Phase I and pharmacokinetic study of gefitinib in children with refractory solid tumors: a Children's Oncology Group Study.

PURPOSE: Epidermal growth factor receptor is expressed in pediatric malignant solid tumors. We conducted a phase I trial of gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, in children with refractory solid tumors. PATIENTS AND METHODS: Gefitinib (150, 300, 400, or 500 mg/m2) was administered orally to cohorts of three to six patients once daily continuously until disease progression or significant toxicity. Pharmacokinetic studies were performed during course one (day 1 through 28). RESULTS: Of the 25 enrolled patients, 19 (median age, 15 years) were fully evaluable for toxicity and received 54 courses. Dose-limiting toxicity was rash in two patients treated with 500 mg/m2 and elevated ALT and AST in one patient treated with 400 mg/m2. The maximum-tolerated dose was 400 mg/m2/d. The most frequent non-dose-limiting toxicities were grade 1 or 2 dry skin, anemia, diarrhea, nausea, and vomiting. One patient with Ewing's sarcoma had a partial response. Disease stabilized for 8 to > or = 60 weeks in two patients with Wilms' tumor and two with brainstem glioma (one exophytic). At 400 mg/m2, the median peak gefitinib plasma concentration was 2.2 microg/mL (range, 1.2 to 3.6 microg/mL) and occurred at a median of 2.3 hours (range, 2.0 to 8.3 hours) after drug administration. The median apparent clearance and median half-life were 14.8 L/h/m2 (range, 3.8 to 24.8 L/h/m2) and 11.7 hours (range, 5.6 to 22.8 hours), respectively. Gefitinib systemic exposures were comparable with those associated with antitumor activity in adults. CONCLUSION: Oral gefitinib is well tolerated in children. Development of the drug in combination with cytotoxic chemotherapy will be pursued.     

Interactions of angiotensin IV and oxytocin on behaviour in mice.

INTRODUCTION: Angiotensin (Ang) IV enhances learning and memory in rats but there are strain differences in its effects in mice. Oxytocin (OT) also influences learning and memory in rats and mice and, in the light of the proposed effects of Ang IV on oxytocinase, the hypothesis that the effects of Ang IV on cognition in mice involve OT was tested. MATERIALS AND METHODS: The effects of Ang IV and OT, alone and combined, were determined in rat isolated uterine smooth muscle and in object recognition and forced swim tests in BKW mice. RESULTS: Ang potentiated the contractile effects of OT in the uterus. Neither peptide had any effect on object recognition nor locomotor activity. Ang IV had no effect in the forced swim test but abolished the effects of OT. CONCLUSIONS: Ang IV influences the actions of OT in vitro and in vivo, possibly by inhibition of oxytocinase, but the lack of effect of Ang IV on object recognition in BKW mice is unlikely to be a consequence of a deficiency endogenous OT. Unlike OT, Ang IV alone has no effect on learned helplessness in the forced swim test, an effect often used to predict potential antidepressant efficacy in humans.     

The effect of age on binding of MK-801 in the cat visual cortex.

We have examined the effect of age on the binding of (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine maleate (MK-801) in the cat visual cortex. We hypothesized that this binding might change with age because: (1) MK-801 binds to a site associated with the N-methyl-D-aspartate (NMDA) receptor; (2) the NMDA receptor complex has been implicated in neural plasticity; (3) plasticity in the cat visual cortex is age dependent. We used standard receptor binding techniques to measure MK-801 binding in membrane homogenates in cats aged 7 days (d), 21 d, 43 d, 83 d, 7-8 months (mo) and over 2 years. Glutamate (100 microM), glycine (30 microM) and spermidine (20 microM) were used to enhance binding. We found that MK-801 binding is maximal at about 6 weeks of age, decreases slightly by 83 days and then decreases more dramatically in adults. Saturation analysis showed that the of binding with age resulted from variation in number of binding sites and not from variation in affinity. The ability of Mg2+ to inhibit MK-801 binding did not change with age. Dark rearing did not alter the development of MK-801 binding sites.     

Critical period for monocular deprivation in the cat visual cortex.

