0.76-1.05 mg/l C(ss,trough) range provided the maximum concentrations that still had a low probability (p < 0.29) of adverse renal effects. 1 mg/kg/day AmB produces C(ss,trough) within this range for children weighing 25-45 kg. Lighter children (10-25 kg) require higher AmB doses (1.25-1.5 mg/kg/day) to achieve target C(ss,trough), while heavier children (45-55 kg) require lower doses (0.75 mg/kg/day). These starting dose guidelines may require individualization and prospective evaluation.

Artefactual reduction in plasma total carbon dioxide concentration in children.

METHODS: The effect on plasma total carbon dioxide (ctCO2) of collecting a small volume of blood into a large tube was investigated. In a 7-month-old infant presenting with diarrhoea the initial ctCO2 was low when 0.3 mL of sample was received in a 4-mL tube. To investigate this further blood samples were obtained from three volunteers on five occasions and various volumes were placed in a 4 mL container and analysed after varying intervals. RESULTS: When the sample volume was less than 2 mL there was a significant decrease in ctCO2. A 42% decrease was seen in the tube containing 0.3 mL after 4 h. CONCLUSIONS: We recommend that when a small volume of sample is collected it should be placed in a smaller tube with minimal air space.