Phase I trial of weekly docetaxel and concurrent radiotherapy for head and neck cancer in elderly patients or patients with complications

OBJECTIVE: We planned a phase I study of radiotherapy combined with weekly docetaxel for elderly patients or patients with complications to find out the optimal dose. METHODS: Five consecutive weekly administrations of docetaxel were accompanied by radiotherapy for patients diagnosed with squamous cell carcinoma of the head and neck. The starting dose of docetaxel was 10 mg/m(2) with escalation at 2 mg/m(2) per step. RESULTS: Fifteen patients were enrolled in this trial. The maximal tolerated dose was 14 mg/m(2), so the recommended dose was determined as 12 mg/m(2). Hematological toxicity was sufficiently weak. Common dose-limiting toxicity was stomatitis within the radiation field. CONCLUSIONS: This protocol was thought to be practical for elderly patients or those with medical complications.     

Urinary excretion of phenytoin metabolites, 5-(4'-hydroxyphenyl)-5-phenylhydantoin and its O-glucuronide in humans and analysis of genetic polymorphisms of UDP-glucuronosyltransferases

The anticonvulsant agent phenytoin (5,5-diphenylhydantoin) is mainly excreted as 5-(4'-hydroxyphenyl)-5-phenylhydantoin (4'-HPPH) O-glucuronide in humans. Previously, we demonstrated that the glucuronidation of 4'-HPPH is catalyzed by multiple UDP-glucuronosyltransferases (UGTs) of UGT1A1, UGT1A4, UGT1A6, and UGT1A9. Since 4'-HPPH may be bioactivated to a reactive metabolite by peroxidase, the glucuronidation in considered to be a detoxification pathway. In the present study, we investigated the relationship between the extent of interindividual variability in the urinary excretion levels of 4'-HPPH and its O-glucuronide and genotyping of CYP2C9, CYP2C19, UGT1A1, UGT1A6, and UGT1A9. 4'-HPPH and its glucuronide in urine samples from 15 patients to whom phenytoin was administered were measured by liquid chromatography-tandem mass spectrometry. When the molar ratio of 4'-HPPH O-glucuronide/4'-HPPH was calculated as an index of glucuronidation, a large interindividual variability (11 fold) was observed in the 15 patients. Phenytoin is metabolized to 4'-HPPH by CYP2C9 and CYP2C19 in which there are genetic polymorphisms. Although 5 patients were genotyped as heterozygotes of mutated alleles of CYP2C9 or CYP2C19 genes, no relationship with the interindividual difference in the total excretion levels of 4'-HPPH and its O-glucuronide was observed. The UGT1A1*6, UGT1A1*28, UGT1A1*60 and UGT1A6*2 alleles were found in 1, 3, 6, and 8 patients, respectively. Although there was no relationship between the genetic polymorphisms of UGT1As and the interindividual difference in the 4'-HPPH glucuronidation, the large interindividual variability of 4'- HPPH glucuronidation may contribute to interindividual differences in toxic reactions to phenytoin.     

Chronic treatment with milnacipran reverses the impairment of synaptic plasticity induced by conditioned fear stress

Rationale Recent studies have focused on neural plasticity at the cellular and molecular levels in the etiology and treatment of stress-related disorders; however, there are no reports concerning modulation of synaptic plasticity in the hippocampus underlying therapeutic effects of antidepressants and/or anxiolytics.Objectives To elucidate the functional interaction between the stress-induced alteration of synaptic plasticity and therapeutic effects, we examined the anxiolytic mechanism(s) of milnacipran, focusing on modulation of long-term potentiation (LTP) in the hippocampal CA1 field.Methods Rats that received footshock stimulation five times (intensity, 0.5 mA; duration, 2 s; shock interval, 30 s) for 5 days were treated with milnacipran (30 mg kg^–1, p.o.) or vehicle for 14 days. On the 15th day, rats were subjected to conditioned fear stress (CFS) to evaluate freezing behavior. Separate from the behavioral study, electrophysiological approach was performed to evaluate the synaptic efficacy under anesthesia.Results Exposure to CFS suppressed LTP in the CA1 field. Chronic treatment with milnacipran (30 mg kg^–1, i.p. after 30 mg kg^–1 day^–1, p.o. ×14 days), but not acute treatment (30 mg kg^–1, i.p. after vehicle 5 ml kg^–1 day^–1, p.o. ×14 days), reduced freezing behavior and reversed the impairment of LTP induced by CFS.Conclusion The present data suggest that a correspondence exists between fear-related behavior and synaptic plasticity in the hippocampus. In other words, anxiolytic mechanism(s) of chronic treatment with milnacipran may be explained by reversal effects on the psychological stress-induced impairment of synaptic plasticity.     

