Long-acting Agonist Research Articles

Backbone Modification Provides a Long-Acting Inverse Agonist of Pathogenic, Constitutively Active PTH1R Variants.

Parathyroid hormone 1 receptor (PTH1R) plays a key role in mediating calcium homeostasis and bone development, and aberrant PTH1R activity underlies several human diseases. Peptidic PTH1R antagonists and inverse agonists have therapeutic potential in treating these diseases, but their poor pharmacokinetics and pharmacodynamics undermine their in vivo efficacy. Herein, we report the use of a backbone-modification strategy to design a peptidic PTH1R inhibitor that displays prolonged activity as an antagonist of wild-type PTH1R and an inverse agonist of the constitutively active PTH1R-H223R mutant both in vitro and in vivo. This peptide may be of interest for the future development of therapeutic agents that ameliorate PTH1R malfunction.

Carbetosine, a Long-acting Oxytocin Agonist, as a Uterotonic in the Prevention of the Occurrence of Postpartum Bleeding

Objective: To evaluate the comparative effect of carbetocin vs. other uterotonic agents in the prevention of the occurrence of postpartum bleeding.
 Methods: Medical search engines like Pubmed, Google Scholar, and Cochrane are used for literature searches. The year period covered by the literature is 2013–2023. “Carbetocin” or “long-acting oxytocin” and “uterotonic” are the essential words, together with “post-partum hemorrhage” or “post-partum bleeding.” Data analysis was performed using the RevMan 5.4 application.
 Results: This study involved 12 clinical trials with a total sample of 32,312 people. Based on forest plot analysis, it was found that patients receiving carbetocin therapy had a risk of developing postpartum bleeding of 0.42 times compared to those receiving other uterotonic agents (misoprostol and oxytocin) (OR: 0.42; 95% CI: 0.26-0.68; p<0.0004; with heterogeneity p<0.00001, I2 85%)
 Conclusion: With its effectiveness and efficacy, carbetocin can be considered one modality that can prevent postpartum hemorrhage. In addition, it can benefit women at risk of having a major obstetric hemorrhage.
 Keywords: carbetocin, uterotonic, meta-analysis, clinical trial

Cost-utility of tiotropium in patients with severe asthma

SummaryAdd-on therapy with tiotropium was cost-effective when added to usual care in patients who remain uncontrolled despite treatment with medium or high-dose ICS/LABA in a middle-income country.BackgroundA significant proportion of asthma patients remain uncontrolled despite inhaled corticosteroids and long-acting beta-agonists. Some add-on therapies, such as tiotropium bromide, have been recommended for this subgroup of patients. This study aimed to assess the cost-effectiveness of tiotropium as an add-on therapy to inhaled corticosteroids and long-acting b2 agonists for patients with severe asthma.MethodsA probabilistic Markov model was created to estimate the cost and quality-adjusted life-years (QALYs) of patients with severe asthma in Colombia. Total costs and QALYs of two interventions include standard therapy with inhaled corticosteroids and long-acting bronchodilators versus add-on therapy with tiotropium. Multiple sensitivity analyses were conducted. Cost-effectiveness was evaluated at a willingness-to-pay value of $5180.ResultsThe expected incremental cost per QALY (ICER) is estimated at US$–2637.59. There is a probability of 0.77 that tiotropium + ICS + LABA is more cost-effective than ICS + LABA at a threshold of US$5180 per QALY. The strategy with the highest expected net benefit is Tiotropium, with an expected net benefit of US$800. Our base-case results were robust to parameter variations in the deterministic sensitivity analyses.ConclusionAdd-on therapy with tiotropium was cost-effective when added to usual care in patients who remain uncontrolled despite treatment with medium or high-dose inhaled corticosteroids and long-acting bronchodilators. Our study provides evidence that should be used by decision-makers to improve clinical practice guidelines and should be replicated to validate their results in other middle-income countries.

