Four professional public administrators returned to their alma mater to serve as role models, offer guidelines and cautions about working in highly political environments, and pose hypothetical case ...studies drawn from their own and others' experiences in such a setting. Counseling that the gravity and complexity of ethical dilemmas increase as one’s career advances, they suggest that the tensions between politics and policy figure among the more serious sources of ethical challenges facing professionals in the public sphere. While proposing that the professional’s duty in part is to empower elected officials to make the right decision with the best information and most useful tools, they note that some frustration is unavoidable in this complex environment; there are no easy answers because the issues themselves are not easy and perspectives about what is right and important vary. Centering on the duty of serving the public interest, their cases focus upon mixed allegiances, clashing loyalties, multiple perspectives, truthfulness and candor, privileged treatment, the appearance of impropriety, and accountability
A series of substituted amidinoindoles have been prepared as mimics of the RGD sequence and were studied as antagonists of the platelet glycoprotein IIb–IIIa receptor (GPIIb–IIIa). The agents were ...potent and selective antagonists of GPIIb–IIIa. Compared to their acyclic counterparts, the amidinoindole series bound with 10- to 20-fold greater affinity, indicating the advantages of added conformational restriction and/or hydrophobicity in the basic region of RGD mimics.
Amidinoindoles have been employed as arginine surrogates in the preparation of RGD mimics which were studied as antagonists of the platelet glycoprotein IIb-IIIa receptor (GPIIb-IIIa).
Interieukin-1 (IL-1) modulation of cytokine receptors (human IL-1 receptor hIL-IR, human granulocyte colony-stimulating factor hG-CSFR, human granulocyte-macrophage CSF receptor hGM-CSFR, and human ...tumor necrosis factor receptor hTNFR) on human neutrophils was studied both in vitro and in vivo. In vitro, incubation of neutrophils with IL-1 at 37°C for 0.5 or 8 hours caused a reduction of IL-1 binding in a dose-dependent manner, but did not demonstrably affect binding of the other cytokines tested. In vivo, neutrophils from patients with gastrointestinal malignancies who were participating in a clinical trial of recombinant human IL-β (rhIL-1β) demonstrated modulation of cytokine receptors in an IL-1β dose- and time-dependent manner. At the two highest dose levels of IL-10 (0.068 and 0.1 µg/kg), reduction (>40%) of G-CSF binding and elevation (twofold to sixfold) of IL-1 binding to neutrophils was observed after 1 hour and 4 to 8 hours, respectively. In addition, IL-10 rapidly elevated G-CSF and glucocorticoid levels in plasma. Patients at the lowest dose level (0.002 µg/kg) had a less dramatic change in these parameters. Further in vitro studies showed that synthetic glucocorticoids and G-CSF synergistically up-modulated IL-1 binding to neutrophils in a dose- and time-dependent manner. Scatchard analysis of binding data showed that this in vitro synergistic modulation was due to an increase in receptor numbers, rather than an increase in binding affinity. In addition, both human umbilical cord blood and bone marrow neutrophils responded to G-CSF and dexamethasone (Dex) with a superadditive increase in IL-1 binding. Therefore, one of mechanisms for IL-1 up-modulation of IL-1 R on human neutrophils in vivo was due to the fact that IL-1 rapidly elevates serum levels of G-CSF and glucocorticoids.
Pharmacokinetic studies were carried out in 25 patients with advanced cancer receiving deoxyspergualin (DSG), a candidate anticancer agent, in a dose-finding Phase I study. The dosage range explored ...was 80 to 2160 mg/m2/day for 5 days by continuous i.v. infusion. The drug levels in plasma and urine were measured by high-performance liquid chromatography with postcolumn derivatization and fluorescence detection. One drug metabolite was demonstrated in plasma and urine of treated patients. This metabolite was extracted from urine and purified to homogeneity; thereafter, it was examined by high-performance liquid chromatography, nuclear magnetic resonance, and fragmentation mass spectrometry and was demonstrated to be identical to chemically synthesized desaminopropyl-DSG. The mean steady state plasma concentrations of DSG ranged from 0.28 to 11.1 microM at, respectively, the 80- and 2160-mg/m2 dosage levels. The plasma concentration at steady state and the area under the plasma concentration versus time curve of DSG were proportional to dose (r = 0.97). Following discontinuance of the infusion, DSG was cleared from the plasma in a biexponential fashion. The mean total body clearance was 364 +/- 78 ml/min/m2. Desaminopropyl-DSG was formed extensively at all dosage levels; mean steady state plasma levels of this metabolite reached a plateau 2.65 microM at a dose of 720 mg/m2/day and did not rise with further dose increments. The urinary content of DSG was examined in 20 patients over the dosage range from 160 to 960 mg/m2/day; in this group less than 10% of the administered dose was excreted as DSG. In four patients at the 720- and 960-mg/m2/day dosage levels, the total DSG plus metabolite excretion ranged from 7 to 18% of the administered dose, with comparable quantities occurring as the parent drug and desaminopropyl-DSG.
