Ellen A. Cannady's research while affiliated with Eli Lilly and Company and other places

... JAK/STAT pathway was inhibited as previously described (Carfagna et al., 2018) by oral gavage of 10 mg/kg body weight Baricitnib (Olumiant, Lilly). Control mice received an equal amount of only vehicles by oral gavage. ...

... Baricitinib (BAR) is predominantly eliminated by renal secretion (approximately 75%) and to a lesser extent by fecal excreted (approximately 20%) [48,49]. Probenecid, a potent OAT3 inhibitor, increased the area under the curve (AUC) of BAR 2-fold in vivo and decreased renal clearance to 69% [50]. LEF, which is a weak OAT3 inhibitor via the metabolite teriflunomide, can also affect BAR concentrations ( [51]; . ...

... Agonists of GPR40 have been shown to reduce neuronal damage caused by Alzheimer's disease GPR40 [15]. LY2922470, a novel small-molecule GPR40 activator, has been demonstrated to be a viable treatment option for type 2 diabetes due to its ability to stimulate insulin production [16][17][18]. However, whether LY2922470 has shown protective effects against ischemic stroke and cerebral I/R injury remains unknown. ...

... Renal dysfunction and hepatic impairment are two disease states notorious for decreased plasma protein concentrations [23,24]; therefore, regulatory agencies advise to assess the unbound pharmacokinetics in plasma in populations with these organ impairments [25][26][27]. In case data on protein binding were not available in pregnancy, we took clues from other populations with similar decreased serum protein concentrations as pregnant women to estimate the effect of changes in unbound concentration of HIV-integrase inhibitors during pregnancy [28][29][30][31][32]. Results from studies in moderate hepatic [29][30][31] and severely renally impaired patients [28] can then be useful. ...

... Therefore, consideration must always be given to how the changes could impact the relative in vivo performance. [1][2][3][4][5] The "gold standard" to understanding the potential impact of these changes on the absorption of a drug is a human in vivo comparability study. Comparability studies can be classified in 2 groups: bioequivalence (BE) studies and relative bioavailability (RBA) studies. ...

... The synthesis of fully substituted (trisubstituted) isoxazoles is more challenging, especially since the regioselectivity of commonly-used 1,3-dipolar cycloadditions varies depending on the electronic properties of the two substrates. This cases [13,14], but is generally unfavorable due to their poor stability. ...

... " The Lilly compound has been shown to generate Ndealkylated products as major metabolites in humans (Scheme 12). 52 Here, a labile 4-(di)alkylaminobenzyl alcohol, whether formed before dealkylation of the amino group (58 to 59) or not, should be an excellent precursor of an imine methide or carbenium ion (sulfate activation is probably not needed; cf. DFT calculation in section 7). ...

... However, coadministration of baricitinib with several other transporter and enzymatic substrates has not yielded clinically meaningful changes in baricitinib exposure, including ketoconazole, fluconazole, rifampicin, and cyclosporine. Conversely, baricitinib had no clinically meaningful effect on serum levels of digoxin, methotrexate, simvastatin, ethinyl estradiol, or levonorgestrel when co-administered [42][43][44]. Jabbari et al. first reported the efficacy of baricitinib in the treatment of AA in 2015 when they noted marked improvement of AA in a patient enrolled in a clinical trial examining baricitinib for the treatment of CANDLE syndrome [45]. Since then, several case reports, followed by the seminal phase II trial and two phase III trials, have demonstrated the efficacy of baricitinib in the treatment of AA [29,34,36,46,47]. ...

... Cerivastatin is a CYP2C8 substrate drug, and many drugs, such as gemfibrozil and inducers, have been identified as CYP2C8 inhibitors, which affect the metabolism of cerivastatin, and thus promote a strong potential for drug interactions (Backman et al., 2016). Evacetrapib may impact the metabolism of simvastatin by inhibiting all of the major CYPs, including CYP2C9, CYP2C19, and CYP3A (Cannady et al., 2015). Amiodarone has been reported to increase the exposure of simvastatin by 1.2-to 2-fold by inhibiting CYP3A (Chen, Mao, & Hop, 2015). ...

... Food effects may explain the interlaboratory variability seen in pharmacokinetic (PK) profiles for the same drug at the same dose (Li et al., 2012;Jiang et al., 2015). Preclinical PK studies are typically performed in fasted rats to reduce the interanimal variability in concentration-time (C-t) profiles (Melander, 1978;Singh et al., 2011;Small et al., 2015). Animals are usually fasted overnight between 12 and 18 hours, which is often noted (Vermeulen et al., 1997). ...