Posted by rob on November 19, 2010 under Uncategorized | 
Imatinib and the Treatment of Fibrosis: Recent Trials and Tribulations.
Curr Rheumatol Rep. 2010 Nov 18;
Authors: Gordon J, Spiera R
Imatinib mesylate has become a therapy of interest for the treatment of systemic sclerosis because of its ability to inhibit c-Abl and platelet-derived growth factor receptor, tyrosine kinases involved in profibrotic pathways. Preclinical data using in vitro and murine models of fibrosis have demonstrated the antifibrotic properties of imatinib. Imatinib is currently used widely in the treatment of chronic myelogenous leukemia, gastrointestinal stromal tumors, and other conditions, and a large amount of information is available regarding the safety of the medication in these patient populations. Whether imatinib will be tolerable or effective in the treatment of systemic sclerosis is the subject of several investigations. The aim of this review is to summarize this body of research to date.
PMID: 21086081 [PubMed - as supplied by publisher]
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Inhibition of Cot1/Tlp2 oncogene in AML cells reduces ERK5 activation and up-regulates p27Kip1 concomitant with enhancement of differentiation and cell cycle arrest induced by silibinin and 1,25-dihydroxyvitamin D3.
Cell Cycle. 2010 Nov 15;9(22):4533-4542
Authors: Wang X, Gocek E, Novik V, Harrison JS, Danilenko M, Studzinski GP
Acute myelogenous leukemia (AML) is a disease characterized by dysregulated cell proliferation associated with impaired cell differentiation, and current treatment regimens rarely save the patient. Thus, new mechanism-based approaches are needed to improve prognosis of this disease. We have investigated in preclinical studies the potential anti-leukemia use of the plant-derived polyphenol Silibinin (SIL) in combination with 1,25-dihydroxyvitamin D3 (1,25D). Although most of the leukemic blasts ex vivo responded by differentiation to treatment with this combination, the reasons for the absence of SIL-1,25D synergy in some cases were unclear. Here we report that failure of SIL to enhance the action of 1,25D is likely due to the SIL-induced increase in the activity of differentiation-antagonizing cell components, such as ERK5. This kinase is under the control of Cot1/Tlp2, and inhibition of Cot1 activity by a specific pharmacological inhibitor 4-(3-chloro-4-fluorophenylamino)-6-(pyridin-3-yl-methylamino-3-cyano-[1-7]-naphthyridine, or by Cot1 siRNA, increases the differentiation by SIL/1,25D combinations. Conversely, over-expression of a Cot1 construct increases the cellular levels of P-ERK5, and SIL/1,25D-induced differentiation and cell cycle arrest are diminished. It appears that reduction in ERK5 activity by inhibition of Cot1 allows SIL to augment the expression of 1,25D-induced differentiation promoting factors and cell cycle regulators such as p27Kip1, which leads to cell cycle arrest. This study shows that in some cell contexts SIL/1,25D can promote expression of both differentiation-promoting and differentiation-inhibiting genes, and that the latter can be neutralized by a highly specific pharmacological inhibitor, suggesting a potential for supplementing treatment of AML with this combination of agents.
PMID: 21084834 [PubMed - as supplied by publisher]
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[Effect of Low-Dose Dasatinib in an Elderly Patient with Chronic Myelogenous Leukemia(CML).]
Gan To Kagaku Ryoho. 2010 Nov;37(11):2213-2215
Authors: Takagi Y, Aota Y, Gotoh A, Sakurai M
We experienced a case of chronic myelogenous leukemia(CML)treated successfully with low-dose dasatinib(20mg/day). An 87-year-old man was diagnosed with CML in January 2003 and was given imatinib(200mg/day). Although complete hematologic responses(CHR)were achieved, we replaced imatinib with hydroxycarbamide(HU)because of the renal dysfunction possibly due to imatinib. However, since the blood count was poorly controlled with HU, treatment with dasatinib, one of the second-generation tyrosine kinase inhibitors, was started at the accelerated phase(AP)in June 2009. Dasatinib was given in a daily dose of 20 mg, intending dose escalation after confirmation of its safety. White blood cells and platelets decreased rapidly, and after 18 days, CHR was achieved. Thereafter, daily dasatinib was reduced twice per week because of the cytopenia. However, the patient has continued CHR without developing AP for more than six months. Lowdose dasatinib might be a useful treatment in the control of selected patients with CML.
PMID: 21084830 [PubMed - as supplied by publisher]
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Use of posaconazole in the treatment of invasive fungal infections.
Expert Rev Hematol. 2009 Dec;2(6):619-630
Authors: Mehta AK, Langston AA
The emergence of invasive fungal infections as an increasingly important clinical problem in immunocompromised patients highlights the need for more effective antifungal agents and better strategies for prevention, diagnosis and treatment. Posaconazole is an extended-spectrum triazole with broad activity against a variety of fungal pathogens, both yeasts and molds. In particular, it has activity against several emerging pathogens, such as the Zygomycetes, which are resistant to many currently available antifungals, making it an attractive agent for use in both prophylactic and therapeutic situations. Studies demonstrating the prophylactic utility of posaconazole in neutropenic patients with acute myelogenous leukemia or myelodysplastic syndrome, and in patients with graft-versus-host disease following allogeneic stem cell transplantation has led to the approval of the drug in the USA. These data have been reviewed elsewhere in detail. Published data on posaconazole as primary antifungal therapy are very limited, although there is a considerable amount of experience with the drug in the salvage setting following failure of or intolerance to other antifungal agents. In this review we will focus on the use of posaconazole for treatment of established invasive fungal infections, with a focus on opportunistic infections in immunocompromised patients.
PMID: 21082953 [PubMed - as supplied by publisher]
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