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.     

Mitogenic effects of thyrotropin and adenosine 3',5'-monophosphate in differentiated normal human thyroid cells in vitro

Previous studies of human thyroid cells in culture (mostly from pathological tissues) failed to demonstrate a mitogenic effect of TSH, leading to the proposal that the growth effect of TSH in vivo might be indirect. To reexamine the influence of TSH on DNA synthesis and cell proliferation, we established primary cultures of normal thyroid tissue from nine subjects. When seeded in a 1% serum-supplemented medium, thyroid follicles released by collagenase/dispase digestion developed as a cell monolayer that responded to TSH by rounding up and by cytoplasmic retraction. When seeded in serum-free medium, the cells remained associated in dense aggregates surrounded by few slowly spreading cells. In the latter condition, the cells responded to TSH and other stimulators of cAMP production, such as cholera toxin and forskolin, by displaying very high iodide-trapping levels. Exposure to serum irreversibly abolished this differentiated function. TSH stimulated the proliferation (as shown by DNA content per culture dish) of 1% serum cultured cells (doubling times were reduced from 106 to 76 h) and increased by 100% the [3H]thymidine labeling indices. In serum-free cultured cells (dense aggregates or cell monolayers after initial seeding with serum), control levels of DNA synthesis were lower, and up to 8-fold stimulation of DNA synthesis occurred in response to 100 mU/L TSH (stimulation was consistently detected with 20 mU/L), based on measurements of [3H]thymidine incorporation into acid-precipitable material and counts of labeled nuclei on autoradiographs (up to 40% labeled nuclei within 24 h). The mitogenic effect of TSH required a high insulin concentration (8.3 X 10(-7) mol/L) or a low insulin-like growth factor I concentration. The mitogenic effects of TSH were mimicked in part by cholera toxin, forskolin, and dibutyryl cAMP. Epidermal growth factor and phorbol myristate ester also stimulated thyroid cell proliferation and DNA synthesis, but they potently inhibited TSH-stimulated iodide transport. We conclude that TSH, acting at least in part through cAMP, is a potent growth factor for human thyroid cells and thus provide an experimental basis in vitro for the well established in vivo goitrogenic action of TSH.     

The development of food allergy after liver transplantation.

The acquisition of new food allergy after orthotopic liver transplantation is now a well described phenomenon, mainly reported in children. The etiology of this phenomenon is at present unclear, but has been ascribed by some to tacrolimus treatment. Here we report a case of liver transplant acquired food allergy (LTAFA) in a child who received a split liver graft. The case is remarkable for the absence of new food allergy in the adult recipient of the same graft. This suggests that host-specific factors play an important role in the development of food allergy after liver transplantation, and emphasizes the predisposition that children have toward this phenomenon. Possible mechanisms underlying the development of food allergy after liver transplantation are discussed. In conclusion, tacrolimus treatment alone cannot account for LTAFA. Host factors such as the maturity of immune regulatory mechanisms are likely to play a critical role in the development of new food allergy after a liver transplant.     

Focus groups: their role in developing calcium-related education materials

Because attitudes concerning a topic can diminish the effectiveness of educational materials, previously identified attitudes concerning calcium intake were explored through focus group interviews during the developmental stages of calcium education materials. Although four focus groups of six to seven participants were planned, each of the four groups consisted of two to six women. All focus groups followed the same format, lasting for 60–90 min; questions progressed from the general to more specific. The focus groups revealed several attitudinal barriers toward dietary behavioural change, including lack of prior interest in the topic and lack of time. Attitudes about dairy calcium included the belief that dairy foods were high in fat and should be avoided, and the belief that dairy foods would cause stomach upsets. Also, neither younger nor older women felt that osteoporosis was a problem their age group needed to address. Readability scales were not necessarily predictive of preference. This study shows that focus group interviews make a valuable contribution to planning and evaluating nutrition education materials.     