The entropy of activation for the synthesis of Ile-tRNA is high and positive. The only likely source of a high Δ S‡is the loss of structured water as the enzyme· substrate complex moves toward the ...transition state. This requires a change in the orientation or nature of water-organizing residues in the interface between the enzyme· substrate complex and the water. Such changes, which may be some distance from the ``active site,'' are coupled to the active site in such a way that the increased entropy and decreased free energy of the water-enzyme interface is available at the ``active site'' to reduce the free energy of activation. The effects of Hofmeister anions on Kms and kcats are consistent with the entropy data.
Although all-transretinoic acid (RA) induces complete remission in a high proportion of patients with acute promyelo-cytic leukemia (APL), all groups have described clinical relapses despite ...continued RA treatment. This finding suggests that resistance to the cytodifferentiating effects of the retinoid had been acquired. To investigate potential mechanisms of clinical resistance to RA, we serially evaluated the clinical pharmacology of the drug in APL patients treated with this agent. Leukemic cells from patients relapsing from RA treatment were cultured in the presence of RA and examined for evidence of morphologic maturation. We also studied messenger RNA expression of the newly described gene product of the (15; 17) translocation in APL, PML/RAreceptor-a (PML/RAR-α). Serial pharmacokinetic studies showed that continuous daily RA treatment was associated with a marked decrease in plasma drug concentrations at the time of relapse compared with the initial day of therapy. Doubling the RA dose in six patients failed to reinduce response at the time of relapse and also failed to signficantly augment plasma RA concentrations. However, leukemic cells obtained at the time of relapse from four patients retained in vitro sensitivity to the differentiating activity of RA (10-6 mol/L). No change was observed in the pattern of PML/ RAR-α expression assessed by Northern blot analysis at the time of relapse compared with pretreatment in two patients who were tested. These results indicate that clinical relapse and “resistance” to continuous treatment with all-trans RA in APL is associated with progressive reduction of plasma concentrations, potentially to levels below those that sustain differentiation of leukemic cells in vivo. Long-term success of this treatment will require the development of strategies that circumvent this pharmacologic phenomenon.
The effect of N-phosphonacetyl-L-aspartate (PALA) pretreatment on the metabolism and cytotoxicity of 5-azacytidine (5-aza-Cyd) was studied in two murine leukemic cell lines. Exposure of P388 and ...L1210 cells to 3 mM PALA for 3 hr before adding 5-aza-Cyd at 75 microM was accompanied by a two-fold increment in acid-soluble and 3-fold increment in acid-insoluble incorporation of 5-aza-Cyd in both cell lines. RNA incorporation of 5-aza-Cyd increased from 97.5 +/- 3.4 pmol 5-aza-Cyd per microgram D-ribose in control cells to 299.2 +/- 4.2 pmol 5-aza-Cyd per microgram D-ribose in PALA-treated cells; a smaller increment in DNA incorporation of 5-aza-Cyd was also noted. Sequential treatment of cells with PALA and 5-aza-Cyd was associated with a 40% reduction in protein synthesis compared to only a 2 and 8% reduction, respectively, produced by the drugs given alone. Sequential administration of PALA and 5-aza-Cyd resulted in greater than additive cytotoxicity as measured by both growth inhibition and in vitro soft-agar cloning assays. Exposure of both cell lines to 3 mM PALA for 3 hr produced 50 and 65% reductions in intracellular levels of cytidine triphosphate and uridine triphosphate; intracellular accumulation of 5-azacytidine triphosphate, the lethal metabolite of 5-aza-Cyd, increased from 43.4 +/- 2.1 pmol/10(6) cells to 92.4 +/- 3.3 pmol/10(6) cells in PALA-treated cells. PALA was able to augment the metabolism and cytotoxicity of 5-aza-Cyd in a uridine-cytidine kinase-mutant 5-aza-Cyd-resistant L5178Y subline. This sequential drug combination has a rational biochemical basis and may offer significant advantages over either drug when administered alone, especially in cells which are resistant to 5-aza-Cyd.
PDF
