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Tesofensine, a nove...
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Appel, LieuweUppsala universitet,Enheten för nuklearmedicin och PET
(författare)
Tesofensine, a novel triple monoamine re-uptake inhibitor with anti-obesity effects : Dopamine transporter occupancy as measured by PET
- Artikel/kapitelEngelska2014
Förlag, utgivningsår, omfång ...
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Elsevier BV,2014
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printrdacarrier
Nummerbeteckningar
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LIBRIS-ID:oai:DiVA.org:uu-221981
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-221981URI
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https://doi.org/10.1016/j.euroneuro.2013.10.007DOI
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Språk:engelska
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Sammanfattning på:engelska
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Ämneskategori:ref swepub-contenttype
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Ämneskategori:art swepub-publicationtype
Anmärkningar
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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.
Ämnesord och genrebeteckningar
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Positron emission tomography
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Dopamine re-uptake
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DAT
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Chronic treatment
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Neurochemistry
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Drug development
Biuppslag (personer, institutioner, konferenser, titlar ...)
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Bergström, MatsUppsala universitet,Institutionen för farmaci
(författare)
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Lassen, Jorgen Buus
(författare)
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Långström, BengtUppsala universitet,Fysikalisk-organisk kemi(Swepub:uu)benglang
(författare)
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Uppsala universitetEnheten för nuklearmedicin och PET
(creator_code:org_t)
Sammanhörande titlar
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Ingår i:European Neuropsychopharmacology: Elsevier BV24:2, s. 251-2610924-977X1873-7862
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