Safety, Tolerability, Pharmacokinetics, and Aβ Levels After Short-term Administration of R-flurbiprofen in Healthy Elderly Individuals

Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
Alzheimer Disease and Associated Disorders (Impact Factor: 2.44). 09/2007; 21(4):292-9. DOI: 10.1097/WAD.0b013e31815d1048
Source: PubMed


To evaluate the safety and tolerability and pharmacokinetic properties of R-flurbiprofen (Tarenflurbil) in normal elderly individuals and to determine the effect of the drug on amyloid beta 42 (Abeta42) levels, we conducted a double-blind, placebo-controlled study of 48 healthy subjects aged 55 to 80. Three successive cohorts were randomized to doses of 400, 800, or 1600 mg/d, or placebo, given as 2 divided doses for 21 days. Blood and cerebrospinal fluid were collected for pharmacokinetic studies and measurement of Abeta levels at baseline and on day 21. R-flurbiprofen was well-tolerated at all 3 doses. The compound penetrated the blood-brain barrier in a dose-dependent manner. From baseline to 21 days, comparisons between study groups revealed no significant differences in changes of cerebrospinal fluid Abeta42 levels and no significant differences in changes of plasma Abeta42 levels at the time of trough drug level at 21 days of treatment. Further analysis of drug concentration-response for plasma samples showed that at the time of peak plasma concentration, higher plasma drug concentration was related to lower Abeta42 plasma levels (P=0.016). R-flurbiprofen had an excellent safety profile and showed dose-dependent central nervous system penetration. Exploratory analyses of plasma Abeta and peak drug levels suggested a short-term effect in plasma that warrants independent verification. The safety, tolerability, and pharmacokinetic profile of R-flurbiprofen in these older individuals support the ongoing studies of this compound in patients with Alzheimer disease.

