Pharmacokinetics of mycophenolate mofetil in stable pediatric liver transplant recipients receiving mycophenolate mofetil and cyclosporine.

There are few pharmacokinetic data for mycophenolate mofetil (MMF) when used in combination with cyclosporine (CsA) in pediatric liver transplant recipients. The aim of this study was to assess the pharmacokinetics of MMF in stable pediatric liver transplant patients and estimate the dose of MMF required to provide a mycophenolic acid (MPA) exposure similar to that observed in adult liver transplant recipients receiving the recommended dose of MMF (target area under the plasma concentration-time curve from 0 to 12 hours [AUC(0-12)] for MPA of 29 mug.hour/mL in the immediate posttransplantation period and 58 microg x hour/mL after 6 months). A 12-hour pharmacokinetic profile was collected for 8 pediatric patients (mean age 20.9 months) on stable doses of MMF and CsA who had received a liver transplant > or = 6 months prior to entry and who had started on MMF within 2 weeks of transplantation. Mean MMF dosage was 285 mg/m(2) (range, 200-424 mg/m(2)). Of 8 patients, 7 had a MPA AUC(0-12) (range, 11.0-37.2 microg x hour/mL) well below the target. One patient had an AUC(0-12) > or = 58 microg x hour/mL but was considered an outlier and was excluded from analyses. Mean MPA AUC(0-12) and maximum plasma concentration values were 22.7 +/- 10.5 microg x hour/mL and 7.23 +/- 3.27 microg/mL, respectively; values normalized to 600 mg/m(2) (the approved pediatric dose in renal transplantation) were 47.0 +/- 21.8 microg x hour/mL and 14.5 +/- 4.21 microg/mL. In conclusion, assuming that MPA exhibits linear pharmacokinetics, when used in combination with CsA, a MMF dose of 740 mg/m(2) twice daily would be recommended in pediatric liver transplant recipients to achieve MPA exposures similar to those observed in adult liver transplant recipients. This finding should be confirmed by a prospective trial.     

Effects of diet-induced ketosis in rats with hypoglycaemia due to a serially transplantable insulinoma

In view of the ability of ketones to partially replace glucose as an alternative fuel in the brain, the potential protective effects of diet-induced ketosis were examined in male NEDH rats with hypoglycaemia due to a serially transplantable radiation-induced insulinoma. Ketosis was induced by daily oral administration of medium chain triglycerides to normal rats and to insulinoma-bearing rats 1 day after subcutaneous subscapular implantation of tumours fragments. All rats treated with medium chain triglycerides became ketotic within 72 hours, and plasma 3-hydroxybutyrate concentrations remained 5-10 fold elevated at 24 days. Untreated insulinoma-bearing rats became moderately hyperinsuliaemic and hypoglycaemic by 17 days, with the later manifestation of more marked hyperinsulineamia (21.6 +/- 0.8 ng/ml, mean +/- SEM) severe hypoglycaemia (1.5 +/- 0.1 mmol/l) and death by 24-28 (26 +/- 1) days. Induction and maintenance of hyperketonaemia did not affect the development of hyperinsulineamia, hypoglycaemia or the exaggerated fall of plasma glucose produced by an 8 hour fast in these rats. However by day 21, the severity of hypoglycaemia was greater in insulinoma-bearing rats receiving medium chain triglycerides, culminating in accelerated death by 22-25 (23 +/- 1) days and an accompanying 50% decrease in final tumour weight. These results demonstrate that induction of ketosis in the face of marked hyperinsulinaemia did not afford protection against the profound hypoglycaemia produced by a serially transplantable rat insulinoma.     

Quantitative Magnetic Resonance Imaging of Human Brain Development: Ages 4-18

Brain magnetic resonance images (MRI) of 104 healthy childrenand adolescents, aged 4–18, showed significant effectsof age and gender on brain morphometry. Males had larger cerebral(9%) and cerebellar (8%) volumes (P < 0.0001 and P = 0.008.respectively), which remained significant even after correctionfor height and weight After adjusting for cerebral size, theputamen and globus pallidus remained larger in males, whilerelative caudate size was larger in females. Neither cerebralnor cerebellar volume changed significantly across this agerange. Lateral ventricular volume increased significantly inmales (trend for females), with males showing an increase inslope after age 11. In males only, caudate and putamen decreasedwith age (P = 0.007 and 0.05, respectively). The left lateralventricles and putamen were significantly greater than the rightP = 0.01 and 0.0001, respectively). In contrast, the cerebralhemispheres and caudate showed a highly consistent right greater-than-leftasymmetry (P < 0.0001 for both). All volumes demonstrateda high degree of variability. These findings highlight gender-specificmaturational changes of the developing brain and the need forlarge gender-matched samples in pediatric neuropsychiatric studies.     

Brain growth among fetuses exposed to cocaine in utero: asymmetrical growth retardation

Fetal growth retardation may be associated with maternal cocaine use during pregnancy. The pattern of fetal growth retardation was analyzed in infants born to 80 women who used cocaine, but not alcohol, during pregnancy, and in two comparison groups: 100 infants born to mothers who used neither alcohol nor cocaine during pregnancy and 67 infants whose mothers used alcohol but not cocaine during pregnancy. There were statistically significant differences in head size between the unexposed and cocaine-exposed infants (P less than .001). Notably, head circumference was reduced proportionately more than birth weight in cocaine-exposed infants, a pattern similar to that observed in alcohol-exposed infants. Alcohol- and cocaine-exposed infants were not statistically different in head circumference. We conclude that brain growth of cocaine-exposed infants is similar to that reported for alcohol-exposed infants, and that cocaine-exposed infants may be characterized as having asymmetrical growth retardation.     