Physiology and pharmacology of glucagon-like peptide-1 receptor

Modern approaches to the treatment of type 2 diabetes mellitus (T2DM) are aimed not only at glycemic control, but also at reducing cardiovascular risks. The increasing prevalence of the disease and the need for effective treatment options highlight the importance of glucagon-like peptide-1 (GLP-1) receptor agonists in the pharmacotherapy structure.The aim of the work was to review the literature regarding the physiology of GLP-1 and the therapeutic potential and development trends of its agonists.Materials and methods. The search for the review materials was carried out using the abstract databases of PubMed, Google Scholar and e-Library. The search was carried out for publications from 2000 to 2023, using the following keywords: “GLP-1”; “GLP-1R agonists”; “GIP”; “exenatide”; “liraglutide”; “dulaglutide”; “semaglutide”; “lixisenatide”; “albiglutide”; “taspoglutide” taking into account various spellings.Results. The interaction of almost all food components with enteroendocrine cells of the intestine leads to the secretion of incretins (primarily GLP-1) into the blood, triggering a complex of physiological reactions aimed primarily at the rapid utilization of incoming glucose (regulation of insulin and glucagon secretion), as well as the central regulation of dietary behavior (slowing gastric emptying and the formation of a feeling of satiety). A wide distribution of the GLP-1 receptor in various tissues and organs, its connection with intracellular signaling cascades aimed at launching energy-consuming remodeling (recovery) processes in endothelial cells, heart, neurons, beta cells, etc., is the basis for a wide range of pleiotropic effects of GLP-1 unrelated to its hypoglycemic effect. The discovery of synthetic GLP-1 receptor agonists with a long period of action has made it possible not only to therapeutically influence various parts of carbohydrate metabolism disorders, but also to increase the functional reserves of the target diabetes organs, reducing the risk of developing complications of the disease. Incretin-like drugs are well tolerated, with nausea being the most common side effect. The factors limiting a wider use of the drugs include their high cost and the preferred form of a subcutaneous solution. The current research is focused on the development of long-acting, oral, dual and triple agonists, fixed-dose combinations, and small molecule drugs.Conclusion. GLP-1 receptor agonists are a class of effective and safe drugs for the treatment of diabetes and obesity, which is rapidly developing in the most advanced areas of pharmacy. A further development of this group and the solution of the identified problems will open up new opportunities for the treatment of diabetes and its complications.

Opioid, methamphetamine, and polysubstance use: perinatal outcomes for the mother and infant.

The escalation in opioid pain relief (OPR) medications, heroin and fentanyl, has led to an increased use during pregnancy and a public health crisis. Methamphetamine use in women of childbearing age has now eclipsed the use of cocaine and other stimulants globally. Recent reports have shown increases in methamphetamine are selective to opioid use, particularly in rural regions in the US. This report compares the extent of our knowledge of the perinatal outcomes of OPRs, heroin, fentanyl, two long-acting substances used in the treatment of opioid use disorders (buprenorphine and methadone), and methamphetamine. The methodological limitations of the current research are examined, and two important initiatives that will address these limitations are reviewed. Current knowledge of the perinatal effects of short-acting opioids, OPRs, heroin, and fentanyl, is scarce. Most of what we know about the perinatal effects of opioids comes from research on the long-acting opioid agonist drugs used in the treatment of OUDs, methadone and buprenorphine. Both have better perinatal outcomes for the mother and newborn than heroin, but the uptake of these opioid substitution programs is poor (<50%). Current research on perinatal outcomes of methamphetamine is limited to retrospective epidemiological studies, chart reviews, one study from a treatment center in Hawaii, and the US and NZ cross-cultural infant Development, Environment And Lifestyle IDEAL studies. Characteristics of pregnant individuals in both opioid and MA studies were associated with poor maternal health, higher rates of mental illness, trauma, and poverty. Infant outcomes that differed between opioid and MA exposure included variations in neurobehavior at birth which could complicate the diagnosis and treatment of neonatal opioid withdrawal (NOWs). Given the complexity of OUDs in pregnant individuals and the increasing co-use of these opioids with MA, large studies are needed. These studies need to address the many confounders to perinatal outcomes and employ neurodevelopmental markers at birth that can help predict long-term neurodevelopmental outcomes. Two US initiatives that can provide critical research and treatment answers to this public health crisis are the US Environmental influences on Child Health Outcomes (ECHO) program and the Medication for Opioid Use Disorder During Pregnancy Network (MAT-LINK).