Nucleoside analogues: 8. Some isomers of B.3839, the original 5-fluorouracil/nitrosourea molecular combination, and their effect on colon, breast and lung tumours in mice

This study describes the manipulation of secondary products arising from the synthesis of the prototypical molecular combination of 5-fluorouracil (5-FU) and chloroethylnitrosourea (CNU), B.3839, in order to investigate the effects produced by connecting the C-S-C-C-CNU chain to the 5-FU ring in different ways. The isolation of phthalimide precursors of these compounds and the transformation into CNUs is described. Anti-tumour activity of these molecular combinations against a series of experimental murine colon, lung and mammary tumours is presented. The spectrum of anti-tumour activity displayed is interesting but defies simple explanation without further detailed in vivo pharmacokinetic and metabolism studies in order to define optimal profiles for activity.     

Trehalose protects against ocular surface disorders in experimental murine dry eye through suppression of apoptosis

The disaccharide trehalose is a key element involved in anhydrobiosis (the capability of surviving almost complete dehydration) in many organisms. Its presence also confers resistance to desiccation and high osmolarity in bacterial and human cells by protecting proteins and membranes from denaturation. The present study used a novel murine dry eye model induced by controlled low-humidity air velocity to determine whether topically applied trehalose could heal ocular surface epithelial disorders caused by ocular surface desiccation. In addition, the efficacy of 87.6 mM trehalose eyedrops was compared with that of 20% serum, the efficacy of which has been well documented. Mice ocular surface epithelial disorders were induced by exposure of murine eyes to continuous controlled low-humidity air velocity in an intelligently controlled environmental system (ICES) for 21 days, which accelerated the tear evaporation. The mice were then randomized into three groups: the control group received PBS (0.01M) treatment; a second group received 87.6 mM trehalose eyedrops treatment; and the third group received mice serum eyedrops treatment. Each treatment was administered as a 10 μl dose every 6 h for 14 days. The resultant changes in corneal barrier function and histopathologic examination of cornea and conjunctiva were analyzed and the level of apoptosis on the ocular surface was assessed using active caspase-3. After 14 days of treatment, the corneal fluorescein staining area, the ruffling and desquamating cells on the apical corneal epithelium, as well as the apoptotic cells on ocular surface epithelium had significantly reduced in eyes treated with trehalose compared with those treated with serum and PBS. In contrast, after 14 days of treatment, improvements in the thickness of the corneal epithelium, the squamous metaplasia in conjunctival epithelium and the number of goblet cells of the conjunctiva were less marked in eyes treated with trehalose compared with serum. These results demonstrated that trehalose could improve the appearance of ocular surface epithelial disorders due to desiccation through suppression of apoptosis. Trehalose produces some of the same responses as serum upon topical application and can maintain corneal health.     

Doctor – How do I use my EpiPen?

Parents and children who have been prescribed an Epipen are often unable to demonstrate its correct administration. One contributory factor may be that doctors are unfamiliar with the EpiPen and are unable to demonstrate the correct administration of the pen to the family. The aim of this study was to determine the rate of correct EpiPen demonstration by junior and Senior Medical Staff at a major tertiary paediatric Hospital. Junior and Senior medical staff were scored on their ability to correctly use the EpiPen trainer. A 6 step scoring system was used. One-hundred doctors were recruited (Residents n = 31, Senior Residents n = 39, Fellow/Consultants n = 30). Junior and Senior Medical staff had similar scores for EpiPen demonstration, the number that needed to read the EpiPen instructions prior to use and the frequancy of accidental self-injection into the thumb. Only two doctors (2%) demonstrated all 6 administration steps correctly. The most frequent errors made were not holding the pen in place for >5 seconds (57%), failure to apply pressure to activate (21%), and self-injection into the thumb (16%). Ninety five doctors needed to read the instructions, and of these, only 39 (41%) then proceeded to correctly demonstrate the remaining 5 steps. Forty-five doctors had previously dispensed an EpiPen, but only three demonstrated its use to parents/children with a trainer. The majority of doctors do not know how to use an Epipen and are unable to provide appropriate education to parents/children. In 37% of cases, the demonstration would not have delivered adrenaline to a patient.