Metabolism of the calmodulin antagonist DY-9760e in animals and humans

The in vitro metabolism of the calmodulin antagonist DY-9760e was investigated using liver microsomes from humans and three other animal species and compared with the in vivo metabolism in rats after intravenous administration of DY-9760e. Seven major metabolites were produced by human liver microsomes by the following metabolic pathways: N-dealkylation, phenyl hydroxylation, O-demethylation and imidazole oxidation. These metabolites were also produced by liver microsomes from monkeys, dogs and rats; additionally, a hydroxylated derivative of the indazole moiety was produced only by rat microsomes. To identify the structures of two imidazole ring metabolites whose authentic compounds could not be obtained, Escherichia coli co-expressing human cytochrome P450 CYP3A4 and NADPH-P450 reductase was used to biosynthesize these metabolites. NMR spectra elucidated the precise structures; oxidation occurred at the imidazole ring, and the subsequent ring-opening resulted in the generation of amide and formylamine groups. Glucuronide conjugates of the hydroxylated and O-demethylated derivatives were major components in rat bile. Therefore, DY-9760e metabolites generated in vitro correspond to the aglycones of the major metabolites observed in rat bile.     

Computed tomographic scanning and selective laparoscopy in the diagnosis of blunt bowel injury: a prospective study

BACKGROUND: We prospectively evaluated whether computed tomographic (CT) scanning and selective laparoscopy (LP) for the diagnosis of blunt bowel injury (BBI) could prevent nontherapeutic laparotomy and delayed diagnosis. METHODS: Between April 1994 and May 2002, hemodynamically stable patients suspected of having BBI were enrolled in this study. Patients with hemodynamic instability or solid organ injuries with hemoperitoneum were excluded. All patients underwent a physical examination and contrast CT scanning at admission and once again approximately 12 hours (range, 6-24 hours) after admission. LP was performed under general anesthesia in patients who had local peritoneal signs and indirect CT signs (bowel thickening or isolated intraperitoneal fluid) or in whom abdominal pain or tenderness increased or intraperitoneal fluid increased on the repeat CT scan. The indications for a celiotomy were diffuse peritonitis, pneumoperitoneum on the abdominal CT scan, or bowel perforation visible on LP. RESULTS: During the study period, 399 of 1,074 patients admitted for blunt torso injuries were enrolled in this study. Eleven patients underwent emergency celiotomy and 11 underwent LP immediately after admission to the emergency department. One nontherapeutic laparotomy was performed among the patients who underwent celiotomy. The LPs revealed seven bowel perforations and one mesenteric laceration. After a repeat CT scan, three and seven of the patients underwent laparotomy and LP, respectively. Four bowel perforations were found by LP. The remaining 198 patients were treated conservatively, and no complications related to a delayed BBI diagnosis occurred. CONCLUSION: CT scanning and selective LP can prevent nontherapeutic laparotomy and delayed diagnosis in patients with suspected BBI.     