Cost-effectiveness of triple therapy with budesonide/glycopyrronium/formoterol fumarate dihydrate compared with dual therapy for the treatment of chronic obstructive pulmonary disease (COPD) in Canada

RATIONALE: Chronic obstructive pulmonary disease (COPD) is associated with significant economic and societal burden in Canada. For patients whose symptoms remain uncontrolled with dual therapies including long-acting muscarinic antagonists (LAMA)/long-acting beta2-adrenergic agonists (LABA) or inhaled corticosteroids (ICS)/LABA, step-up to triple-therapy with ICS/LAMA/LABA is recommended. Budesonide/glycopyrronium/formoterol fumarate dihydrate (BGF) is an ICS/LAMA/LABA therapy with demonstrated efficacy compared to dual therapies in pivotal phase 3 trials (ETHOS and KRONOS). OBJECTIVES The objectives of this study were to conduct a cost-utility analysis to compare BGF with dual therapies (ICS/LABA and LAMA/LABA) for patients with COPD requiring escalation to triple therapy. METHODS A Markov cohort-based cost-utility analysis was conducted over a 30-year time horizon from a public payer perspective, to compare costs and outcomes in patients with COPD requiring escalation from dual therapy to triple therapy. The analysis was based on data from the ETHOS trial, Canadian administrative data, and published sources. Health states were characterized by forced expiratory volume (FEV1) severity and exacerbations (none, moderate, severe). RESULTS Over a 30-year time horizon in probabilistic analysis across several scenario analyses, BGF was associated with modest but consistent benefits to overall costs ($40,406 total for BGF, $40,685 for LAMA/LABAs and $43,261 for ICS/LABAs), as well as life years and quality-adjusted life year (QALYs) gained compared to dual therapies (8.7 total QALYs for BGF triple therapy, 8.5 for LAMA/LABAs and 8.4 for ICS/LABAs). CONCLUSIONS From a Canadian public healthcare perspective, BGF is associated with both cost-savings and improved health benefits compared with dual therapies for maintenance treatment of COPD patients at risk of exacerbations. These results may help to inform optimal decision-making.

Clinical case of delivery of a pregnant woman with large uterine leiomyoma and rehabilitation in the postoperative period

Abstract. Uterine leiomyoma is a benign neoplasm of the smooth muscles of the uterus, which is one of the causes of infertility and miscarriage in women in the modern world. Delivery of pregnant women with large uterine leiomyoma is a current problem, since there is no single and clear opinion regarding the tactics of managing such patients. In the past, most specialists were inclined to perform hysterectomy after cesarean section, as they considered it the safest method of therapy, since myomectomy during cesarean section raised many questions related to complications during surgery and in the postoperative period. This article examines the modern view of specialists and the experience of the authors on organ-preserving tactics for the treatment of large uterine leiomyomas in women during pregnancy and delivery and analyzes rehabilitation in the postpartum period. The aim of the study. The aim of the study was to analyze scientific literature data on the advisability of performing myomectomy during cesarean section and combining the experience of other specialists with our own experience of delivery of pregnant woman with large uterine leiomyoma using a complex of intraoperative preventive measures. Materials and methods. A clinical case of delivery of a pregnant woman with large uterine leiomyoma and rehabilitation in the postoperative period is described. A systematic online study of articles on the topic of myomectomy during cesarean section was conducted. Results and discussion. Data from a significant number of works by other specialists indicate that preliminary substantiation of factors that may complicate surgical intervention (uterine contractility, anatomical localization, number and diameter of fibroids, as well as the presence of large vascular structures), the use of a set of preventive intraoperative measures and modern suture materials can reduce the amount of blood loss and prevent unfavorable postoperative results. Our proposed algorithm of action, including the administration of tranexamic acid before opening the anterior abdominal wall, a long-acting oxytocin agonist and the hemostatic sponge «Surgicel», allows us to minimize the amount of intraoperative bleeding and the risks of uncontrolled bleeding. It should also be noted that the addition of a cesarean section with myomectomy does not affect the course of rehabilitation in the postoperative period. Conclusions. Based on a study of literary sources over the past 10 years and our own research, we can conclude that myomectomy during cesarean section is advisable in the absence of contraindications. A combination of postoperative rehabilitation measures, tactics and techniques of surgical intervention, and prevention of intraoperative blood loss make it possible to ensure high-quality recovery for patients.

