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36 results on '"Jhee, Stanford S."'

2. Robust Pharmacodynamic Effect of LY3202626, a Central Nervous System Penetrant, Low Dose BACE1 Inhibitor, in Humans and Nonclinical Species

Author

Willis, Brian A., primary, Lowe, Stephen L., additional, Monk, Scott A., additional, Cocke, Patrick J., additional, Aluise, Christopher D., additional, Boggs, Leonard N., additional, Borders, Anthony R., additional, Brier, Richard A., additional, Dean, Robert A., additional, Green, Steven J., additional, James, Douglas E., additional, Jhee, Stanford S., additional, Lin, Qun, additional, Lo, Albert C., additional, May, Patrick C., additional, Watson, Brian M., additional, Winneroski, Leonard L., additional, Yang, Zhixiang, additional, Zimmer, Jennifer A., additional, McKinzie, David L., additional, and Mergott, Dustin J., additional

Published
2022
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6. Bridging strategies may help put western drugs on the Japanese market: restrictive regulations and cultural differences make regulatory approval in Japan elusive, but adopting new strategies may make that lucrative pharmaceutical market more accessible to non-Japansese companies

Author

Jhee, Stanford S. and Frackiewicz, Edyta J.

Subjects
International trade, International aspects, Marketing, Company marketing practices, Pharmaceutical industry -- International trade -- Marketing, Drug approval -- International aspects
Abstract

Many of the new medications that come into the Japanese market originate in foreign countries, because the pharmaceutical industry in Japan is comparatively small. Despite this, foreign companies still have [...]

Published
2003

12. Identifying Pharmacodynamic Protein Markers of Centrally Active Drugs in Humans: A Pilot Study in a Novel Clinical Model

Author

Patil, Sandeep T., primary, Higgs, Richard E., additional, Brandt, John E., additional, Knierman, Michael D., additional, Gelfanova, Valentina, additional, Butler, Jon P., additional, Downing, AnnCatherine M., additional, Dorocke, Jill, additional, Dean, Robert A., additional, Potter, William Z., additional, Michelson, David, additional, Pan, Alan X., additional, Jhee, Stanford S., additional, and Hale, John E., additional

Published
2007
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16. The Potent BACE1 Inhibitor LY2886721 Elicits Robust Central Aβ Pharmacodynamic Responses in Mice, Dogs, and Humans.

Author

May, Patrick C., Willis, Brian A., Lowe, Stephen L., Dean, Robert A., Monk, Scott A., Cocke, Patrick J., Audia, James E., Boggs, Leonard N., Borders, Anthony R., Brier, Richard A., Calligaro, David O., Day, Theresa A., Ereshefsky, Larry, Erickson, Jon A., Gevorkyan, Hykop, Gonzales, Celedón R., James, Douglas E., Jhee, Stanford S., Komjathy, Steven F., and Li, Linglin

Subjects
PROTEASE inhibitors, AMYLOID beta-protein, ALZHEIMER'S disease, CLINICAL trials, NEURODEGENERATION, MEMORY loss, DEMENTIA
Abstract

BACE1 is a key protease controlling the formation of amyloid β, a peptide hypothesized to play a significant role in the pathogenesis of Alzheimer's disease (AD). Therefore, the development of potent and selective inhibitors of BACE1 has been a focus of many drug discovery efforts in academia and industry. Herein, we report the nonclinical and early clinical development of LY2886721, a BACE1 active site inhibitor that reached phase 2 clinical trials in AD. LY2886721 has high selectivity against key off-target proteases, which efficiently translates in vitro activity into robust in vivo amyloid β lowering in nonclinical animal models. Similar potent and persistent amyloid β lowering was observed in plasma and lumbar CSF when single and multiple doses of LY2886721 were administered to healthy human subjects. Collectively, these data add support for BACE1 inhibition as an effective means of amyloid lowering and as an attractive target for potential disease modification therapy in AD. [ABSTRACT FROM AUTHOR]

Published
2015
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33. Robust Central Reduction of Amyloid-β in Humans with an Orally Available, Non-Peptidic β-Secretase Inhibitor.

Author

May, Patrick C., Dean, Robert A., Lowe, Stephen L., Martenyi, Ferenc, Sheehan, Scott M., Boggs, Leonard N., Monk, Scott A., Mathes, Brian M., Mergott, Dustin J., Watson, Brian M., Stout, Stephanie L., Timm, David E., LaBell, Elizabeth Smith, Gonzales, Celedon R., Nakano, Masako, Jhee, Stanford S., Yen, Mark, Ereshefsky, Larry, Lindstrom, Terry D., and Calligaro, David O.

