Abstract | BACKGROUND: OBJECTIVE: This study aimed to further the preclinical development of rytvela by evaluating its optimal dose and minimal duration of treatment to inhibit the inflammatory cascade, prolong gestation, and promote neonatal outcomes. STUDY DESIGN: Pregnant CD-1 mice were administered with lipopolysaccharide (10 μg, intraperitoneal administration) or interleukin 1 (1 μg/kg, intrauterine administration) on gestational day 16 to induce preterm labor. Rytvela was administered at different doses (0.1, 0.5, 1.0, 2.0, 4.0 mg/kg/d subcutaneously) from gestational days 16 to 18.5. To evaluate the minimal duration of treatment, the mice were administered with rytvela (2 mg/kg/d subcutaneously) for 24, 36, or 48 hours. The rate of prematurity (gestational day <18.5) and neonate survival and weight were evaluated. Gestational tissues were collected at gestational day 17.5 to quantify cytokines, proinflammatory mediators, and uterine activating proteins by real-time quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. The neonatal lungs and intestines were collected from postnatal days 5 to 7 and analyzed by histology. RESULTS:
Rytvela exhibited a dose-response profile and achieved maximum efficacy at a dose of 2 mg/kg/d by reducing 70% of lipopolysaccharide-induced preterm births and 60% of interleukin 1β-induced preterm births. In addition, rytvela attained maximum efficacy at a dose of 1 mg/kg/d by increasing neonate survival by up to 65% in both models of preterm birth. Rytvela protected fetuses from inflammatory insult as of 24 hours, preserving lung and intestinal integrity, and prevented preterm birth and fetal mortality by 60% and 50%, respectively, as of 36 hours of treatment. CONCLUSION: The maximum efficacy of rytvela was achieved at 2 mg/kg/d with improved birth outcomes and prevented inflammatory up-regulation upon 36 hours (only) of treatment. Rytvela exhibited desirable properties for the safe prevention of preterm birth and fetal protection.
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Authors | Tiffany Habelrih, David-Étienne Tremblay, Erica Di Battista, Xin Hou, Allan Reuben, Béatrice Ferri, Sarah-Eve Loiselle, France Côté, Pénélope Abram, William D Lubell, Kelycia B Leimert, Christiane Quiniou, Sylvie Girard, David M Olson, Sylvain Chemtob |
Journal | American journal of obstetrics and gynecology
(Am J Obstet Gynecol)
Vol. 228
Issue 4
Pg. 467.e1-467.e16
(04 2023)
ISSN: 1097-6868 [Electronic] United States |
PMID | 36244408
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2022 Elsevier Inc. All rights reserved. |
Chemical References |
- 101.10 peptide
- Lipopolysaccharides
- Anti-Inflammatory Agents
- Interleukin-1
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Topics |
- Infant, Newborn
- Pregnancy
- Humans
- Female
- Animals
- Mice
- Premature Birth
(prevention & control)
- Lipopolysaccharides
(adverse effects)
- Fetus
- Inflammation
- Anti-Inflammatory Agents
- Interleukin-1
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