Glucose-dependent insulinotropic polypeptide regulates body weight and food intake via GABAergic neurons in mice

The development of single-molecule co-agonists for the glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) is considered a breakthrough in the treatment of obesity and type 2 diabetes. But although GIPR–GLP-1R co-agonism decreases body weight with superior efficacy relative to GLP-1R agonism alone in preclinical1–3 and clinical studies4,5, the role of GIP in regulating energy metabolism remains enigmatic. Increasing evidence suggests that long-acting GIPR agonists act in the brain to decrease body weight through the inhibition of food intake3,6–8; however, the mechanisms and neuronal populations through which GIP affects metabolism remain to be identified. Here, we report that long-acting GIPR agonists and GIPR–GLP-1R co-agonists decrease body weight and food intake via inhibitory GABAergic neurons. We show that acyl-GIP decreases body weight and food intake in male diet-induced obese wild-type mice, but not in mice with deletion of Gipr in Vgat(also known as Slc32a1)-expressing GABAergic neurons (Vgat-Gipr knockout). Whereas the GIPR–GLP-1R co-agonist MAR709 leads, in male diet-induced obese wild-type mice, to greater weight loss and further inhibition of food intake relative to a pharmacokinetically matched acyl-GLP-1 control, this superiority over GLP-1 vanishes in Vgat-Gipr knockout mice. Our data demonstrate that long-acting GIPR agonists crucially depend on GIPR signaling in inhibitory GABAergic neurons to decrease body weight and food intake.

Abstract 16840: A Novel Long-Acting CRF2 Receptor Agonist COR-1167 Improves Cardiac and Renal Function on Top of Furosemide in a Sheep Model of Pacing Induced Heart Failure

Urocortin-2 (UCN-2), a member of the corticotrophin releasing factor family, has cardiovascular protective effects mediated via activation of CRF2 receptors. Exploratory studies in ovine heart failure (HF) and in HF patients demonstrated that acute intravenous (IV) infusion of UCN-2 (1-4hrs), on top of standard of care, temporarily improved cardiac function. However, the short t 1/2 of recombinant UCN-2 (~15 min) limits its therapeutic utility. A stable CRF2 peptide agonist was developed, named COR-1167, that is potent and selective for CRF2 versus CRF1 receptors and it was tested chronically in vivo. Adult female sheep were anesthetized, and instrumented with 7F His bundle electrodes, arterial, venous and Swan-Ganz catheters, pressure transducers, and flow probes. After recovery, HF was induced by rapid cardiac pacing that was maintained during the study. COR-1167 (5 μg/kg/day SC) in combination with furosemide (0.35 mg/kg/day IV) versus furosemide alone was administered for 5 days and cardiorenal parameters were constantly monitored in conscious sheep. Furosemide had no effect on cardiac function while it increased urine Na + , when compared to pre-treatment measurements. Compared to furosemide, COR-1167 plus furosemide significantly enhanced cardiac and renal function parameters (Table). Mean + SEM for Days 1-5 (CV, biomarker and renal parameters), F (n=5-7), F + COR-1167 (n=6-7), Repeated Measures ANOVA; *BW Day 0 minus Day 5 = BW change, Unpaired t test. COR-1167 cardiorenal benefits occurred within 2 hours of the first dose and were sustained, without changing SBP. It increased natriuresis and decreased net fluid balance (water intake minus urine volume) and BW (reflecting a reduction in congestion). In conclusion, chronic CRF2 receptor activation by COR-1167 significantly improved both cardiac and renal function on top of furosemide in ovine HF and potentially is a unique therapy for HF patients.

GIPR Agonism Enhances TZD-Induced Insulin Sensitivity in Obese IR Mice.

