Muscle Nerve. 2008 Jul;38(1):837-44.
Arimoclomol at dosages up to 300 mg/day is well tolerated and safe in amyotrophic lateral sclerosis.
Cudkowicz ME, Shefner JM, Simpson E, Grasso D, Yu H, Zhang H, Shui A, Schoenfeld D, Brown RH, Wieland S, Barber JR; Northeast ALS Consortium.
Neurology Clinical Trials Unit, Massachusetts General Hospital, Building 149, 13th Street, Room 2274, Charlestown, Massachusetts 02129, USA.
Arimoclomol is an investigational drug for amyotrophic lateral sclerosis (ALS) that amplifies heat shock protein gene expression during cell stress. The objectives of the present study were to assess the safety, tolerability, and pharmacokinetics of arimoclomol in ALS. Eighty-four participants with ALS received arimoclomol at one of three oral doses (25, 50, or 100 mg three times daily) or placebo. The primary outcome measure was safety and tolerability. A subset of 44 participants provided serum and cerebrospinal fluid (CSF) samples for pharmacokinetic analysis. Participants who completed 12 weeks of treatment could enroll in a 6-month open-label study. Arimoclomol at doses up to 300 mg/day was well tolerated and safe. Arimoclomol resulted in dose-linear pharmacologic exposures and the half-life did not change with continued treatment. Arimoclomol CSF levels increased with dose. Arimoclomol was shown to be safe, and it crosses the blood-brain barrier. Serum pharmacokinetic profiles support dosing of three times per day. An efficacy study in ALS is planned.
Stroke. 2008 Mar;39(3):1022-4.
Reverse regulation of endothelial cells and myointimal hyperplasia on cell proliferation by a heatshock protein-coinducer after hypoxia.
Denes L, Bori Z, Csonka E, Entz L, Nagy Z.
BACKGROUND AND PURPOSE: Myointimal hyperplasia (MIH) cells are related to permanent upregulated proliferation as tumor-like cells. The aim of this study is to assess whether treatment of cells after hypoxia by Iroxanadine heat-shock protein (HSP-coinducer) predicts recovery through cell proliferation. METHODS: Vascular smooth muscle cells (VSMC) and brain capillary endothelial cells (HBEC) were isolated from human origin and MIH-cells from early carotid restenosis after surgery. Cell proliferation was quantified by bromuridine (BrdU) incorporation after hypoxia/reoxygenation. HSP72 and cyclin-dependent kinase (CDKN1A) mRNA expression was assessed by reverse transcription-polymerase chain reaction (PCR) and cell cycle distribution by flow cytometry (FACS) analysis. RESULTS: After hypoxia/reoxygenation, the proliferation of MIH-cells increased, whereas endothelial cells decreased (MIH: 0.266+/-0.016 versus 0.336+/-0.024; P<0.05; HBEC: 1.249+/-0.10 versus 0.878+/-0.11; P<0.05). Whereas augmented proliferation of MIH-cells was reduced (40% to 45%) by HSP-coinducer, diminished HBEC proliferation increased (46.2%). Stress-activated-protein-kinase (SAPK)p38-dependent cell cycle redistribution was generated by an increase in HSP72 and CDKN1A mRNA levels in MIH-cells. CONCLUSIONS: The 2 key players of early restenosis (MIH, EC) were oppositely regulated and correspondingly after treatment by HSP-coinducer reverse recovered. Drug candidate may have therapeutic potential in (re)restenosis.
(and a little info. on RXI's first target, for obesity...)
Blood. 2008 May 9. [Epub ahead of print]
Co-activator function of RIP140 for NF{kappa}B/RelA-dependent cytokine gene expression.
Zschiedrich I, Hardeland U, Krones-Herzig A, Berriel Diaz M, Vegiopoulos A, Muggenburg J, Sombroek D, Hofmann TG, Zawatzky R, Yu X, Gretz N, Christian M, White R, Parker MG, Herzig S.
Molecular Metabolic Control, German Cancer Research Center, Heidelberg, Germany.
Inflammatory responses represent a hallmark of numerous pathologies including sepsis, bacterial infection, insulin resistance, and malign obesity. Here we describe an unexpected co-activator function for the nuclear receptor interacting protein (RIP) 140 for nuclear factor (NF) kappaB, a master transcriptional regulator of inflammation in multiple tissues. Previous work has shown that RIP140 suppresses the expression of metabolic gene networks but we have found that genetic as well as acute deficiency of RIP140, leads to the inhibition of the pro-inflammatory program in macrophages. The ability of RIP140 to function as a coactivator for cytokine gene promoter activity relies on direct protein-protein interactions with the NFkappaB subunit RelA and histone acetylase CREB-binding protein (CBP). RIP140-dependent control of pro-inflammatory gene expression via RelA/CBP may, therefore, represent a molecular rational for the cellular integration of metabolic and inflammatory pathways. |
