This complex syndrome interferes with growth and development of the neonate and often requires care in costly neonatal intensive care units for the first days, and even weeks, of life ( Strahan et al., 2020). NOWS is defined by multisystem dysregulation, resulting in poor feeding, vomiting, diarrhea, sweating, lacrimation, tremors, seizures, hyperalgesia, poor sleep, extreme irritability, and sensitivity to lights and sounds ( Jansson et al., 2009). Neonatal opioid withdrawal syndrome ( NOWS) is a major adverse consequence of prenatal opioid exposure. The maximum concentration and the area under the curve of NorBUP in the blood of rats that received BUP-D2 were over 19- and 10-fold lower, respectively, than in rats that received BUP.ĭiscussion: These results indicate that BUP-D2 retains key pharmacodynamic properties of BUP and resists metabolism to NorBUP and therefore holds promise as an alternative to BUP.Ĭhronic use of opioids during pregnancy negatively affects mothers and their children, and prenatal opioid use has increased more than five-fold in the United States since the beginning of the opioid addiction and overdose crisis ( Haight et al., 2018 Hirai et al., 2021). BUP-D2 also activated opioid receptors and induced antinociception with equal potency and efficacy as BUP. Like BUP, BUP-D2 had sub-nanomolar affinity for opioid receptors. Results: The synthesis provided a 48% yield and the product was ≥99% deuterated. Blood concentration versus time profiles of BUP, BUP-D2, and NorBUP were measured in rats following intravenous BUP-D2 or BUP injection. The antinociceptive effects of BUP-D2 and BUP were compared using the warm-water tail withdrawal assay in rats. Methods: We determined opioid receptor affinities of BUP-D2 relative to BUP with radioligand competition receptor binding assays, and the potency and efficacy of BUP-D2 relative to BUP to activate G-proteins via opioid receptors with GTPγS binding assays in homogenates containing the human mu, delta, or kappa opioid receptors. Here, we report the synthesis and testing of deuterated buprenorphine ( BUP-D2). Precision deuteration alters pharmacokinetics of drugs without altering pharmacodynamics. Therefore, reducing or eliminating metabolism of BUP to NorBUP is a novel strategy that will likely lower total fetal exposure to opioids and thus improve offspring outcomes. Introduction: An active metabolite of buprenorphine ( BUP), called norbuprenorphine ( NorBUP), is implicated in neonatal opioid withdrawal syndrome when BUP is taken during pregnancy.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |