Treatment of relapsed chronic lymphocytic leukemia by 72-hour continuous infusion or 1-hour bolus infusion of flavopiridol: results from Cancer and Leukemia Group B study 19805.

PURPOSE: Flavopiridol has in vitro activity in chronic lymphocytic leukemia (CLL) and promotes apoptosis independent of p53 function or prior fludarabine exposure. We sought to determine if flavopiridol has activity in previously treated CLL using two schedules of administration. PATIENTS AND METHODS: Patients with previously treated CLL were enrolled in two sequentially done phase II studies. Patients in the first trial received flavopiridol (50 mg/m(2)/d) as a continuous infusion (CI) for 72 hours every 2 weeks. Patients in the second trial received flavopiridol 50 mg/m(2) as a 1-hour bolus (IVB) daily for 3 days repeated every 3 weeks. Patients received up to 12 (CI cohort) or 8 (IVB cohort) cycles of therapy. RESULTS: Fifteen patients were enrolled in the 72-hour CI phase II trial; 6 (40%) had intermediate-risk (Rai stage I or II) and 9 (60%) had high-risk (Rai stage III and IV) stages. No responses were noted in this group; 27% had stable disease and 73% had progressive disease. Thirty-six patients were enrolled in the second IVB trial, with 13 (36%) having intermediate and 23 (64%) having high-risk disease. Four patients (11%) had partial responses, 19 (53%) had stable disease, and 13 (36%) had progressive disease. The progression-free survival for responders in the IVB trial was 3, 3, 9, and 19 months. The median progression-free survival was 2 months [95% confidence interval (95% CI), 1.8-3.8] for patients in the CI trial and 3 months (95% CI, 2.5-7.4) for the IVB trial. The median overall survival was 27 months (95% CI, 20-42) for the CI trial and 24 months (95% CI, 18-31) for the IVB trial. Toxicity was manageable and included mainly myelosuppression, infections, diarrhea, and fatigue. CONCLUSIONS: Flavopiridol has modest, schedule-dependent clinical activity in relapsed CLL and warrants future investigation utilizing alternative schedules of administration.     

Phase II trial of oral aminopterin for adults and children with refractory acute leukemia.

PURPOSE: To determine the antileukemic activity of weekly oral aminopterin in patients with refractory acute leukemia; to describe the pharmacodynamic properties of aminopterin; and to contrast the intracellular metabolism of aminopterin and methotrexate by patients' blasts in vitro. EXPERIMENTAL DESIGN: Forty-six patients were enrolled in three strata: children with acute lymphoblastic leukemia (ALL), adults with ALL, and patients with acute myeloid leukemia (AML). Aminopterin was given weekly, in two doses of 2 mg/m(2), 12 hours apart. Limited sampling pharmacokinetic analysis was done during the first week of therapy. Accumulation of [(3)H]aminopterin and [(3)H]methotrexate by leukemic blasts was studied in vitro. RESULTS: Six of 22 children with ALL (27%; 95% confidence interval, 8-47%) had clinically significant responses. None of those with AML and only two of 11 adults with ALL had responses meeting protocol definitions, although peripheral blast counts tended to decrease with therapy in all groups. Mucosal toxicity was minimal, even with limited use of leucovorin rescue. Complete bioavailability of aminopterin was confirmed, with a mean area under the curve of 0.52 +/- 0.03 micromol hour/L after oral dosing. No relationship between aminopterin pharmacokinetics and response was seen. In vitro, aminopterin showed more consistent metabolism by leukemic blasts to polyglutamates than methotrexate. Lineage-specific differences in the pattern of intracellular antifolylpolyglutamates were observed. CONCLUSIONS: Weekly oral aminopterin has significant activity among children with refractory ALL. With greater cellular accumulation and metabolism, more reliable bioavailability than methotrexate, and tolerable toxicity at this dose and schedule, aminopterin deserves further study as a potent alternative to methotrexate.     

Inhalation of Tetramethyllead and Tetraethyllead

In a study of the specificity of the iodine-azide reaction in carbon disulfide (CS₂) exposure, iodine-azide reaction and dithiocarb (sodium diethyidithiocarbamate) in the urine of alcoholics treated with disulfiram (tetraethylthiuram disulfide) were determined.

After application of disulfiram, the iodine-azide reaction was negative 40% of the time, but some dithiocarb is always present in urine. Therefore, dithiocarb determination could be used to measure the patient’s discipline.

The great dispersion of dithiocarb results is discussed as a possible influence of pathologic condition and compared with other drugs, especially, meprobamate.

The application of meprobamate increased the percentage of positive iodine-azide reaction in disulfiram, treated alcoholics, but dispersion of dithiocarb results was the same as in alcoholics not using meprobamate.

The iodine-azide test (IAT) does not provide a satisfactory index of exposure in individuals taking disulfiram for alcoholism.     

Metabolic Syndrome and Inflammatory Biomarkers: a community-based cross-sectional Study at the Framingham Heart Study

ABSTRACT: BACKGROUND: Prior studies reported conflicting findings on the association between metabolic syndrome and inflammatory biomarkers. We tested the cross-sectional association between metabolic syndrome, its components, and 9 inflammatory markers. METHODS: We measured C-reactive protein, CD40 ligand, interleukin-6, intercellular adhesion molecule-1, monocyte chemoattractant protein-1, osteoprotegerin, P-selectin, tumor necrosis factor-alpha, and tumor necrosis factor receptor-2 in 2570 Framingham Offspring Study participants free of diabetes and cardiovascular disease at exam 7. Metabolic syndrome was defined by criteria of the National Cholesterol Education Program. We performed multivariable linear regressions for each biomarker with metabolic syndrome as the exposure adjusting for age, sex, smoking, aspirin use, and hormone replacement. We subsequently added each component of the metabolic syndrome as a continuous trait to the models, adjusting for age, sex, smoking, aspirin use, hormone replacement, lipid lowering treatment and hypertension therapy. We considered P < 0.05 as statistically significant. RESULTS: Metabolic syndrome was present in 984 participants, and statistically significantly associated with each biomarker (all P<0.0001) except osteoprotegerin. After adjusting for its components, the metabolic syndrome was only associated with P-selectin (beta=0.16, 95% CI (0.05, 0.27)). CONCLUSIONS: Metabolic syndrome was associated with multiple inflammatory biomarkers. However, adjusting for each of its components eliminated the association with most inflammatory markers, except P-selectin. Our results support the hypothesis that the relation between metabolic syndrome and inflammation is largely accounted for by its components.