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A Phase 1B, Double-blind, Placebo-controlled, Parallel-group, Multi-dose Study of the Pharmacodynamics of NGM282 on Colonic Transit, Bile Acid Homeostasis and Fecal Fat in Subjects with Functional Constipation
Başlık:
A Phase 1B, Double-blind, Placebo-controlled, Parallel-group, Multi-dose Study of the Pharmacodynamics of NGM282 on Colonic Transit, Bile Acid Homeostasis and Fecal Fat in Subjects with Functional Constipation
Yazar:
Oduyebo, Ibironke, author.
ISBN:
9780438005280
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (63 pages)
Genel Not:
Source: Masters Abstracts International, Volume: 57-06M(E).
Advisors: Michael Camilleri Committee members: Felicity Enders; David Katzka; Laura Raffals.
Özet:
Objective: NGM282 is an analog of fibroblast growth factor 19 (FGF19), a potent inhibitor of bile acid (BA) synthesis in animals and humans. In phase 2 trials in type 2 diabetes and primary biliary cholangitis, NGM282 was associated with dose-related abdominal cramping and diarrhea. We aimed to examine effects of NGM282 on colonic transit, stool frequency and consistency, hepatic BA synthesis (fasting serum C4), fecal fat and BA in functional constipation (FC). Design: Two-dose NGM282 (1mg and 6mg, subcutaneously daily), parallel-group, randomized, placebo-controlled, 14-day study in patients with FC (Rome III criteria) and baseline colonic transit 24h geometric center (GC) <3.0. We explored treatment interaction with SNPs in genes KLB, FGFR4 and TGR5 (GPBAR1). Statistical analysis: Overall ANCOVA at alpha=0.025 (baseline as covariate where available), with 3 pairwise comparisons among the three groups (alpha=0.008). Results: Overall, NGM282 altered bowel function (number of bowel movements, looser stool form, and increased ease of passage) and significantly accelerated gastric and colonic transit. Dose-related effects were seen with GC24h, but not with gastric emptying (GE) and GC48h. There were no differences in fecal fat or weight, but there was reduced fecal total BA excretion with NGM282. The most common adverse events were increased appetite (n=0 with placebo, 2 with 1mg, 9 with 6mg), injection site reaction (n=2 placebo, 4 with 1mg, 8 with 6mg), and diarrhea (n=1 with 1 mg and 4with 6mg). There was treatment interaction with KLB SNP, with greater increase in colonic transit in participants with the minor A allele (p=0.056). Conclusion: NGM282 significantly impacts GE and colonic transit, consistent with the observed clinical symptoms. The specific mechanism of prokinetic activity requires further research.
Notlar:
School code: 1542
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(688584.1) | 688584-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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