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Alzheimer's Disease
Published in Marc E. Agronin, Alzheimer's Disease and Other Dementias, 2014
Several agents have been developed to decrease the formation of Ab42 by blocking β- or γ-secretase, the enzymes believed responsible for cleaving APP into Ab42. The nonselective γ-secretase inhibitor semagacestat not only failed in clinical trials but also worsened symptoms in some subjects, perhaps because it inhibited the important Notch receptor (Imbimbo & Giardina, 2011). Active clinical trials are currently testing several new agents. An alternate approach to inhibiting the action of γ-secretase would be to modify its action sufficiently to lower Ab42 production. Tarenflurbil is an allosteric modulator of γ-secretase that shifts APP cleavage away from producing the toxic Ab42 and instead to producing less toxic protein fragments such as Ab38. It was the first selective Ab42 lowering agent in clinical trials but failed to show significant benefit for AD patients in a large Phase III trial (Imbimbo & Giardina, 2011).
Anti-inflammatory flurbiprofen nasal powders for nose-to-brain delivery in Alzheimer’s disease
Published in Journal of Drug Targeting, 2019
Laura Tiozzo Fasiolo, Michele Dario Manniello, Fabrizio Bortolotti, Francesca Buttini, Alessandra Rossi, Fabio Sonvico, Paolo Colombo, Georgia Valsami, Gaia Colombo, Paola Russo
Among the NSAIDs tested, tarenflurbil or R-flurbiprofen had been selected in clinical trials on AD patients as modulator of γ-secretase rather than as anti-inflammatory agent. The modulation of this enzyme reduced Aβ42 accumulation in vitro and in vivo (transgenic AD model mouse) [12–14]. The R-enantiomer of flurbiprofen has no anti-cyclooxygenase activity [15]. However, in a phase III clinical trial, oral administration of tarenflurbil failed to produce a clinical benefit on mild to moderate AD patients. Weak pharmacological activity and poor pharmacokinetics were advocated as reasons for the failure [16,17].