Recent studies have found that GIPR agonism can enhance the metabolic efficacy of GLP-1R agonist treatment by promoting both weight-dependent and -independent improvements on systemic insulin sensitivity. These findings have prompted new investigations aimed at better understanding the broad metabolic benefit of GIPR activation. Herein, we determined whether GIPR agonism favorably influenced the pharmacologic efficacy of the insulin sensitizing thiazolidinedione, rosiglitazone in obese insulin resistant (IR) mice. Genetic and pharmacological approaches were employed to examine the role of GIPR signaling on rosiglitazone-induced weight gain, hyperphagia, and glycemic control. RNA-sequencing was conducted to uncover potential mechanisms by which GIPR activation influences energy balance and insulin sensitivity. In line with previous findings, treatment with rosiglitazone induced the mRNA expression of the GIPR in white and brown fat. However, obese GIPR null mice dosed with rosiglitazone displayed equivalent weight gain to that of wild-type (WT) animals. Strikingly, chronic treatment of obese IR WT animals with a long-acting GIPR agonist (LAGIPRA) prevented rosiglitazone-induced weight-gain and hyperphagia, and it enhanced the insulin-sensitivity effect of this thiazolidinedione. The systemic insulin sensitization was accompanied by increased glucose disposal in brown adipose tissue (BAT), which was underlined by the recruitment of metabolic and thermogenic genes. These findings suggest that GIPR agonism can counter the negative consequences of rosiglitazone treatment on body weight and adiposity, while at the same time improving its insulin sensitizing efficacy.

Effect of long-acting versus short-acting glucagon-like peptide-1 receptor agonists on improving body weight and related metabolic parameters in type 2 diabetes: A head-to-head meta-analysis.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) showed great value in treating nonalcoholic fatty liver disease (NAFLD). We aimed to compare the effectiveness of long-acting and short-acting GLP-1RAs on improving body weight and related metabolic parameters in patients with type 2 diabetes (T2DM) as a reference for the treatment of NAFLD with T2DM. We searched eligible randomized controlled trials (RCTs) in PubMed, Embase, Cochrane and web of science database until August 2023. The risk of bias of included RCTs were assessed by the Risk Assessment of Cochrane Review items. We mainly drew forest plots to compare the effects of long and short acting GLP-1 RAs using RevMan 5.4. Twelve RCTs involving 2751 patients were included in our meta-analysis. Compared with short-acting GLP-1 RAs, the long-acting group was better in body weight (P < .00001, MD = -0.65, 95% confidence interval [CI] [-0.90, -0.40], I2 = 20%), and the same results in glycosylated hemoglobin (HbA1c) (P < .00001, MD = -0.43, 95% CI [-0.54, -0.33], I2 = 55%) and fasting plasma glucose (FPG) (P < .00001, MD = -0.77, 95% CI [-1.01, -0.52], I2 =70%). For the lipid parameters, long-acting drugs lowered cholesterol (TC) (P = .02, SMD = -0.19, 95% CI [-0.35, -0.03], I2 =57%) and low-density lipoprotein (LDL) (P = .02, SMD = -0.17, 95% CI [-0.33, -0.02], I2 =51%) more significantly compared with short-acting drugs. But treatment differences were not significant in triglycerides (TG) (P = .40, SMD = -0.05, 95% CI [-0.15, -0.06], I2 = 0%), and high-density lipoprotein (HDL) (P = .85, SMD = -0.01, 95% CI [-0.11, -0.09], I2 = 0%). Long-acting GLP-1RAs may be more promise than short-acting GLP-1RAs in improving weight and related metabolic parameters.

A new HPLC method for selexipag analysis in pharmaceutical formulation and bulk form

Selexipag is a new non-prostanoid prostacyclin receptor agonist used to treat pulmonary arterial hypertension. Selexipag is a long-acting IP receptor agonist with a shorter half-life than all other licensed drugs targeting the prostacyclin pathway, mostly administered intravenously or by subcutaneous infusion or inhalation. In this study, a new high performance liquid chromatography (HPLC) method was developed to analyze Selexipag in bulk and pharmaceutical formulations. The method used a column with Supelco Ascentis® Express (Sigma Aldrich, USA) model phenyl hexyl functional group (100×4.6 mm, ID, 2.7µm). Chromatographic separation was in isocratic elution mode, and the mobile phase mixture was acetonitrile containing 0.1% formic acid: water containing 0.1% formic acid (60:40, v/v) ratio. The method was linear in the concentration range of 15.7-117.6 µg/mL, and the LOD and LOQ were obtained as 2.4 and 3.1 µg/mL, respectively. Various method parameters have been tested according to the ICH Q2(R1) manual, and it is a method with high accuracy and precision. Therefore, the developed method is suitable for selexipag’s bulk and pharmaceutical formulation analysis.