Modification of skin composition by conjugated linoleic acid alone or with combination of other fatty acids in mice

The effects of conjugated linoleic acid (CLA), gamma-linolenic acid (GLA), linoleic acid (LA), and their combinations, on skin composition in mice were investigated. Mice (8 weeks old) were orally administered with either LA, GLA, CLA, LA + GLA, LA + CLA, or CLA + GLA for 4 weeks. Then, the skin was analysed for triacylglycerol content, fatty acid composition and collagen content. Additionally, thicknesses of the dermis layer and subcutaneous tissue layer, and the size and number of adipocytes were measured histologically. The skin fatty acid composition was modified depending upon the fatty acid composition of supplemented oils. In each oil-alone group, skin triacylglycerol content was the highest in LA, followed by GLA and CLA treatments. Combinations with CLA had a similar triacylglycerol content compared with the CLA-alone group. No significant changes in collagen content were observed among any treatments. The effects on subcutaneous thickness were similar to the results obtained in the triacylglycerol contents, where groups supplemented with CLA alone or other fatty acids had significantly thinner subcutaneous tissue compared with the LA-alone group. However, no significant difference was detected in the thickness of the dermis layers. The number of adipocytes was highest in the LA + GLA group and tended to be reduced by CLA with or without the other fatty acids. These results suggest that CLA alone or in combination with other fatty acids strongly modifies skin composition in mice.     

Shiftwork locus of control, situational and behavioural effects on sleepiness and fatigue in shiftworkers

A number of situational and behavioural individual differences moderate the impact of shift and night work. The aims of this study were to identify individual differences correlates of sleep and fatigue-related shiftwork outcomes and examine their potential relative causal impact. Power company shiftworkers completed a questionnaire that measured age/experience, number of dependents, shiftwork locus of control, morningness-eveningness, workload and sleep/health-related behaviours. Shiftwork sleep and fatigue outcome variables were also measured. Hierarchical multiple regression was used to examine predictive contributions of the individual difference variables and to generate path coefficients from situational and psychological predictors through behavioural variables to the outcome variables. Shiftwork-specific internality showed the most systematic significant causal relationships with sleep and fatigue outcomes. While not having as strong a direct causal influence on sleep and fatigue outcomes as internality, the other predictors did show more significant causal effects upon sleep-related behaviours than did internality. Behavioural variables made little contribution to the total causal effects of the predictors on the outcome variables. The results suggest control beliefs to be a moderating factor in shiftwork exposure and the potential utility of this construct in aiding more effective targeting of interventions.     

Insulin-induced lipohypertrophy: report of a case with histopathology

An 82-year-old woman with type 2 diabetes had been treated with recombinant human insulin for 16 years. She developed large swellings in both sides of her lower abdomen. The masses were soft, painless, and located around her insulin injection sites. Based on the history and clinical features, a diagnosis of insulin-induced lipohypertrophy was made. Total resection revealed that the lesions were composed entirely of fatty tissue. Microscopic examination showed nests of mature adipocytes expanding toward the dermal reticular layer. The hypertrophic adipocytes were twice as large as those from normal subcutaneous areas and contained numerous small lipid droplets. Electron microscopic analysis also revealed a minor population of small adipocytes, suggesting active differentiation or proliferation. Thus, the possible in vivo effects of insulin on adipocytes were clearly observed in this case of insulin-induced lipohypertrophy. To our knowledge, this is the first report of insulin-induced lipohypertrophy with detailed histological examinations.     

Multiplex polymerase chain reaction assay for simultaneous detection of black-pigmented Prevotella species in oral specimens

Prevotella species are a major component of the oral microflora and some have been implicated in various forms of periodontal disease. Despite the importance of understanding the prevalence of these organisms in the oral microflora, no rapid, simultaneous detection system for these species has been reported. This study developed a multiplex polymerase chain reaction assay for the simultaneous detection of four oral black-pigmented Prevotella species in various oral specimens. This assay will be useful for determining the prevalence of these organisms in the oral ecosystem. Furthermore, this assay system should prove a useful tool for analyzing the role of black-pigmented Prevotella species in the mouth.