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.     

Is there a genetic susceptibility locus for Parkinson's disease on chromosome 22q13?

The cytochrome P450 mono-oxygenase gene, CYP2D6 on chromosome 22q13 (ch22q13), has been inconsistently associated with Parkinson's disease. Associations with CYP2D6 have either been absent altogether or have involved more than one polymorphism, many of which have the same metabolic effect on gene expression. We examined the association between CYP2D6 polymorphisms and Parkinson's disease in a case-control study and included 10 polymorphic dinucleotide repeat markers linked to CYP2D6 to determine whether the association was present or due to linkage disequilibrium. There was no association between any polymorphism of CYP2D6 and Parkinson's disease, but two of 10 dinucleotide repeat markers linked to CYP2D6 were associated with the disease. These results provide evidence to suggest that there may be an unidentified locus for susceptibility to Parkinson's disease that is in linkage disequilibrium with dinucleotide repeat markers mapping near CYP2D6 on ch22q13.     

Disposition of 14C-dapoxetine in rats: Complementary experiments with whole-body autoradiographic and tissue dissection techniques

Tissue distribution studies, utilizing whole-body autoradiography and organ dissection techniques, were conducted in male Fischer 344 rats following the oral administration of ¹⁴C-dapoxetine HCl, a potent serotonin reuptake inhibitor. The preliminary study using whole-body autoradiography proved invaluable in locating radioactivity in an organ not usually harvested in a tissue distribution study, namely the preputial gland. Selected organs, based on whole-body autoradiography findings, were dissected from rats and analyzed for radiocarbon content by liquid scintillation counting and for parent drug and N-dealkylated metabolites by extraction and HPLC analysis. Highest concentrations of radiocarbon were observed in the organs of absorption and elimination (ileum, cecum, stomach, duodenum, liver, colon, and kidney) but notable quantities were observed in the lung and preputial and Harderian glands. Most tissues had returned to background radioactive levels 72 h after dosing but persistent concentrations of radiocarbon were present in the preputial gland and liver one week after the single dose of ¹⁴C-dapoxetine. Analysis by HPLC demonstrated the presence of parent drug and N-desmethyl metabolite (nor-dapoxetine) in those organs examined; however, the majority of the radioactivity remained unidentified.     

二甲亚砜对人表皮的核酸和蛋白质合成的影响

用体外培养的人的伪表皮作为模型，进行药物毒理学作用的研究，观察了二甲亚砜（ＤＭＳＯ）在不同浓度和不同接触时间条件下，对人的伪表皮细胞脱氧核糖核酸（ＤＮＡ）、核糖核酸（ＲＮＡ）和蛋白质合成的影响：随着接触时间的延长，ＤＮＡ、ＲＮＡ和蛋白质合成均受抑制。低浓度条件下（１％），ＤＮＡ、ＲＮＡ和蛋白质合成增加；在１５～５０％浓度下，ＤＮＡ和蛋白质合成抑制，而ＲＮＡ合成仍增加；在高浓度条件下（７０％～１００％），ＤＮＡ、ＲＮＡ和蛋白质合成均明显抑制。     

Dynamic skinfold thickness measurement in infants fed breast-milk, low- or high-sodium formula

A stratified sample of normal infants born at term at Johannesburg Hospital, who attended the hospital for a routine 6-week follow-up visit, were selected to include 43 infants who were exclusively breast-fed, 42 fed a low-sodium formula and 39 fed a high-sodium formula (greater than 10 mmol sodium/l). Dynamic skinfold thickness measurements (DSTM), designed to assess the amount of interstitial fluid, were performed on each infant by the application of a skinfold caliper for a 3-second sampling period at two sites. The curves generated by these applications were recorded and analysed by microcomputer. There were no differences between any of the feeding groups for DSTM measurements of blood pressure suggesting that the range of sodium ingested by these groups of infants had no significant effects on extracellular water content. However, using multiple linear regression, both DSTM and blood pressure were best predicted by body weight and not by age or any other anthropometric measurement. Thus the normal postnatal decrease in extracellular fluid volume and increase in blood pressure appears to be most closely related to an increase in body weight.     

Speech training aids for hearing-impaired individuals: III. Preliminary observations in the clinic and childrens' homes

Preliminary evaluation of 2 related computer-based speech training and practice aids for profoundly deaf children was conducted. The Speech Training Station (STS) uses both acoustic and physiological transducters for assessment and training in a school of clinic. The Speech Practice Station (SPS) uses the acoustic signal, and was designed primarily for use in the home. A series of games and activities was implemented on the 2 systems. Use of the STS was evaluated by 2 speech clinicians during a 15-month period. Fifteen children were subjects in the evaluation. The aid was found to be easily incorporated into clinic activities and useful for diagnosis and therapy. The SPS was evaluated during a 1-to-2-week period, during which it was placed in the homes of 5 profoundly deaf children. Using an activity log and questionnaire completed by the childrens' parents, usage statistics and impressions were obtained. Potential value and problems with such aids are discussed.     

Clinical assessment and management of depression.

Major depressive disorder is a psychiatric disorder that encompasses a broad range of emotional, psychological, behavioral, and physical symptoms (Fava et al., 2004). The nurse in the hospital, office, school, or community setting can provide the essential elements of effective care for depression, including early detection by screening, medication teaching, depression education, teaching coping skills, and appropriate use of specialists and resources. Utilizing the nursing process, the nurse can provide comprehensive care to improve the depressed patient's physical and psychological well-being.