Proof of mechanism for the DGAT1 inhibitor AZD7687: results from a first-time-in-human single-dose study

↓ Direkt till sidans innehåll
↓ Direkt till sidans sekundära innehåll (sidomenyn)

Sökning: onr:"swepub:oai:DiVA.org:uu-220694" > Proof of mechanism ...

1 av 1
Föregående post
Nästa post
Till träfflistan

LIBRIS Formathandbok (Information om MARC21)

Fältnamn	Indikatorer	Metadata
000		03163naa a2200337 4500
001		oai:DiVA.org:uu-220694
003		SwePub
008		140319s2013 \| \|\|\|\|\|\|\|\|\|\|\|000 \|\|eng\|
024	7	a https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-2206942 URI
024	7	a https://doi.org/10.1111/dom.120022 DOI
040		a (SwePub)uu
041		a engb eng
042		9 SwePub
072	7	a ref2 swepub-contenttype
072	7	a art2 swepub-publicationtype
100	1	a Denison, H4 aut
245	1 0	a Proof of mechanism for the DGAT1 inhibitor AZD7687 :b results from a first-time-in-human single-dose study
264		c 2012-09-30
264	1	b Wiley,c 2013
338		a print2 rdacarrier
520		a AIMS: Inhibition of diacylglycerol acyltransferase 1 (DGAT1), which catalyses the final step in triacylglycerol (TAG) assembly, is suggested as a treatment for type 2 diabetes and obesity based on animal data indicating insulin sensitization and weight reduction. This first-time-in-human single ascending dose study explored the safety, tolerability, pharmacokinetics and pharmacodynamics of the selective DGAT1 inhibitor AZD7687.METHODS: Eighty healthy male subjects were enrolled. In each of 10 cohorts, six subjects received the same dose of AZD7687 orally (range across cohorts 1-60 mg) and two placebo. Plasma AZD7687 exposure was measured repeatedly. Postprandial serum TAG excursion was measured during 8 h after a standardized mixed meal with fat energy content of 60% (SMM 60%; five cohorts, 1-20 mg), before (baseline) and after dosing, to assess effects on gut DGAT1 activity.RESULTS: AZD7687 markedly reduced postprandial TAG excursion with a steep concentration-effect relationship. Incremental TAG AUC (area under the serum concentration vs. time curve) following SMM 60% was decreased >75% from baseline at doses ≥5 mg (p < 0.0001 vs. placebo). Serum levels of diacylglycerol, specifically measured with mass spectrometry, did not increase after AZD7687 administration. Nausea, vomiting and diarrhoea were reported with increasing doses and they limited dose escalation. Lowering of SMM fat content to 45 or 30% in five cohorts gradually reduced the frequency of gastrointestinal symptoms at a given dose of AZD7687.CONCLUSIONS: The attenuating effect of AZD7687 on postprandial TAG excursion provides proof of mechanism with respect to gut DGAT1 inhibition. However, dose and diet-related gastrointestinal side effects may impact further development of DGAT1 inhibitors.
700	1	a Nilsson, C4 aut
700	1	a Kujacic, M4 aut
700	1	a Löfgren, L4 aut
700	1	a Karlsson, C4 aut
700	1	a Knutsson, M4 aut
700	1	a Eriksson, Jan Wu Uppsala universitet,Klinisk diabetologi och metabolism,Department of Molecular and Clinical Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden4 aut0 (Swepub:uu)janer909
710	2	a Uppsala universitetb Klinisk diabetologi och metabolism4 org
773	0	t Diabetes, obesity and metabolismd : Wileyg 15:2, s. 136-143q 15:2<136-143x 1462-8902x 1463-1326
856	4 8	u https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-220694
856	4 8	u https://doi.org/10.1111/dom.12002

Hitta via bibliotek

Diabetes, obesity and metabolism (Sök värdpublikationen i LIBRIS)

Till lärosätets databas

1 av 1
Föregående post
Nästa post
Till träfflistan

Hitta mer i SwePub

Av författaren/redakt...: Denison, H; Nilsson, C; Kujacic, M; Löfgren, L; Karlsson, C; Knutsson, M; visa fler...; Eriksson, Jan W; visa färre...

Artiklar i publikationen: Diabetes, obesit ...

Av lärosätet: Uppsala universitet

Sök utanför SwePub

Sök vidare i:: Google; Google Book Search; Google Scholar

Kungliga biblioteket hanterar dina personuppgifter i enlighet med EU:s dataskyddsförordning (2018), GDPR. Läs mer om hur det funkar här.
Så här hanterar KB dina uppgifter vid användning av denna tjänst.

LIBRIS.kb.se