title: Intermittent oral coadministration of a gamma secretase inhibitor with dexamethasone mitigates intestinal goblet cell hyperplasia in rats.
abstract: Dexamethasone was given in 2 oral dosing regimens with repeat dose oral administration of the gamma secretase inhibitor (GSI), PF-03084014, in Sprague-Dawley (SD) rats in order to evaluate the effects of coadministration of dexamethasone on GSI-induced goblet cell hyperplasia (GCH) in the intestinal tract. Safety end points were evaluated in 1 week and 1 month studies. The dosing regimens tested in the 1-month studies included a 1-week pretreatment with 1.0 mg/kg dexamethasone followed by a 3-week repeat dose treatment with 100 mg/kg GSI or concurrent intermittent treatment with 1.0 mg/kg dexamethasone on weeks 1 and 3 and repeat dose treatment with 100 mg/kg GSI for 4 weeks. Pretreatment with dexamethasone for 1 week transiently mitigated the severity of intestinal GCH for up to 1 week. Intermittent coadministration of dexamethasone on weeks 1 and 3 with GSI repeat dosing for 4 weeks mitigated intestinal GCH for up to 4 weeks post treatment. Treatment-related morbidity and mortality occurred on day 7 with 150 mg/kg GSI and 5 mg/kg dexamethasone coadministration, and on days 13, 14, and 23 with 100 mg/kg GSI and 1 mg/kg dexamethasone coadministration.
authors: 1Drug Safety Research & Development, Pfizer Global Research and Development, La Jolla Laboratories, San Diego, California, USA.
authors: Shirley A
authors: SA
authors: Aguirre
authors: Ling
authors: L
authors: Liu
authors: Natilie A
authors: NA
authors: Hosea
authors: Wesley
authors: W
authors: Scott
authors: Jeffrey R
authors: JR
authors: May
authors: Leigh Ann
authors: LA
authors: Burns-Naas
authors: Sophia
authors: S
authors: Randolph
authors: Robert H
authors: RH
authors: Denlinger
authors: Bora
authors: B
authors: Han
mesh_terms: D000284:Administration, Oral; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003907:Dexamethasone / Q000008:administration & dosage* / Q000097:blood / Q000633:toxicity; D020397:Goblet Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006965:Hyperplasia / Q000473:pathology*; D007422:Intestines / Q000166:cytology / Q000187:drug effects; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage* / Q000097:blood / Q000633:toxicity; D014633:Valine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000633:toxicity
chemical_list: D013764:Tetrahydronaphthalenes; D003907:Dexamethasone; D053829:Amyloid Precursor Protein Secretases; D014633:Valine; C550722:nirogacestat
keywords: dexamethasone; gamma (γ) secretase inhibitor; goblet cell hyperplasia.