Real-world Evidence for Impact of Opioid Agonist Therapy on Nonfatal Overdose in Patients with Opioid Use Disorder during the COVID-19 Pandemic.

The primary objectives of this study were to describe the demographics and clinical characteristics of patients who were treated with buprenorphine extended-release versus buprenorphine-naloxone sublingual tablets versus methadone in a real-world setting and to evaluate the difference in nonfatal overdose events between treatment cohorts. This study was a retrospective chart review of patients with opioid use disorder initiating opioid agonist therapy in Canada during the outset of the COVID-19 pandemic (March 11, 2020 to October 31, 2021). Three treatment cohorts were defined by the initial prescribed opioid agonist therapy regimen: buprenorphine extended-release, buprenorphine-naloxone sublingual tablets, and methadone. Baseline characteristics, as well as treatment status, overdose events, and substance use 6 months after treatment initiation were collected using a standardized form. Nine clinics provided data on 379 patient cases. The incidence rate (number of events per 100 person-years) for a self-reported nonfatal overdose was 46.8 (n = 18), 19.3 (n = 10), and 1.7 (n = 1) in the methadone, buprenorphine-naloxone sublingual tablets, and buprenorphine extended-release cohorts, respectively. The risk-adjusted difference for the proportion of patients with nonfatal overdose was 8.59% (95% confidence interval, 3.10-14.08%; P = 0.0022) for methadone versus buprenorphine extended-release and 6.51% (95% confidence interval, 1.46-11.56%; P = 0.0115) for buprenorphine-naloxone sublingual tablets versus buprenorphine extended-release. Buprenorphine extended-release was associated with lower rates of nonfatal overdose events compared with daily opioid agonist therapy. Given the limitations of this naturalistic, retrospective design, further prospective studies are needed to validate these findings and demonstrate the potential for long-acting opioid agonist therapy in addressing the opioid crisis.

Design of a Dual Agonist of Exendin-4 and FGF21 as a Potential Treatment for Type 2 Diabetes Mellitus and Obesity.

Fibroblast growth factor 21 (FGF21) is a metabolic, endocrine hormone regulating insulin sensitivity, energy expenditure, and lipid metabolism. It has significant potential as a therapeutic drug for treating type 2 diabetes and obesity. However, the clinical efficacy of FGF21 analogs is limited due to their instability and short half-life. Glucagon-like peptide 1 (GLP-1) receptor agonists have been recognized as effective medications for type 2 diabetes mellitus and obesity over the past two decades. This study designed a new long-acting dual-agonist, exendin-4/FGF21, utilizing albumin-binding-designed ankyrin repeat proteins (DARPins) as carriers. The purified fusion proteins were subcutaneously injected into mice for pharmacokinetic and biological activity studies. Ex-DARP-FGF21 had a high binding affinity for human serum albumin (HSA) in vitro and a prolonged half-life of 27.6 hours in vivo. Bioactivity results reveal that Ex-DARP-FGF21 significantly reduced blood glucose levels in healthy mice. Moreover, compared to Ex-DARP alone, the Ex-DARP-FGF21 dual agonist displayed enhanced blood glucose lowering bioactivity and superior body weight management in the diet-induced obesity (DIO) mouse model. These results indicate that the long-acting dual agonist of exendin-4 and FGF21 holds considerable potential as a treatment for type 2 diabetes mellitus (T2DM) and obesity in the future.

Efficacy and safety of an extended-release sebacoyl dinalbuphine ester for laparoscopic cholecystectomy: A randomized controlled trial.

