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PDF file - 1469K, Different ABL TKIs demonstrate potency differences in relative cellular and biochemical target inhibition (S1); Incomplete restoration of BCR-ABL signaling activity following washout of dasatinib or ponatinib tracks with intracellular drug retention and commitment to apoptosis in LAMA cells (S2); Incomplete restoration of BCR-ABL signaling activity following washout of nilotinib, imatinib, or DCC-2036 tracks with intracellular drug retention and commitment to apoptosis in LAMA cells (S3); BCR-ABL signaling is partially attenuated in conditions of continuous low concentrations of ABL TKIs that induce apoptosis (S4); Commitment to apoptosis in primary CML cells tracks with intracellular retention of ABL TKIs (S5); Intracellular retention of dasatinib, nilotinib, and imatinib is reduced following washout in primary CML cells harboring the resistant BCR-ABLT315I mutant (S6).

PDF file - 337K, Summary of mean fluorescence intensity values for levels of CrkL and STAT5 phosphorylation in K562 cells following acute ABL TKI exposure followed by standard and expanded washout (S1); Kinase:inhibitor dissociation off-rates for ABL TKIs (S2).

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Physicians' adherence to prescribing evidence-based inpatient and outpatient therapies for chronic obstructive pulmonary disease (COPD) is low, and there is a paucity of information about the utility of admission order sets for patients with COPD exacerbations.To determine if implementation of a locally designed, evidence-based, multidisciplinary computer physician order entry set in the electronic health record improves the quality of physician pharmacologic prescribing for patients hospitalized for COPD exacerbations.This study was performed before and after implementation of a computerized order set for patients hospitalized for COPD exacerbations. The primary outcome was the rate of zero prescribing errors by physicians for inpatient and discharge drugs for COPD over a 1-year period before implementation and for 6 months after implementation. Errors were defined as no therapy or inappropriate therapy in the following categories: antibiotic, systemic corticosteroid, short-acting bronchodilator, long-acting bronchodilator, and inhaled corticosteroid. Secondary outcomes included mean physician pharmaceutical prescribing error rate; types of errors; hospital lengths of stay; and unscheduled physician visits, emergency department visits, rehospitalizations, and deaths within 30 days from discharge.There were 194 COPD exacerbation admissions during the 1-year preimplementation period and 81 admissions during the 6-month postimplementation period. Compared with the preimplementation period, the percentage of patients receiving all recommended pharmacologic therapies for the 6 months after implementation increased from 18.6% to 54.3% (P 0.001). The mean number of errors decreased from 1.76 to 0.65 (P 0.001). Antibiotic and systemic corticosteroid errors decreased from 39% to 16% (P 0.001) and from 58% to 28% (P 0.001), respectively. Fewer patients were discharged without a short-acting bronchodilator (13.9% vs. 2.5%; P = 0.005), a long-acting bronchodilator (16.5% vs. 7.4%; P = 0.047), or inhaled corticosteroid (18% vs. 9.9%; P = 0.089). Improvements were sustained over the 6-month postimplementation period. Hospital length of stay decreased from 4 (±3) days preimplementation to 2.9 (±1.9) days postimplementation (P = 0.002). There were no significant differences in 30-day clinical outcomes, including the rates of unscheduled physician or emergency department visits, rehospitalizations, or deaths.Computerized multidisciplinary admission order set implementation for patients hospitalized for a COPD exacerbation improved physicians' adherence to evidence-based pharmacologic treatment, and they were associated with reductions in length of hospital stay.

Monitoring patients treated with single antineoplastic agents is aiding our understanding of what hazard these drugs pose in vivo. In this study, the frequency of mutant 6-thioguanine-resistant (TG(R)) peripheral blood lymphocytes was monitored before treatment and for < or =35 weeks after treatment of patients with cyclophosphamide (CP) or chlorambucil (CAB). The mean mutant frequency before treatment for six multiple sclerosis patients treated with high-dose CP was 2.53 x 10(-5) and increased after treatment to 4.61 x 10(-5) (P = 0.08, paired t-test). Using each patient as their own control, there were significant increases (each at P < 0.04) detectable within 2-4 weeks in four of the multiple sclerosis patients treated with CP. There was no increase in an untreated control monitored over the same period. In a patient receiving five sequential CP treatments at 1 month intervals, there were cumulative increases in the frequency of mutant cells. The mutant frequency increased from 0.31 x 10(-5) before treatment to 3.64 x 10(-5) after the final treatment and had decreased to 0.53 x 10(-5) at 35 weeks after treatment. In one of two CAB-treated patients with indolent non-Hodgkin's lymphoma, there was a significant increase in mutant frequency (P < 0.03) after treatment. Freshly isolated peripheral blood lymphocytes treated with 4-hydroperoxy-CP in vitro demonstrate a dose-dependent increase in mutant frequency. The increment in mutant frequency observed in vivo is of the order expected from the in vitro experiments. Although this study demonstrates that single or multiple doses of a single antineoplastic agent are mutagenic in vivo for some patients, further studies are needed to determine the extent and mechanism of the inter-individual variations in mutagenic response.

The alkylating agents in clinical use as antineoplastics are strongly implicated as human carcinogens on the basis of animal studies and human epidemiologic studies. However, there is little quantitative information on the extent to which exposure to these drugs is mutagenic for normal (non-malignant) cells and the extent to which such mutagenicity correlates with cytotoxicity of these agents. Human lymphoblastoid cells (WIL2-NS) were exposed to graded doses of eight antineoplastic alkylating agents. Cell killing and mutation induction at the hypoxanthine -guanine phosphoribosyltransferase (HPRT) locus were measured by cloning in microplates in the presence and absence of 6-thioguanine. Dose-dependent decreases in survival were used to calculate IC50s for each of the drugs tested. The IC50s, for 1 hr exposure, ranged from 4 x 10(-7) M for nitrogen mustard to 5 x 10(-4) M for busulfan. The eight drugs tested each induced detectable increases in the frequency of mutant cells. The mutagenicity of these agents is correlated strongly with cytotoxicity. However, at equitoxic doses (IC50), the frequency of induced mutants ranged from approximately 3 x 10(-6) for 1,3-bis(2-chlorethyl)-1-nitrosourea (BCNU) to 2 x 10(-5) for busulfan and cisplatin. These results quantitate the dose-dependent cytotoxic and mutagenic effects of these bifunctional alkylating agents on human cells. All are cytotoxic and mutagenic, although their mutagenic efficiency varies.