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Lanabecestat, a novel β-site amyloid precursor protein-cleaving enzyme 1 inhibitor evaluated for Alzheimer treatment, inhibits P-glycoprotein (P-gp) activity in vitro. After oral 50-mg lanabecestat administration, gastric fluid lanabecestat concentrations exceed half-maximal inhibitory concentration (IC50 ), suggesting P-gp inhibition at the intestinal wall. Plasma drug concentrations following 50 mg lanabecestat administered once daily are

Lanabecestat (AZD3293; LY3314814) is an orally active potent inhibitor of human β-secretase 1 in clinical development for the treatment of Alzheimer disease. In this first Japanese clinical study for an Alzheimer disease intervention to include cerebrospinal fluid (CSF) sampling in Japanese elderly healthy subjects, we report the pharmacokinetics and effects on plasma and CSF amyloid-β (Aβ) peptides of lanabecestat in a phase 1 study involving 40 healthy Japanese subjects (NCT02005211). No safety and tolerability concerns were identified in healthy Japanese subjects exposed to lanabecestat up to the highest doses given, which is consistent with observations in a US phase 1 study of lanabecestat. Exposure to lanabecestat was similar for young and elderly subjects and increased in a dose-dependent manner. For elderly subjects, plasma lanabecestat half-life after multiple dosing was 12 to 17 hours (on days 10 and 14). Robust plasma and CSF Aβ peptide reductions were also seen at all doses, with CSF Aβ42 concentrations reduced by 63% and 79% in the 15- and 50-mg lanabecestat groups, respectively. CSF soluble amyloid-β precursor protein β also decreased following lanabecestat treatment. Suppression of CSF Aβ peptides was similar in elderly healthy Japanese subjects and US patients with mild to moderate Alzheimer disease. Lanabecestat is a promising potentially disease-modifying treatment in phase 3 development for patients with early Alzheimer disease.

Subjects Completing Month 12, n (%) 28(77.8) 27(73) 30(83.3) 29(78.4) Male, n (%) 13(36.1) 18(48.6) 19(52.8) 12(32.4) Mean Age (SD) 73.3(8.79) 73.5(8.34) 74.1(9.26) 70.5(8.68) ApoE *e4 Carriers, n (%) 22(61.1) 22(59.5) 22(61.1) 22(59.5) Symptomatic AD Treatment 29(80.6) 30(81.1) 34(94.4) 30(81.1) Mean Florbetapir PET GCA SUVR (SD) 1.74(0.294) 1.75(0.313) 1.87(0.299) 1.85(0.316) Mean MMSE Total Score (SD) 22.3(2.84) 22.3(2.78) 21.5(2.47) 21.9(2.99) Mean ADAS-Cog/11 Total Score (SD) 18.3(6.70) 19.6(9.47) 20.9(7.66) 18.4(8.34) Mean DAD Total Score (SD) 86.5(15.31) 81.7(17.41) 86.1(12.92) 85.2(13.25) Florbetapir PET GCA SUVR Change From Baseline at Month 12 Within-treatment LS Mean 0.000 -0.014 -0.066 -0.021 (95% CI) (-0.062, .063) (-0.078, .050) (-0.129, -0.004) (-0.084, 0.004) p-value 0.991 0.661 0.038 0.492 Florbetapir PET GCA SUVR Change From Baseline at Month 12 Between-treatment Difference of LS Means -0.015 -0.067 -0.022 (95% CI) (-0.103, 0.074) (-0.155, 0.022) (-0.109, 0.066) p-value 0.747 0.138 0.627 Poster Presentations: P1 P447

Objective The results of past research have identified changes in brain structure in anorexia nervosa. We observed previously unreported MRI alterations in two cases of anorexia nervosa. Method: For both cases, we reviewed the clinical history, MRI scans and conducted a pertinent literature review. Results: The MRI brain scans of two patients with the diagnosis of anorexia nervosa revealed evidence of subcortical hyperintense changes on T2-weighted images. Discussion: No previous reports of these findings have been described in the literature on anorexia nervosa to date. Clinical and pathologic correlates associated with these brain observations in anorexia nervosa are discussed. © 1997 by John Wiley & Sons, Inc. Int J Eat Disord 21: 391–394, 1997.

The tubular uptake and esterolysis of quinapril and quinaprilat were studied in male Sprague‐Dawley rats using an in vivo micropuncture technique. [ 3 H]Quinapril or [ 3 H]quinaprilat was injected with [ 14 C]inulin into either proximal or distal segments of the renal tubules, and urine was collected over 30 min. Urine and perfusate were assayed for [ 14 C]inulin using dual label spectrometry. [ 3 H]Quinapril and [ 3 H]quinaprilat concentrations were determined in urine and perfusate using a reversed‐phase HPLC procedure with radiochemical detection, coupled to liquid scintillation spectrometry. These studies demonstrated that quinapril could access the esterase enzyme from tubular fluid and be metabolized to quinaprilat in both proximal and to a lesser extent distal segments of the kidney tubule. Quinapril, but not quinaprilat, was extensively reabsorbed. Its reabsorption along the proximal tubule and/or the loop of Henle could account for as much as 45–50% of the available dose of quinapril. Further, the urinary recovery of quinapril and quinaprilat (after dosing quinapril into proximal segments) was urine flow rate dependent.