A long-acting κreceptor agonist parenteral analgesic may theoretically improve acute pain and reduce incidence of chronic postsurgical pain (CPSP) after laparoscopic cholecystectomy with minimal drug-related side effects of the traditional μreceptor opioids. Eighty adult patients undergoing elective laparoscopic cholecystectomy were randomly assigned to receive single intramuscular injection of an extended-release sebacoyl dinalbuphine ester (SDE, Naldebain 150 mg; n = 40) or placebo (n = 40) after anesthesia induction. Standard multimodal analgesia (MMA) was administered for postoperative pain control. The primary endpoint was pain intensity within 7 days after surgery. The secondary endpoints were incidence CPSP at 3 months and adverse reactions up to 7 days after surgery. The highest visual analogue scale (VAS) and area under the curve of VAS 0 to 48 hours after operation were not different between the two groups and a similar proportion of patients requested rescue parenteral analgesics. Average pain intensities were also not different at 72 hours and 7 days after surgery. Incidence of CPSP was 22.5% and 13.1% in patients who received placebo and SDE treatment, respectively (P = .379). Significantly higher incidence of drug-related adverse events, including dizziness, nausea and injection site reactions, were recorded in the SDE group. A single dose of extended-release analgesic SDE given intraoperatively did not provide sufficient add-on effect for acute and chronic pain management after laparoscopic cholecystectomies in patients who received standard postoperative MMA. Intramuscular injection of 150 mg SDE in patients with average body mass causes adverse events that could have been overlooked. More clinical studies are warranted to determine the target populations who may benefit from SDE injections for improvement of acute and chronic postsurgical pain management.

The Therapeutic Values of IL-7/IL-7R and the Recombinant Derivatives in Glioma: A Narrative Review.

Interleukin-7 (IL-7) is essential for maintaining the immune system's defense functions by regulating the development and homeostasis of lymphocytes. Findings have shown the high efficacy of IL-7/IL-7 receptor (IL-7R)-based immunotherapy on various malignancies, with confirmation in both animal models and humans. In recent years, the progression-free survival and overall survival of patients suffering from gliomas significantly increased by introducing C7R-expressing chimeric antigen receptor (CAR)-T cells and long-acting IL-7 agonists such as NT-I7 (rhIL-7-hyFc, Efineptakin alfa). However, the effect of IL-7-based immunotherapies on the resistance of tumor cells to chemotherapy (when used simultaneously with chemotherapy agents) is still ambiguous and requires further studies. This article first reviews the pathophysiological roles of IL-7/IL-7R in tumors, focusing on gliomas. Subsequently, it discusses the therapeutic values of IL-7/IL-7R and the recombinant derivatives in gliomas.

Effects of a long-acting secretin peptide analog alone and in combination with a GLP-1R agonist in a diet-induced obesity mouse model

ObjectiveObesity is a major global health problem which can be targeted with new mechanistic diverse pharmacological interventions. Here we evaluate a new long-acting secretin receptor agonist as a potential treatment for obesity. MethodsBI-3434 was designed as a secretin analog with stabilized peptide backbone and attached fatty acid-based half-life extension group. The peptide was evaluated in vitro for its ability to stimulate cAMP accumulation in a cell line stably expressing recombinant secretin receptor. On the functional level, stimulation of lipolysis in primary adipocytes after treatment with BI-3434 was determined. The ability of BI-3434 to activate secretin receptor in vivo was assessed in a cAMP reporter CRE-Luc mouse model. Furthermore, a diet-induced obesity mouse model was used to test the effects of BI-3434 on body weight and food intake following repeated daily subcutaneous administration alone and in combination with a GLP-1R agonist. ResultsBI-3434 potently activated human secretin receptor. However, lipolysis was only weakly induced in primary murine adipocytes. BI-3434 had an extended half-life compared to endogenous secretin and activated target tissues like pancreas, adipose tissue, and stomach in vivo. BI-3434 did not lower food intake in lean or diet-induced obese mice, but it increased energy expenditure after daily administration. This led to a loss of fat mass, which did not translate in a significant effect on body weight. However, treatment in combination with a GLP-1R agonist led to a synergistic effect on body weight loss. ConclusionsBI-3434 is a highly potent and selective agonist of secretin receptor with an extended pharmacokinetic (PK) profile. Increased energy expenditure after daily treatment with BI-3434 suggests that secretin receptor is involved in metabolic regulation and energy homeostasis. Targeting secretin receptor alone may not be an efficient anti-obesity treatment, but could be combined with anorectic principles like GLP-1R agonists.