1. Cats were monocularly deprived for 3 mo starting at 8-9 mo, 12 mo, 15 mo, and several years of age. Single cells were recorded in both visual cortexes of each cat, and the ocular dominance and layer determined for each cell. Ocular dominance histograms were then constructed for layers II/III, IV, and V/VI for each group of animals. 2. There was a statistically significant shift in the ocular dominance for cells in layers II/III and V/VI for the animals deprived between 8-9 and 11-12 mo of age. There was a small but not statistically significant shift for cells in layer IV from the animals deprived between 8-9 and 11-12 mo of age, and for cells in layers V/VI from the animals deprived between 15 and 18 mo of age. There was no noticeable shift in ocular dominance for any other layers in any other group of animals. 3. We conclude that the critical period for monocular deprivation is finally over at approximately 1 yr of age for extragranular layers (layers II, III, V, and VI) in visual cortex of the cat.     

Sequencing of the alpha-synuclein gene in a large series of cases of familial Parkinson's disease fails to reveal any further mutations. The European Consortium on Genetic Susceptibility in Parkinson's Disease (GSPD)

A mutation in exon 4 of the human alpha-synuclein gene was reported recently in four families with autosomal dominant Parkinson's disease (PD). In order to examine whether mutations in this exon or elsewhere in the gene are common in familial PD, all seven exons of the alpha- synuclein gene were amplified by PCR from index cases of 30 European and American Caucasian kindreds affected with autosomal dominant PD. Each product was sequenced directly and examined for mutations in the open reading frame. No mutations were found in any of the samples examined. We conclude that the A53T change described in the alpha- synuclein gene is a rare cause of PD or may even be a rare variant. Mutations in the regulatory or intronic regions of the gene were not excluded by this study.      

Effect of the group I metabotropic glutamate agonist DHPG on the visual cortex

Metabotropic glutamate receptors have a variety of effects in visual cortex that depend on the age of the animal, the layer of the cortex, and the group of the receptor. Here we describe these effects for group I receptors, using both in vivo and in vitro preparations. The metabotropic group I glutamate receptor agonist 3,5 dihydroxyphenylglycine (DHPG) potentiates the responses to N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) in slices of rat visual cortex. It also increases, initially, the visual response in the cat visual cortex. Both these effects are largest at 3-4 wk of age and decline to insignificance by 10 wk of age. Both are also largest in lower layers of cortex, which explains why the facilitatory effects found with the general metabotropic glutamate agonist 1S,3R aminocyclopentane-1,3-dicarboxylic acid (ACPD) are observed only in lower layers. Prolonged application of DHPG in the cat visual cortex, after the initial excitatory effect, produces depression. We also found that DHPG facilitates the NMDA response in fast-spiking cells, which are inhibitory, providing a partial explanation for this. Thus there are multiple effects of group I metabotropic glutamate receptors, which vary with layer and age in visual cortex.     

Reversible blockade of experience-dependent plasticity by calcineurin in mouse visual cortex

Numerous protein kinases have been implicated in visual cortex plasticity, but the role of serine/threonine protein phosphatases has not yet been established. Calcineurin, the only known Ca2+/calmodulin-activated protein phosphatase in the brain, has been identified as a molecular constraint on synaptic plasticity in the hippocampus and on memory. Using transgenic mice overexpressing calcineurin inducibly in forebrain neurons, we now provide evidence that calcineurin is also involved in ocular dominance plasticity. A transient increase in calcineurin activity is found to prevent the shift of responsiveness in the visual cortex following monocular deprivation, and this effect is reversible. These results imply that the balance between protein kinases and phosphatases is critical for visual cortex plasticity.     

Monte Carlo Markov chain methods for genome screening

We used Monte Carlo Markov chain (MCMC) methods to analyze a quantitative trait, MAO level, and a discrete trait, Collaborative Study on the Genetics of Alcoholism (COGA) alcoholism. Segregation, linkage, and haplotype sharing were analyzed and effects of marker map features were examined. For MAO, modest signals were found on chromosomes 1 and 17 for raw data, and 15 for covariate-adjusted data. For alcoholism, a strong signal was found on chromosome 1 with modest signals on chromosomes 4 and 10.