Subjects
AMYLOID, AMYLOID beta-protein, ALZHEIMER'S disease, BIOAVAILABILITY, BIOMARKERS, SECRETASE inhibitors
Abstract

According to the amyloid cascade hypothesis, cerebral deposition of amyloid-β peptide (Aβ) is critical for Alzheimer's disease (AD) pathogenesis. Aβ generation is initiated when β-secretase (BAC£1) cleaves the amyloid precursor protein. For more than a decade, BAC£1 has been a prime target for designing drugs to prevent or treat AD. However, development of such agents has turned out to be extremely challenging, with major hurdles in cell penetration, oral bioavailability/metabolic clearance, and brain access. Using a fragment-based chemistry strategy, we have generated LY2811376 [ (S)-4-(2,4-difluoro-5-pyrimidin-5-yl-phenyl)-4-methyl-5,6-dihydro- 4H-[1,3]thiazin-2-ylamine], the first orally available non-peptidic BACEl inhibitor that produces profound Af3-lowering effects in animals. The biomarker changes obtained in preclinical animal models translate into man at doses of LY2811376 that were safe and well tolerated in healthy volunteers. Prominent and long-lasting Aβ reductions in lumbar CSF were measured after oral dosing of30 or 90 mg ofLY2811376. This represents the first translation ofBAC£1-driven biomarker changes in CNS from preclinical animal model to man. Because of toxicology findings identified in longer-term preclinical studies, this compound is no longer progressing in clinical development. However, BAC£1 remains a viable target because the adverse effects reported here were recapitulated in LY2811376-treated BACEl KO mice and thus are unrelated to BAC£1 inhibition. The magnitude and duration of central Aβ reduction obtainable with BAC£1 inhibition positions this protease as a tractable small-molecule target through which to test the amyloid hypothesis in man. [ABSTRACT FROM AUTHOR]

Published
2011
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34. A Pharmacokinetic, Pharmacodynamic and Safety Study of Celecoxib in Subjects with Probable Alzheimer's Disease.

Author

Jhee, Stanford S., Frackiewicz, Edyta J., Tolbert, Dwain, Sainati, Stephen, Karim, Aziz, Zolnouni, Parvaneh P., and Choi, Kyung‐Eob

Subjects
*CYCLOOXYGENASE 2 inhibitors, *CEREBROSPINAL fluid, *PAIN, *HEALTH outcome assessment, *INTERLEUKIN-6, *NEUROPSYCHOLOGICAL tests, *ABDOMINAL diseases
Abstract

OBJECTIVES: To evaluate the plasma and cerebrospinal fluid (CSF) of subjects with Alzheimer's disease (AD) to assess celecoxib pharmacokinetics (PK) and its effects on pharmacodynamic (PD) outcome measures, prostaglandin (PG) synthesis, inflammation processes, and protein markers for AD progression and cognition. METHODS: This was a 4-week, double-blind, placebo-controlled trial evaluating 3 dose levels of celecoxib (50, 200 and 400 mg BID), placebo, or 1 dose level of celecoxib 400 mg BID in age-matched controls in concurrent panels of 5 subjects each. RESULTS: 21 subjects with AD and 5 age-matched controls were controlled. The mean concentration of celecoxib in CSF gradually increased and peaked at 4 hours post-dose on Day 28 for all groups, and decreased to near or below the 30-minute pre-dose levels by 12 hours post-dose. Mean peak celecoxib plasma concentration peaked at 2 hours post dose on Day 28 and was not dose dependent. PD analysis revealed that Prostaglandin E2 (PGE2) levels in the CSF indicated COX-2 inhibition at Day 28, however other inflammatory markers (Interleukin-6) and markers for disease progression (Aβ1–42 and tau protein) were unaffected by celecoxib treatment. Cognitive performance on the ADAS-COG improved in all treatment groups except for 50 mg BID group. The mean MMSE (Mini-Mental Status Exam) score improved in the 50 mg BID and 400 mg BID groups, worsened in the 200 mg BID and age-matched control groups, and remained unchanged in placebo. Computerized Neuropsychological Test Battery (CNTB) scores showed a varied response by parameter. All reported AEs were mild or moderate in intensity. The most frequently reported AEs were headache, dizziness, back pain and abdominal pain. CONCLUSION: Celecoxib penetrates the blood brain barrier. The PK profile is similar in AD and age-matched control subjects. The PD analysis was inconclusive. None of the markers tested represented a useful surrogate for any effect of celecoxib. Tests of cognitive ability did not show notable or consistent improvements during celecoxib administration. Oral doses of celecoxib 50, 200, 400 mg BID were well tolerated in patient with AD and the age-matched control subjects. [ABSTRACT FROM AUTHOR]

Published
2004
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