| 1. |
- Leohr, Jennifer, et al.
(författare)
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A Semi-physiological Model of Postprandial Triglyceride Response in Lean, Obese and Very obese Subjects Following a high-fat meal
- 2018
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Ingår i: Diabetes, obesity and metabolism. - : John Wiley & Sons. - 1462-8902 .- 1463-1326. ; 20:3, s. 660-666
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: To quantify the postprandial triglyceride (TG) response of chylomicrons and very-low-density lipoprotein-V6 (VLDL-V6) after a high-fat meal in lean, obese and very obese healthy individuals, using a mechanistic population lipokinetic modelling approach.METHODS:. Healthy subjects from three BMI population categories: lean (18.5-24.9), obese (30-33), and very obese (34-40) were enrolled in a clinical study to assess the triglyceride response after a high-fat meal, containing 60% fat. Nonlinear mixed-effect modeling was used to analyze the triglyceride concentrations of chylomicrons and large VLDL-V6 particlesRESULTS: The triglycerides in chylomicrons and VLDL-V6 particles had a prominent postprandial peak and represented the majority of the postprandial response; only the VLDL-V6 showed a difference across the populations. A turn-over model successfully described the TG concentration-time profiles of both chylomicrons and large VLDL-V6 particles after the high-fat meal. This model consisted of four compartments: two transit compartments for the lag between meal consumption and appearance of TGs in the blood, and one compartment each for the chylomicrons and large VLDL-V6 particles. The rate constants for the production of chylomicrons and elimination of large VLDL-V6 particles, along with the conversion rate of chylomicrons to large VLDL-V6 particles were well defined.CONCLUSIONS: This is the first lipokinetic model to describe the absorption of triglycerides from dietary fats into the blood stream and compares the dynamics of triglycerides in chylomicrons and large VLDL-V6 particles among lean, obese and very obese people. Such a model can be used to identify where pharmacological therapies act, thereby improving the determination of efficacy, and identifying complementary mechanisms for combinational drug therapies.
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| 2. |
- Leohr, Jennifer, et al.
(författare)
-
Postprandial triglyceride reduction following acute treatment of a selective 5-hydroxytryptamine-2c agonist and characterization using a semi-physiological model
- 2021
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Ingår i: Diabetes, obesity and metabolism. - : John Wiley & Sons. - 1462-8902 .- 1463-1326. ; 23:4, s. 1001-1010
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: To investigate the tolerability, pharmacokinetics (PK), and postprandial triglyceride (TG) response of single, escalating oral doses of a selective 5-hydroxytryptamine-2c (5-HT2c) agonist in subjects with overweight/obesity and apply mechanistic population pharmacokinetic-pharmacodynamic modeling to identify a plausible drug mechanism of action.METHODS: This phase 1, single-center, double‑blind, randomized, placebo-controlled, 4 period, 2-alternating cohort, evaluated single escalating oral doses ranging 5-130 mg of LY2140112 (LY) in subjects with overweight/obesity (BMI: 27-39 kg/m2). Postprandial TG response (total TG, chylomicrons, and VLDL-V6) following a high fat meal were assessed for 11-hours post-meal for each dose level. The PK profile was assessed for 96 hours post-dose. Drug exposure and TG concentrations in chylomicrons and VLDL-V6 were used to characterize the drug mechanism of action using nonlinear mixed-effect modeling.RESULT: Seventeen subjects entered the study and 16 subjects received at least one dose of LY. LY2140112 was generally well tolerated up to 75mg. The PK of LY were described by a two-compartment model with first-order elimination. The 100 mg and 130 mg dose levels of LY significantly reduced the postprandial TG of VLDL-V6 by ~50%, while total TG and chylomicrons were not significantly different from placebo. The application of a published lipokinetic model successfully described the postprandial TG response in this study and indicated that LY reduced the conversion of TGs from chylomicron to VLDL-V6.CONCLUSIONS: LY significantly reduced in the postprandial TG of VLDL-V6 following a single dose, when food consumption was controlled. The data indicates that a selective 5-HT2c agonist alters lipid metabolism, beyond the reported reduction in satiety. The application of a lipokinetic model enabled identification of a plausible drug mechanism of action of LY.
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| 3. |
- Meresse, Y, et al.
(författare)
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X-ray diffraction studies of AuCu3-type neptunium compounds under pressure
- 2000
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Ingår i: JOURNAL OF ALLOYS AND COMPOUNDS. - : ELSEVIER SCIENCE SA. - 0925-8388. ; 296:1-2, s. 27-32
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Tidskriftsartikel (refereegranskat)abstract
- NpX3 (AuCu3-type structure) compounds with X=Al, Ga, Ge, In and Sn were studied up to 50 GPa using the energy dispersive X-ray diffraction (EDXRD) technique. No structural phase transitions were observed for any of the compounds studied up to the highest
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