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- Rahnev, D, et al.
(författare)
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The Confidence Database
- 2020
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Ingår i: Nature human behaviour. - : Springer Science and Business Media LLC. - 2397-3374. ; 4:3, s. 317-325
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Tidskriftsartikel (refereegranskat)
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| 2. |
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| 4. |
- Denison, H, et al.
(författare)
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Proof of mechanism for the DGAT1 inhibitor AZD7687 : results from a first-time-in-human single-dose study
- 2013
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Ingår i: Diabetes, obesity and metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 15:2, s. 136-143
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 5. |
- Pawlowski, Katharina, et al.
(författare)
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Truncated Hemoglobins in Actinorhizal Nodules of Datisca glomerata.
- 2007
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Ingår i: Plant Biol (Stuttg). - 1435-8603. ; 9:6, s. 776-785
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Three types of hemoglobins exist in higher plants, symbiotic, non-symbiotic, and truncated hemoglobins. Symbiotic (class II) hemoglobins play a role in oxygen supply to intracellular nitrogen-fixing symbionts in legume root nodules, and in one case (Parasponia sp.), a non-symbiotic (class I) hemoglobin has been recruited for this function. Here we report the induction of a host gene, Dgtrhb1, encoding a truncated hemoglobin in Frankia-induced nodules of the actinorhizal plant Datisca glomerata Induction takes place specifically in cells infected by the microsymbiont, prior to the onset of bacterial nitrogen fixation. A bacterial gene (Frankia trHbO) encoding a truncated hemoglobin with O (2)-binding kinetics suitable for the facilitation of O (2) diffusion ( ) is also expressed in symbiosis. Nodule oximetry confirms the presence of a molecule that binds oxygen reversibly in D. glomerata nodules, but indicates a low overall hemoglobin concentration suggesting a local function. Frankia TrHbO is likely to be responsible for this activity. The function of the D. glomerata truncated hemoglobin is unknown; a possible role in nitric oxide detoxification is suggested.
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| 7. |
- Berglund, K. M., et al.
(författare)
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Prevalence of pain and dysfunction in the cervical and thoracic spine in persons with and without lateral elbow pain
- 2008
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Ingår i: Manual Therapy. - : Elsevier BV. - 1356-689X .- 1532-2769. ; 13:4, s. 295-299
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this study was to Survey the prevalence of pain in the cervical and thoracic spine (C2-T7) in persons with and Without lateral elbow pain. Thirty-one subjects with lateral elbow pain and 31 healthy controls participated in the study. The assessment comprised a pain drawing, provocation tests of the cervical and thoracic spine, a neurodynamic test of the radial nerve, and active cervical range of motion. Seventy percent of the subjects with lateral elbow pain indicated pain in the cervical or thoracic spine, as compared to 16% in the control group (p< ;0.001). The frequency of pain responses to the provocation tests of the cervical and thoracic spine was significantly higher (p< ;0.05) in the lateral elbow pain (LEP) group, as was the frequency of pain responses to the neurodynamic test of the radial nerve (p< ;0.001). Cervical flexion and extension range of motion was significantly lower (p< ;0.01) in the LEP group. The results indicate a relation between lateral elbow pain and pain in the vertebral spine (C2-T7). The cervical and thoracic spine should be included in the assessment of patients with lateral elbow pain.
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| 10. |
- Denison, H, et al.
(författare)
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Diacylglycerol acyltransferase 1 inhibition with AZD7687 alters lipid handling and hormone secretion in the gut with intolerable side effects : a randomized clinical trial
- 2014
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Ingår i: Diabetes, obesity and metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 16:4, s. 334-343
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Tidskriftsartikel (refereegranskat)abstract
- AIM:Inhibition of diacylglycerol acyltransferase 1 (DGAT1) is a potential treatment modality for patients with type 2 diabetes mellitus and obesity, based on preclinical data suggesting it is associated with insulin sensitization and weight loss. This randomized, placebo-controlled, phase 1 study in 62 overweight men explored the effects and tolerability of AZD7687, a reversible and selective DGAT1 inhibitor.METHODS:Multiple doses of AZD7687 (1, 2.5, 5, 10 and 20 mg/day, n = 6 or n = 12 for each) or placebo (n = 20) were administered for 1 week. Postprandial serum triacylglycerol (TAG) was measured for 8 hours after a standardized 45% fat meal. Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) were measured and a paracetamol challenge was performed to assess gastric emptying.RESULTS:Dose-dependent reductions in postprandial serum TAG were demonstrated with AZD7687 doses ≥5 mg compared with placebo (p < 0.01). Significant (p < 0.001) increases in plasma GLP-1 and PYY levels were seen at these doses, but no clear effect on gastric emptying was demonstrated at end of treatment. With AZD7687doses >5 mg/day, gastrointestinal (GI) side effects increased; 11/18 of these participants discontinued treatment owing to diarrhoea.CONCLUSIONS:Altered lipid handling and hormone secretion in the gut were demonstrated during 1-week treatment with the DGAT1 inhibitor AZD7687. However, the apparent lack of therapeutic window owing to GI side effects of AZD7687, particularly diarrhoea, makes the utility of DGAT1 inhibition as a novel treatment for diabetes and obesity questionable.
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