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Safety, Pharmacokin...
Safety, Pharmacokinetic, and Positron Emission Tomography Evaluation of Serotonin and Dopamine Transporter Occupancy Following Multiple-Dose Administration of the Triple Monoamine Reuptake Inhibitor BMS-820836
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Zheng, Ming (author)
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Appel, Lieuwe (author)
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Luo, Feng (author)
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Lane, Roger (author)
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Risinger, Robert (author)
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- Antoni, Gunnar (author)
- Uppsala universitet,Plattformen för preklinisk PET
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Cahir, Matthews (author)
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Sanjay, Keswani (author)
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Hayes, Wendy (author)
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Burt, David (author)
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Zubin, Bhagwaragar (author)
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(creator_code:org_t)
- 2014-08-14
- 2015
- English.
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In: Psychopharmacology. - : Springer Publishing Company. - 0033-3158 .- 1432-2072. ; 232:3, s. 529-540
- Related links:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
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- RationaleBMS-820836 is a novel antidepressant that selectively inhibits the reuptake of serotonin, norepinephrine, and dopamine.ObjectiveThis Phase I study assessed safety, tolerability, and pharmacokinetics of multiple daily doses of BMS-820836 in healthy subjects. Central serotonin transporter (SERT) and dopamine transporter (DAT) occupancy were assessed using positron emission tomography and [11C]MADAM or [11C]PE2I, respectively.MethodsFifty-seven healthy volunteers were enrolled in this double-blind, placebo-controlled, ascending multiple-dose study (ClincalTrials.gov identifier: NCT00892840). Eight participants in seven dose cohorts received oral doses of BMS-820836 (0.1–4 mg) or placebo for 14 days to assess safety, tolerability, and pharmacokinetics. Additionally, SERT and DAT occupancies were evaluated in 4–8 subjects per cohort at 8 h post-dose on Day 10 and 24 h post-dose on Day 15 at anticipated steady-state conditions.ResultsMost adverse events were mild to moderate; there were no serious safety concerns. Median maximum concentrations of BMS-820836 were observed at 4.0–5.5 h post-dose; estimated elimination half-life was 44–74 h. About 80 % striatal SERT occupancy was achieved after multiple doses of 0.5 mg BMS-820836 at both 8 and 24 h post-dose. Striatal DAT occupancy ranged between 14 % and 35 % at 8 h post-dose with a slight decline at 24 h post-dose.ConclusionsMultiple daily doses of up to 4 mg BMS-820836 appeared to be generally safe and well tolerated in a healthy population. SERT and DAT occupancies were in a range associated with therapeutic efficacy of antidepressants. Together with the pharmacokinetic profile of BMS-820836, the occupancy data support once-daily administration.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Psykiatri (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Psychiatry (hsv//eng)
Keyword
- PET
- reuptake inhibitors
- Pharmacokinetics and Drug Therapy
- Farmakokinetik och läkemedelsterapi
Publication and Content Type
- ref (subject category)
- art (subject category)
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Zheng, Ming
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Appel, Lieuwe
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Luo, Feng
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Lane, Roger
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Risinger, Robert
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Antoni, Gunnar
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show more...
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Cahir, Matthews
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Sanjay, Keswani
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Hayes, Wendy
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Burt, David
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Zubin, Bhagwarag ...
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show less...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Pharmacology and ...
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Psychopharmacolo ...
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Uppsala University