Transition from Oxycodone to Buprenorphine/Naloxone in a Hospitalized Patient with Sickle Cell Disease: A Case Report

Buprenorphine is increasingly used to treat pain in patients with sickle cell disease but optimal timing and approach for transitioning patients from full agonist opioids to buprenorphine is unknown. We present the case of a 22-year-old woman with sickle cell disease and acute on chronic pain who transitioned from high-dose oxycodone to buprenorphine/naloxone during a hospital stay for vaso-occlusive episode. Utilizing a microdosing approach to minimize pain and withdrawal, buprenorphine/naloxone was gradually uptitrated while she received full agonist opioids. During the transition, she experienced some withdrawal in the setting of swallowed buprenorphine/naloxone tablets, which were intended to be dosed sublingually. Nevertheless, the transition was tolerable to the patient and her pain and function significantly improved with buprenorphine treatment. This case also highlights the challenges and unique considerations that arise when providing care for the hospitalized patient who is also incarcerated.

Predicting the Effects of Per- and Polyfluoroalkyl Substance Mixtures on Peroxisome Proliferator-Activated Receptor Alpha Activity in Vitro

Human exposure to per- and polyfluoroalkyl substances (PFAS) is ubiquitous, with mixtures of PFAS detected in drinking water, food, household dust, and other exposure sources. Animal toxicity studies and human epidemiology indicate that PFAS may act through shared mechanisms including activation of peroxisome proliferator activated receptor α (PPARα). However, the effect of PFAS mixtures on human relevant molecular initiating events remains an important data gap in the PFAS literature. Here, we tested the ability of modeling approaches to predict the effect of diverse PPARα ligands on receptor activity using Cos7 cells transiently transfected with a full length human PPARα (hPPARα) expression construct and a peroxisome proliferator response element-driven luciferase reporter. Cells were treated for 24 hours with two full hPPARα agonists (pemafibrate and GW7647), a full and a partial hPPARα agonist (pemafibrate and mono(2-ethylhexyl) phthalate), or a full hPPARα agonist and a competitive antagonist (pemafibrate and GW6471). Receptor activity was modeled with three additive approaches: effect summation, relative potency factors (RPF), and generalized concentration addition (GCA). While RPF and GCA accurately predicted activity for mixtures of full hPPARα agonists, only GCA predicted activity for full and partial hPPARα agonists and a full agonist and antagonist. We then generated concentration response curves for seven PFAS, which were well-fit with three-parameter Hill functions. The four perfluorinated carboxylic acids (PFCA) tended to act as full hPPARα agonists while the three perfluorinated sulfonic acids (PFSA) tended to act as partial agonists that varied in efficacy between 28-67% of the full agonist, positive control level. GCA and RPF performed equally well at predicting the effects of mixtures with three PFCAs, but only GCA predicted experimental activity with mixtures of PFSAs and a mixture of PFCAs and PFSAs at ratios found in the general population. We conclude that of the three approaches, GCA most accurately models the effect of PFAS mixtures on hPPARα activity in vitro.HighlightsPerfluorinated carboxylic acids are full human PPARα agonistsPerfluorinated sulfonic acids are partial human PPARα agonistsGCA predicts human PPARα activity for mixtures of full and partial agonistsGCA predicts human PPARα activity for mixtures of agonists and competitive antagonistsGCA accurately predicts human PPARα activity in response to PFAS mixtures

SCO-267, a GPR40 Full Agonist, Stimulates Islet and Gut Hormone Secretion and Improves Glycemic Control in Humans

SCO-267 is a full agonist of the free fatty acid receptor 1 (GPR40), which regulates the secretion of islet and gut hormones. In this phase 1 study, we aimed to evaluate the clinical profile of single and multiple once-daily oral administration of SCO-267 in healthy adults and patients with diabetes. Plasma SCO-267 concentration was seen to increase in a dose-dependent manner after administration, and its plasma exposure was maintained for 24 h. Repeated dose did not alter the pharmacokinetic profile of SCO-267 in healthy adults. SCO-267 was generally safe and well tolerated at all evaluated single and multiple doses. Single and repeated doses of SCO-267 stimulated the secretion of insulin, glucagon, glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide, and peptide YY in healthy adults. Furthermore, a single dose of SCO-267 stimulated the secretion of these hormones, decreased fasting hyperglycemia, and improved glycemic control during an oral glucose tolerance test in patients with diabetes, without inducing hypoglycemia. This study is the first to demonstrate the clinical effects of a GPR40 full agonist. SCO-267 is safe and well tolerated and exhibits once-daily oral dosing potential. Its robust therapeutic effects on hormonal secretion and glycemic control make SCO-267 an attractive drug candidate for the treatment of diabetes.

SCO-267, a GPR40 Full Agonist, Stimulates Islet and Gut Hormone Secretion and Improves Glycemic Control in Humans

SCO-267 is a full agonist of the free fatty acid receptor 1 (GPR40), which regulates the secretion of islet and gut hormones. In this phase 1 study, we aimed to evaluate the clinical profile of single and multiple once-daily oral administration of SCO-267 in healthy adults and patients with diabetes. Plasma SCO-267 concentration was seen to increase in a dose-dependent manner after administration, and its plasma exposure was maintained for 24 h. Repeated dose did not alter the pharmacokinetic profile of SCO-267 in healthy adults. SCO-267 was generally safe and well tolerated at all evaluated single and multiple doses. Single and repeated doses of SCO-267 stimulated the secretion of insulin, glucagon, glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide, and peptide YY in healthy adults. Furthermore, a single dose of SCO-267 stimulated the secretion of these hormones, decreased fasting hyperglycemia, and improved glycemic control during an oral glucose tolerance test in patients with diabetes, without inducing hypoglycemia. This study is the first to demonstrate the clinical effects of a GPR40 full agonist. SCO-267 is safe and well tolerated and exhibits once-daily oral dosing potential. Its robust therapeutic effects on hormonal secretion and glycemic control make SCO-267 an attractive drug candidate for the treatment of diabetes.