Salvage pathways play an important role in providing nucleobases to cells, which are unable to synthesize sufficient amounts for their needs. Cellular uptake systems for pyrimidines have been described, but in higher eukaryotes, transporters for thymine and uracil have not been identified. Two plant transporters, AtUPS1 and PvUPS1, were recently identified as transporters for allantoin in Arabidopsis and French bean, respectively. However, Arabidopsis, in contrast to tropical legumes, uses mainly amino acids for long distance transport. Allantoin transport has not been described in the Brassicaceae. Thus, the physiological substrates of ureide permease (UPS) transporters in Arabidopsis may be compounds structurally related to allantoin. A detailed analysis of the substrate specificities of two members of the AtUPS family shows that AtUPS1 and AtUPS2 mediate high affinity uracil and 5-fluorouracil (a toxic uracil analogue) transport when expressed in yeast and Xenopus oocytes. Consistent with a function during germination and early seedling development, AtUPS1 expression is transiently induced during the early stages of seedling development followed by up-regulation of AtUPS2 expression. Arabidopsis ups2 insertion mutants and ups1 lines, in which transcript levels were reduced by post-transcriptional gene silencing, are more tolerant to 5-fluorouracil as compared with wild type plants. The results suggest that in Arabidopsis UPS transporters are the main transporters for uracil and potentially other nucleobases, whereas during evolution legumes may have taken advantage of the low selectivity of UPS proteins for long distance transport of allantoin.

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Background LY3372689, an O‐GlcNAcase (OGA) enzyme inhibitor, is being developed as a potential treatment of tauopathies, including Alzheimer’s disease. OGA inhibition is proposed to delay the progression of tau‐related diseases by slowing the accumulation of hyper‐phosphorylated, insoluble tau filaments. Herein, we report on nonclinical and clinical studies that assessed the effect of LY3372689 on brain OGA enzyme occupancy (EO). Method Brain OGA EO of LY3372689 was measured in the frontal cortex of rats using tracer LSN3291920, a non‐fluorinated analog of a positron emission tomography (PET) radioligand 18F‐ LY3316612. A single oral dose study in healthy volunteers (HV) utilizing18F‐LY3316612 is ongoing to assess brain OGA EO of LY3372689 (NCT03944031). The study consists of up to 5 Cohorts (N = 3 – 6 subjects per Cohort). Upon completion, each subject will have participated in one cohort and have received a baseline PET scan and up to two post‐dose PET scans. In the initial cohorts, the post‐dose PET scans were conducted at approximately 2 and 24 hours after LY3372689 administration. The study design is adaptive to allow adjustment of the LY3372689 dose, timing of PET scans and pharmacokinetic samples, and number of subjects, pending results of prior cohorts. Result In rat studies, LY3372689 demonstrated a dose‐dependent change in OGA EO following a single oral dose with a maximum EO of greater than 90%. In the human PET study, a total of 12 healthy volunteers across 3 dose cohorts (N = 4 HV per cohort) have been enrolled to date. A plasma concentration‐dependent increase in brain OGA EO was observed with EO exceeding 90% at 24 hours following the highest dose of LY3372689 administered. Conclusion Non‐clinical and clinical EO studies demonstrated that occupancy of the OGA enzyme effectively translated from rats to humans after single doses of LY3372689. The human PET data can be used to support LY3372869 dose selection for efficacy trials in tauopathies.

SUMMARY This study tested the hypothesis that hypocholesterolemic interventions interfere with the bioavailability of orally administered digoxin. Using single dose studies of bioavailability, cumulative six-day urinary digoxin excretion (expressed as a percentage of each individual's control value) was 103% with a normal fiber diet, 82% with a high fiber diet, 83% with 4 g of cholestyramine, 69% with 8 g of cholestyramine, 80% with 8 g cholestyramine administered eight hours before digoxin, 92% with 8 g of cholestyramine administered eight hours after digoxin and 80% after completion of two weeks of treatment with para-aminosalicylic acid.Analysis of the urinary excretion data and associated serum levels revealed significant interference with the absorption of digoxin in all instances except for administration of digoxin either with a normal fiber diet or administration eight hours before cholestyramine. The cholestyramine-digoxin interaction was further studied using steady-state investigation of bioavailability. Serum levels and daily urinary digoxin excretions (expressed as a percentage of each individual's control value) were: 75% and 80% for digoxin administered simultaneously with 4 g of cholestyramine daily; 69% and 86% for digoxin administered simultaneously with the first daily dose of cholestyramine given as 4 g, four times a day, and 96% and 93% with cholestyramine 8 g twice a day, eight hours before and eight hours after digoxin ingestion. Serum levels and urinary excretions for all three cholestyramine interventions were significantly less than control.The results of the single dose and steady-state experiments demonstrate that cholestyramine's reduction of digoxin oral bioavailability is related to the dose of cholestyramine and the proximity of the time of administration of the two drugs.CLINICALLY SIGNIFICANT INTERFERENCE with absorption of oral digoxin due to concomitant administration of such drugs as antacids,' kaolinpectin' and sulfasalazine (salicylazosulfapyridine)2 has been demonstrated. Hypocholesterolemic interventions which alter intestinal function are also likely to cause significant interference. Cholestyramine is an effective oral hypocholesterolemic agent which has been well documented to bind both digoxin and digitoxin in vitro.3 However, Hall and co-workers did not demonstrate any dramatic effect of cholestyramine upon digoxin absorption.4Para-aminosalicylic acid (PAS-C) also effectively lowers cholesterol.5 6 While it may not correlate directly with its hypocholesterolemic effect, induction of malabsorption is a proven effect of this drug.7Based on epidemiologic data, an association between atherosclerosis and a low intake of dietary fiber has been suggested.8 Like cholestyramine, these non-nutritive fibers have been shown to be adsorbent agents capable of binding such materials as bile salts.9Based on these considerations, the present investigation studied systematically the the effects of these hypocholesterolemic interventions upon the ab-

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A B S T R A C T To identify any metabolic effects of dietary fiber upon cholesterol metabolism in man, six adult volunteer subjects were fed eucaloric cholesterolfree formula diets, with and without added dietary fiber for two 4-wk periods. A large quantity of dietary fiber was fed, some 60 g of plant cell wall material (or 16 g of crude fiber) derived from corn, beans, bran, pectin, and purified cellulose. This provided about five times the fiber intake of the typical American diet. The addition offiber to the cholesterol-free diet did not change either the plasma cholesterol level (171+21 mg/dl, SEM, to 167+18) or the triglyceride (103±39 to 93±27 mg/dl). The excretion of both endogenous neutral steroids and bile acids were unchanged with fiber (505±41 to 636 ±75 mg/day and 194±23 to 266±47 mg/day, respectively). However, total fecal steroid excretion was increased 699±29 to 902±64 mg/day, P < 0.025). With fiber, intestinal transit time was decreased (59±9 to 35±8 h, P < 0.005), and both the wet and dry stool weights were greatly increased.A second group of six subjects was fed similar diets containing 1,000 mg cholesterol derived from egg yolk. The addition of fiber to the 1,000-mg cholesterol diet did not alter either plasma cholesterol level (233±26 to 223±36 mg/dl) or triglyceride (102±19 to 83±11 mg/ dl). The excretion of endogenous neutral steroids (618 ±84 to 571±59 mg/day), of bile acids (423±122 to 401 ±89 mg/day), and of total fecal steroids (1,041±175 to 972±+111 mg/day) were unchanged by fiber. The absorption of dietary cholesterol was not altered when

Background LY3372689, an O‐GlcNAcase (OGA) enzyme inhibitor, is being developed as a potential treatment for tauopathies, including Alzheimer’s disease. OGA inhibition is proposed to delay the progression of tau‐related diseases by slowing the accumulation of hyper‐phosphorylated, insoluble tau filaments. Herein we report the first clinical study that assessed safety and pharmacokinetics (PK) of LY3372689 after single oral doses in healthy volunteers (HV). Method The phase 1 clinical trial (NCT03819270) was a single ascending dose, randomized, crossover, placebo controlled, investigator‐ and subject‐blind study. Each HV received up to 3 escalating single doses of LY3372689 or placebo over 3 study periods with an approximately 7‐day follow‐up period after each dose, such that a total of 6 LY3372689 dose levels were evaluated. Safety was assessed by adverse events (AE), safety laboratories, electrocardiograms, vital signs, physical exams, and neurological exams. Plasma PK was assessed up to 48 hours after LY3372689 administration. Result A total of 23 HV (15 males, 8 females; 22 – 63 years) participated in the study, of which 18 completed and 5 did not complete due to loss to follow up procedures or did not meet randomization criteria. LY3372689 was generally well tolerated up to the maximum dose administered. There were no serious AE reported and no subjects discontinued the study because of an AE. A total of 13 treatment‐emergent AE reported by 5 subjects considered as possibly related to study treatment were mostly mild in severity, and included pain of skin, headache, limb discomfort, pain in extremity, chest discomfort, muscle fatigue, nausea, and rash macular. The PK of LY3372689 supported daily dosing and was generally dose proportional based on AUC and Cmax. Conclusion LY3372689 demonstrated an acceptable safety and PK profile following single oral doses of LY3372689 in HV, which supports further investigation of LY3372689 as a potential treatment for tauopathies.