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    • "In this experimental setup, free flurbiprofen did not reduce Aβ42 levels, because it was not sufficiently transported across the endothelial cell monolayer at high enough concentration. This is in agreement with phase I dosing studies of R-flurbiprofen in humans [46]. In these studies, healthy volunteers were treated for 21 days with up to 800 mg twice daily of R-flurbiprofen. "
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    ABSTRACT: The amyloid-β42 (Aβ42) peptide plays a crucial role in the pathogenesis of Alzheimer's disease (AD), the most common neurodegenerative disorder affecting the elderly. Over the past years, several approaches and compounds developed for the treatment of AD have failed in clinical studies, likely in part due to their low penetration of the blood-brain barrier (BBB). Since nanotechnology-based strategies offer new possibilities for the delivery of drugs to the brain, this technique is studied intensively for the treatment of AD and other neurological disorders. The Aβ42 lowering drug flurbiprofen was embedded in polylactide (PLA) nanoparticles by emulsification-diffusion technique and their potential as drug carriers in an in vitro BBB model was examined. First, the cytotoxic potential of the PLA-flurbiprofen nanoparticles on endothelial cells and the cellular binding and uptake by endothelial cells was studied. Furthermore, the biological activity of the nanoparticulate flurbiprofen on γ-secretase modulation as well as its in vitro release was examined. Furthermore, the protein corona of the nanoparticles was studied as well as their ability to transport flurbiprofen across an in vitro BBB model. PLA-flurbiprofen nanoparticles were endocytosed by endothelial cells and neither affected the vitality nor barrier function of the endothelial cell monolayer. The exposure of the PLA-flurbiprofen nanoparticles to human plasma occurred in a rapid protein corona formation, resulting in their decoration with bioactive proteins, including apolipoprotein E. Furthermore, luminally administered PLA-flurbiprofen nanoparticles in contrast to free flurbiprofen were able to modulate γ-secretase activity by selectively decreasing Aβ42 levels in the abluminal compartment of the BBB model. In this study, we were able to show that flurbiprofen can be transported by PLA nanoparticles across an in vitro BBB model and most importantly, the transported flurbiprofen modulated γ-secretase activity by selectively decreasing Aβ42 levels. These results demonstrate that the modification of drugs via embedding in nanoparticles is a promising tool to facilitate drug delivery to the brain, which enables future development for the treatment of neurodegenerative disorders like AD.
    Full-text · Article · Nov 2013 · Alzheimer's Research and Therapy
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    • "This agent is a first-generation, low-specificity inhibitor that has side effects probably because of its interaction with Notch1 protein. Flurizan TM (also named R-flurbiprofen or tarenflurbil), a -secretase modulator developed by Myriad, exhibited low potency and poor brain penetrance and failed also in Phase III [211]. The clinical trials for Elan's ELND006 were also halted in October 2010 because of liver side effects that may not be related to the mechanism of action of the drug. "
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    ABSTRACT: The neurodegenerative process that defines Alzheimer's disease (AD) is initially characterized by synaptic alterations followed by synapse loss and ultimately cell death. Decreased synaptic density that precedes neuronal death is the strongest pathological correlate of cognitive deficits observed in AD. Substantial synapse and neuron loss occur early in disease progression in the entorhinal cortex (EC) and the CA1 region of the hippocampus, when memory deficits become clinically detectable. Mounting evidence suggests that soluble amyloid-β (Aβ) oligomers trigger synapse dysfunction both in vitro and in vivo. However, the neurodegenerative effect of Aβ species observed on neuronal culture or organotypic brain slice culture has been more challenging to mimic in animal models. While most of the transgenic mice that overexpress Aβ show abundant amyloid plaque pathology and early synaptic alterations, these models have been less successful in recapitulating the spatiotemporal pattern of cell loss observed in AD. Recently we developed a novel animal model that revealed the neurodegenerative effect of soluble low-molecular-weight Aβ oligomers in vivo. This new approach may now serve to determine the molecular and cellular mechanisms linking soluble Aβ species to neurodegeneration in animals. In light of the low efficiency of AD therapies based on the amyloid cascade hypothesis a novel framework, the aging factor cascade hypothesis, is proposed in attempt to integrate the new data and concepts that emerged from recent research to develop disease modifying therapies.
    Full-text · Article · Jul 2013 · Current pharmaceutical design
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    • "Due to the worse cognitive outcome and secondary effects (severe gastrointestinal toxicity, immunomodulation and skin cancer) in patients treated with GSIs [73], research in this area has shifted towards GSMs that spare Notch signaling. These GSM have also shown a decrease of plasma Aβ [74-76] but the results regarding any Aβ-rebound are contradictory for GSMs [75,76]. On the other hand, passive immunotherapy results from clinical trials suggest that there is a dose-dependent transient increase of plasma Aβ in response to the monoclonal anti-Aβ antibody infusion and this was reported to last several weeks [77]. "
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    ABSTRACT: Cerebrospinal fluid and positron emission tomography biomarkers accurately predict an underlying Alzheimer's disease (AD) pathology; however, they represent either invasive or expensive diagnostic tools. Therefore, a blood-based biomarker like plasma amyloid beta (Aβ) that could correlate with the underlying AD pathology and serve as a prognostic biomarker or an AD screening strategy is urgently needed as a cost-effective and non-invasive diagnostic tool. In this paper we review the demographic, biologic, genetic and technical aspects that affect plasma Aβ levels. Findings of cross-sectional and longitudinal studies of plasma Aβ, including autosomal dominant AD cases, sporadic AD cases, Down syndrome cases and population studies, are also discussed. Finally, we review the association between cerebrovascular disease and Aβ plasma levels and the responses observed in clinical trials. Based on our review of the current literature on plasma Aβ, we conclude that further clinical research and assay development are needed before measures of plasma Aβ can be interpreted so they can be applied as trait, risk or state biomarkers for AD.
    Full-text · Article · Mar 2013 · Alzheimer's Research and Therapy
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