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Pharmacokinetics of drugs may differ between small and large mammals (including humans); therefore, drug testing in animal models must be carefully designed. Sprague–Dawley rats were used in cardiac experiments, during which the lopinavir concentration in serum had to match human therapeutic levels (4–10 μg/mL). Lopinavir was administered as a co-formulated drug of lopinavir and ritonavir. It was found that after a single administration of a standard human peroral dose (lopinavir 13.3 mg/kg of body weight), the serum concentration of lopinavir was only one-tenth of the target level. It remained below the minimum target level even after 10-fold the standard dose was administered. After initial pilot tests, a dose escalation study was conducted with oral doses 10- and 15-fold the standard clinical dose of lopinavir (i.e. 133 and 200 mg/kg, respectively). A second administration 2 h later effectively increased and maintained higher concentrations during the experimental ischaemia and reperfusion periods. A dose-dependent increase in serum concentration of the drug was observed. Thus, the target therapeutic serum level of lopinavir in the rats was achieved by administrating 10- to 15-fold the standard human dose twice, separated by a 2 h interval.

In an environment of changing demographics and health care disparities, it is essential that nurses continue to develop competence in providing care across cultures. This article presents the findings of a pilot project to measure and compare self-reported cultural competence scores before and after participation in one of the core classes of a cultural competence curriculum. Cultural competence of the staff of a patient care unit ( N = 98) was assessed prior to the class, at 3 months, and at 6 months posteducation using the Inventory for Assessing the Process of Cultural Competence Among Healthcare Professionals–Revised. The results demonstrated that following an educational intervention the participants self-reported a statistically significant increase ( p = .03) in cultural competence within the category range of cultural awareness. Providing cultural competence education may better equip nurses to care for patients from diverse cultures.