Sirolimus allows renal recovery in lung and heart transplant recipients with chronic renal impairment.

BACKGROUND: Until recently, there has been no practical alternative to the use of calcineurin inhibitors (CIs) as primary immunosuppressants in lung transplantation (LTx) and heart transplantation (HTx). Sirolimus (SRL) is a novel powerful immunosuppressant without renal toxicity, a common post-transplant problem associated with CI therapy. METHODS: SRL was used in 20 LTx and 5 HTx recipients >90 days post-transplant, where serious renal impairment was limiting CI dosing. Patients started on 2 to 5 mg/day orally at a median of 1,185 days post-transplant. Dosage adjustments were made according to trough levels, toxicity and perceived efficacy. With SRL initiation, 48% ceased CI therapy and the remainder decreased their dose substantively. RESULTS: After 30 days, 4 of 5 dialyzed patients ceased dialysis and 15 of 20 patients with an elevated serum creatinine (Cr) (mean Cr 0.29 mmol/liter) improved their Cr. The direction of change in Cr at 30 days predicted longer term Cr. The starting Cr did not predict the 30-day or long-term value. There were two bouts of acute and one bout of chronic rejection. There were 35 infectious complications in 16 patients and 24 episodes of potential SRL-related toxicity in 17 patients. These events generally responded to dose reduction or temporary cessation and were level-related. Fifteen recipients presently remain on the drug. None of the 7 deaths could be directly related to toxicity. CONCLUSION: SRL is a useful alternative immunosuppressant, allowing significant CI withdrawal in transplant recipients with renal impairment. Whether the resulting improvement in Cr can be maintained in the long term probably depends on the balance between the extent of acute and chronic renal damage.     

Effect of inhaled fluticasone propionate on BAL TGF-beta(1) and bFGF concentrations in clinically stable lung transplant recipients.

BACKGROUND: Inhaled fluticasone propionate (FP) therapy decreases inflammation and sub-basement membrane thickness in asthmatic airways. Bronchiolitis obliterans syndrome (BOS) in lung transplant recipients (LTRs) involves progressive airway fibrosis and obliteration. Therefore, augmented immunosuppression may be of some benefit in treating BOS. In this study, we examined the effect of 3 months of treatment with high-dose inhaled FP on the concentrations of 2 fibrogenic factors, transforming growth factor (TGF)-beta(1) and beta fibrogenic growth factor (bFGF) in bronchoalveolar lavage (BAL) fluid from clinically stable LTRs. METHODS: We conducted a randomized, double-blind, placebo-controlled, parallel group study with inhaled FP (750 microg, twice/day for 3 months) in 28 LTRs (15 FP and 13 placebo). We recruited 23 healthy controls. We performed spirometry, bronchoscopy, and bronchoalveolar lavage procedures before treatment and after 3 months of treatment. We used commercially available enzyme-linked immunosorbent assay kits to measure BAL fluid TGF-beta(1) and bFGF concentrations. RESULTS: In LTRs before treatment, BAL TGF-beta(1) concentrations (but not bFGF concentrations), total cell counts, and neutrophil percentage increased compared with controls (p < 0.05). We found no significant differences between FP and placebo groups at baseline measurements. After treatment, BAL TGF-beta(1) concentrations significantly increased in the FP group (p = 0.03), but we found no difference between FP and placebo groups; BAL bFGF concentrations increased during treatment in both groups compared with controls (p < 0.05), but not significantly within either patient group (p > 0.05). We found a reverse correlation between forced expiratory volume in 1 second (FEV(1)) and BAL TGF-beta(1) concentration in the FP group (r = -0.53, p = 0.04), and between FEV(1) and BAL TGF-beta(1) concentration in the placebo group (r = -0.74, p = 0.004). Multivariable analysis indicated no significant independent effects of inhaled FP in either BAL TGF-beta(1) or bFGF concentrations. CONCLUSIONS: Bronchoalveolar fluid TGF-beta(1) concentrations increased in LTRs after transplantation and may correlate with the decrease in lung function. Inhaled FP added to conventional immunosuppression had no effect on TGF-beta(1) or bFGF production in BAL fluid.     

Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products

Tuberous sclerosis (TSC) is an autosomal dominant disorder caused by a mutation in either the TSC1 or TSC2 tumour suppressor gene. The disease is characterized by a broad phenotypic spectrum that can include seizures, mental retardation, renal dysfunction and dermatological abnormalities. TSC2 encodes tuberin, a putative GTPase activating protein for rap1 and rab5. The TSC1 gene was recently identified and codes for hamartin, a novel protein with no significant homology to tuberin or any other known vertebrate protein. Here, we show that hamartin and tuberin associate physically in vivo and that the interaction is mediated by predicted coiled-coil domains. Our data suggest that hamartin and tuberin function in the same complex rather than in separate pathways.