Comparison of enhancement of GGTase-positive foci and induction of ornithine decarboxylase in rat liver by barbiturates

The induction of ornithine decarboxylase (ODC) by barbituratesand the ability of barbiturates to enhance neoplastic progressionof chemically initiated cancer was examined in rat liver. Allseven barbiturates induced ODC with barbital (7.7 fold increase)and phenobarbital (5.7 fold increase) demonstrating the mostpotent activity. Maximum induction of ODC by phenobarbital wasobtained in 18 h. Barbital (500–5000 p.p.m.) and phenobarbital(500 p.p.m.) administered in the drinking water enhanced theappearance of diethylnitrosamine (DENA)-initiated -glutamyltranspeptidase(GGTase)-positive foci. Amobarbital, hexabarbital and pentabarbitaldid not enhance the appearance of GGTase-positive foci. In theabsence of previous initiation by DENA, the enhancing regimenof the barbiturates did not cause the appearance of GGTase-positivefoci. Barbiturates induced ODC activity in rat liver and enhancedthe incidence of DENA initiated GGTase-positive foci.     

Metabolism and pharmacokinetics of a dipeptidyl peptidase IV inhibitor in rats, dogs, and monkeys with selective carbamoyl glucuronidation of the primary amine in dogs.

The pharmacokinetics and metabolism of the l-threo isoleucine thiazolidide dipeptidyl peptidase IV inhibitor, di-[2S,3S]-2-amino-3-methyl-pentanoic-1,3-thiazolidine fumarate (ILT-threo) and its allo stereoisomer (ILT-allo) were evaluated in rats, dogs, and monkeys. Both compounds were well absorbed (>80%) in all species, and most of the dose (>60%) was recovered in urine. Metabolites identified in all species included a sulfoxide (M1), a sulfone (M2), and a carbamoyl glucuronide (M3). For both compounds, parent drug had moderate systemic clearance in rats and dogs ( approximately 20-35 ml/min/kg in both species) and lower clearance in monkeys ( approximately 6-9 ml/min/kg). In rats, M1 was present in systemic circulation in concentrations similar to that of parent drug, whereas in dogs and monkeys, exposures to M1 were higher than for parent drug. In dogs, exposures to the sulfoxide metabolite were approximately 2 to 3 times higher after administration of ILT-allo than after administration of ILT-threo. Carbamoyl glucuronidation was an important biotransformation pathway in dogs. Circulating levels of M3 were significant in the dog, and present only in trace levels in rats and monkeys. M3 could be produced in in vitro systems in a NaHCO3 buffer under a CO2-saturated atmosphere and in the presence of UDP-glucuronic acid and alamethicin.     

Prognostic value of E-cadherin immunoexpression in patients with primary ovarian carcinomas.

PURPOSE: To analyse the negative versus positive immunoexpression of E-cadherin in patients with primary ovarian carcinomas, and determine its significance in relation to clinicopathological features, overall and recurrence-free survival (RFS). PATIENTS AND METHODS: The protein expression of E-cadherin was immunohistochemically evaluated in formalin-fixed, paraffin-embedded samples in 104 patients with primary ovarian carcinomas. The clinicopathological factors studied were age, FIGO staging, histological type, tumour differentiation, the appearance of the ovarian capsule, peritoneal implants and residual tumour after cytoreductive surgery. Overall survival and RFS were evaluated using the Kaplan-Meier method, and multivariate analysis was completed using the Cox regression model. RESULTS: Of the 104 carcinomas, negative E-cadherin immunoexpression was observed in seven (7%) cases, and positive immunoexpression in 97 (93%). E-cadherin categorised into negative versus positive expression did not associate with any of the established clinicopathological parameters. However, negative E-cadherin expression significantly predicted a poorer overall survival when compared with positive expression (P=0.006). In the multivariate analyses, negative E-cadherin and the presence of residual tumour after cytoreductive surgery were independent prognostic factors for survival (P=0.014 and P=0.034, respectively). CONCLUSIONS: The presence of residual tumour after primary cytoreductive surgery and negative E-cadherin expression seem to be useful markers in patients with ovarian carcinomas likely to have an unfavourable clinical outcome. The assessment of E-cadherin immunoreactivity may be a useful prognostic indicator in ovarian cancer, complementary to established prognostic factors.     

Twenty-four-hour oral tracer studies with L-[1-13C]lysine at a low (15 mg.kg (-1).d (-1) and intermediate (29 mg.kg (-1).d(-1)) lysine intake in healthy adults

BACKGROUND: We proposed previously that the mean lysine requirement value is approximately 30 mg * kg(-)(1) * d(-)(1) rather than the proposed 1985 FAO/WHO/UNU estimate of the upper range of the requirement, which is 12 mg * kg(-)(1) * d(-)(1). OBJECTIVE: Our objective was to explore the 24-h pattern and rate of whole-body lysine [l-(13)C]oxidation and status of whole-body lysine balance in healthy, young adults given an L-amino acid diet supplying either a low lysine intake (14-15 mg * kg(-)(1) * d(-)(1)) or an intermediate lysine intake (29 mg * kg(-)(1) * d(-)(1)) for 6 d before a continuous tracer study with L-[1-(13)C]lysine. DESIGN: Five subjects received the low lysine intake, 6 subjects received the intermediate intake, and all were studied by using a standard 24-h oral tracer protocol that was described earlier for studies at a generous lysine intake. RESULTS: The rate of lysine oxidation was not significantly different between the 12-h fasted and 12-h fed states. The daily oxidation rate (f1.gif" BORDER="0"> +/- SD) was 27. 9 +/- 8.8 and 27.3 +/- 17.6 mg lysine * kg(-)(1) * d(-)(1) for the low- and intermediate-intake groups, respectively (NS). Daily lysine balance was -12.4 +/- 92 and 1.8 +/- 17.7 mg * kg(-)(1) * d(-)(1), respectively (P < 0.025), for the low and intermediate intakes. The balance was significantly less than zero (P < 0.001) for the low intake. CONCLUSION: The FAO/WHO/UNU lysine requirement value is not sufficient to maintain lysine homeostasis in healthy adults. From the results of this and tracer studies done by others, the mean lysine requirement of healthy adults was determined to be 30 mg * kg(-)(1) * d(-)(1).