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Tesofensine, a nove...
Tesofensine, a novel triple monoamine re-uptake inhibitor with anti-obesity effects : Dopamine transporter occupancy as measured by PET
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- Appel, Lieuwe (författare)
- Uppsala universitet,Enheten för nuklearmedicin och PET
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- Bergström, Mats (författare)
- Uppsala universitet,Institutionen för farmaci
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Lassen, Jorgen Buus (författare)
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- Långström, Bengt (författare)
- Uppsala universitet,Fysikalisk-organisk kemi
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(creator_code:org_t)
- Elsevier BV, 2014
- 2014
- Engelska.
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Ingår i: European Neuropsychopharmacology. - : Elsevier BV. - 0924-977X .- 1873-7862. ; 24:2, s. 251-261
- Relaterad länk:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Tesofensine (TE) is a novel triple monoannine re-uptake inhibitor inducing a potent inhibition of the re-uptake process in the synaptic cleft of the neurotransmitters dopamine, norepinephrine, and serotonin. In recent preclinical and clinical evaluations TE showed a robust anti-obesity effect, but the specific mechanism of this triple monoamine re-uptake inhibitor still needs to be further elucidated. This positron emission tomography (PET) study, using [C-11]beta CIT-FE, aimed to assess the degree of the dopamine transporter (DAT) occupancy, at constant TE plasma levels, following different oral, multiple doses of TE during totally 8-12 days. In addition, the relationships between DAT occupancy and TE plasma concentrations, or doses, were investigated to enable assessment of DAT occupancies in subsequent clinical trials. The results demonstrated that TE induced a dose-dependent blockade of DAT following multiple doses of 0.125-1 mg TE at anticipated steady-state conditions. The mean striatal DAT occupancy varied dose-dependently between 18% and 77%. A signnoid E-max model well described the relationship between striatal DAT occupancy and TE plasma concentrations or doses. It was estimated that the maximum achievable DAT occupancy was about 80% and that half of this effect was accomplished by approximately 0.25 mg TE and a plasma drug concentration of 4 ng/ml. The results indicated an important mechanism of action of TE on DAT. Further, these results suggest that the previously reported dose-dependent weight loss, in TE treated subjects, was in part mediated by an up-regulation of dopaminergic pathways due to enhanced amounts of synaptic dopamine after blockade of DAT.
Nyckelord
- Positron emission tomography
- Dopamine re-uptake
- DAT
- Chronic treatment
- Neurochemistry
- Drug development
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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