Abstract Myeloproliferative diseases (MPDs) are a subset of myeloid malignancies that are characterized by the expansion of a multipotent hematopoietic stem cell. Chronic MPDs can be classified into two categories, those harboring the BCR-ABL oncogene and those that are negative. This later category of neoplasms encompasses polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Recent discovery of activating mutations in the tyrosine kinase gene, JAK2 and constitutive activation of JAK2-STAT pathway, in large number of MPD patients has ignited considerable interest in MPD and has highlighted JAK2 as a therapeutic intervention point for drug discovery efforts. However, high-sequence homology with other JAK family members has posed a major challenge to design selective JAK2 inhibitors. Given that other JAK family members are involved in the regulation of immune function, it is important to maintain selectivity for JAK2 over these family members in order to mitigate the risks associated with undesired immunosuppression. Several JAK2 inhibitors with varying selectivity profiles are currently being evaluated in preclinical testing as well as in clinical trials for the treatment of MPD. Additionally, emerging genetic and pharmacologic evidence suggest that inhibition of the JAK2-STAT pathway may be an important therapeutic intervention point in other hematological malignancies as well as in certain solid tumors. We report here the discovery and characterization of BMS-911543, a functionally selective small molecule inhibitor of the Janus kinase family (JAK) member, JAK2. BMS-911543 is a potent and reversible inhibitor of JAK2 with a biochemical Ki of 0.48 nM. It has over 65-, 74- and 350-fold selectivity against the other JAK family members, TYK2, JAK3 and JAK1, respectively. Importantly, examination of > 450 other kinases in competition binding assays and in selected biochemical kinase assays did not reveal significant inhibitory activity for this JAK2 inhibitor, highlighting its high degree of biochemical selectivity for JAK2. Functionally, BMS-911543 displayed potent antiproliferative and pharmacodynamic (PD) effects in mutated JAK2-expressing cell lines dependent upon JAK2-STAT signaling and had little activity in cell types dependent upon other pathways such as JAK1 and JAK3. Further, single agent antiproliferative activity was not observed for BMS-911543 in a variety of solid tumor cell lines dependent upon other signaling pathways. In contrast, BMS-911543 was evaluated in colony growth assays using primary progenitor cells isolated from patients with JAK2V617F-positive myeloproliferative disease (MPD) and resulted in an increased antiproliferative response in MPD cells as compared with those from healthy volunteers. Similar to these in vitro observations, BMS-911543 was also highly active in in vivo models of JAK2-pSTAT signaling in multiple species with durable and potent pathway suppression observed after a single oral dose. Additionally, BMS-911543 was evaluated for effects in a JAK2V617F-expressing SET-2 xenograft model system and displayed a minimally effective dose of <2 mg/kg on pSTAT5 pathway suppression, which lasted up to 8 hours. To test the hypothesis that a JAK2 selective inhibitor would have less effect on immune system function, BMS-911543 was compared to pan-JAK inhibitors in a mouse model of immunosuppression. At low dose levels active in JAK2-dependent PD models, no effects were observed on antigen-induced IgG and IgM production for BMS-911543 whereas a pan-JAK family inhibitor showed pronounced effects at all dose levels tested. The mechanistic selectivity of BMS-911543 to pan-JAK family inhibitors was extended through comparative analysis of these inhibitors in whole genome gene expression profiling experiments performed in sensitive and resistant cell types. In this comparison, BMS-911543 modulated a distinct subset of transcriptional changes as compared to pan-JAK inhibitors in clinical testing, thereby defining a minimal set of transcriptional changes underlying the pharmacologic effects of JAK2 inhibition. Collectively these results define the mechanistic basis for a differential therapeutic index between selective JAK2 and pan-JAK family inhibition pre-clinically and suggest a therapeutic rationale for the further characterization of BMS-911543 in patients with MPD and in other malignancies reliant upon constitutively active JAK2 signaling. References: Levine, R.L., et al. Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders (2007). Nature Rev. Cancer, 7, 673-683. Atallah, E. and Verstovsek, S. Prospect of JAK2 inhibitor therapy in myeloproliferative neoplasms. (2009). Expert Rev. Anticancer Ther. 9, 663-670. Ghoreschi, K., et al. Janus kinases in immune cell signaling. (2009). Immunol. Rev.,228, 273-287. Mesa, R.A. and Tefferi, A. Emerging drugs for the therapy of primary and post essential thrombocythemia, post polycythemia vera myelofibrosis (2009). Expert Opin. Emerging Drugs, 14, 1-9. Roll, J.D. and Reuther, G.W. CRLF2 and JAK2 in B-progenitor acute lymphoblastic leukemia: a novel association in oncogenesis. (2010) Cancer Res, 70, 7347-7352. Rui et al., Cooperative epigenetic modulation by cancer amplicon genes (2010). Cancer Cell, 18, 590-605. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr DDT01-03. doi:10.1158/1538-7445.AM2011-DDT01-03

Abstract Risk factors for acute GVHD (AGVHD), overall survival, and transplant-related mortality were evaluated in adults receiving allogeneic hematopoietic cell transplants (1999-2005) from HLA-identical sibling donors (SDs; n = 3191) or unrelated donors (URDs; n = 2370) and reported to the Center for International Blood and Marrow Transplant Research, Minneapolis, MN. To understand the impact of transplant regimen on AGVHD risk, 6 treatment categories were evaluated: (1) myeloablative conditioning (MA) with total body irradiation (TBI) + PBSCs, (2) MA + TBI + BM, (3) MA + nonTBI + PBSCs, (4) MA + nonTBI + BM, (5) reduced intensity conditioning (RIC) + PBSCs, and (6) RIC + BM. The cumulative incidences of grades B-D AGVHD were 39% (95% confidence interval [CI], 37%-41%) in the SD cohort and 59% (95% CI, 57%-61%) in the URD cohort. Patients receiving SD transplants with MA + nonTBI + BM and RIC + PBSCs had significantly lower risks of grades B-D AGVHD than patients in other treatment categories. Those receiving URD transplants with MA + TBI + BM, MA + nonTBI + BM, RIC + BM, or RIC + PBSCs had lower risks of grades B-D AGVHD than those in other treatment categories. The 5-year probabilities of survival were 46% (95% CI, 44%-49%) with SD transplants and 33% (95% CI, 31%-35%) with URD transplants. Conditioning intensity, TBI and graft source have a combined effect on risk of AGVHD that must be considered in deciding on a treatment strategy for individual patients.