56-OR: A Long-Acting Glucose-Dependent Insulinotropic Polypeptide Receptor Agonist Shows Weight Loss without Nausea or Vomiting

The contributions of glucose-dependent insulinotropic polypeptide (GIP) to overall metabolic and weight effects of incretin therapies are unclear. Weight loss efficacy has been observed with glucagon-like peptide 1 (GLP-1) and GIP receptor agonist tirzepatide, but weight loss efficacy has also been observed with GLP-1 agonism mixed with GIP antagonism. LY3537021 (LY), a selective, long-acting GIP receptor agonist, was tested in single [SAD, LY vs placebo (PBO)] and multiple ascending doses (MAD, LY vs PBO once weekly for 4 weeks) to evaluate safety, tolerability, pharmacokinetics (PK), and pharmacodynamics. In SAD, healthy participants (N=39) had a mean age of 43.5 yrs and mean weight of 74.4 kg. People with T2D (N=6) had a mean age of 58.5 yrs and mean weight of 75.1 kg. Median Tmax was 12 to 84 hrs post dose and mean terminal T½ was approximately 11 to 14 days. PK in people with T2D appeared comparable to healthy participants. In MAD, healthy participants (N=18) had a mean age of 38.3 yrs and mean weight of 75.4 kg. People with T2D (N=18) had a mean age of 57.1 yrs and mean weight of 74.3 kg. In healthy MAD participants at day 57, numerically greater mean weight loss was reported in those who received LY (-1.1 to -2.2 kg) versus PBO (-0.4 kg). In people with T2D, numerically greater mean weight loss was reported for those receiving LY (-1.9 to -3.1 kg) versus PBO (-0.4 kg). LY did not result in gastric emptying delay. No serious adverse events or hypoglycemia occurred. Study participants had few mild gastrointestinal (GI) adverse events. Study findings included decreased appetite (LY: n=4, PBO: n=1), abdominal pain (LY: n=1, PBO: n=0) and diarrhea (LY: n=1, PBO: n=2). No nausea or vomiting was observed. Repeated dosing of a long-acting GIP receptor agonist, once weekly for 4 weeks, induced weight loss without gastric emptying delay or nausea and vomiting. The results suggest that GIP agonism can contribute to weight loss effects seen with multi-agonist incretins such as tirzepatide. Disclosure F.K.Knop: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Novo Nordisk, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Lundbeck. S.Urva: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. M.Rettiganti: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. C.Benson: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. W.Roell: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. K.J.Mather: Employee; Eli Lilly and Company. A.Haupt: Employee; Lilly, Stock/Shareholder; Lilly. E.J.Pratt: Employee; Eli Lilly and Company.

1648-P: Triagonism Targeting GCGR/GLP-1/GIP-1 Receptors Improves Insulin Sensitivity in Obese Mice

Glucagon is best known as the primary counter-regulatory hormone against insulin action. Glucagon secretion is likewise elevated in Diabetes and thus it is often implicated as a diabetogenic hormone. However, emerging data from our group and others have uncovered that Glucagon receptor (GCGR) agonism improves insulin sensitivity in both lean and obese mice. Mechanistically, this improvement is associated with enhanced AKT phosphorylation and mTOR signaling in the liver. Novel, single-molecule, triagonists targeting GCG/GLP-1/GIP receptors (GGG) have recently been described to exert stronger anti-obesity effects than dual or single agonism in obese mice. Thus, we evaluated the effect of these agonists on insulin sensitivity using hyperinsulinemic euglycemic clamp. Diet-induced obese (DIO) mice were randomly assigned to 4d treatment (10 nmole/kg subcutaneous injection) of vehicle, GGG, GCGR agonism (IUB288), GLP-1R agonism (Semaglutide), or a long-acting GIP-1R agonist (GIP-FA 085). On the fourth day, mice were fasted for 5 hours, continuously infused with 1.2mU/kg/min insulin, and blood glucose levels clamped around 80-100 mg/dL. Under these conditions Semaglutide and GGG treatments stimulated the greatest glucose infusion rate (p&amp;lt;0.0001) and significantly improved insulin-mediated suppression of Endo Ra (p&amp;lt;0.01). Smaller, but significant, enhancement was also observed in the IUB288-treated mice. Moreover, [14C]-2GDp uptake into brown adipose tissue was improved in GGG, Semaglutide, and IUB288 treated mice compared to Vehicle treated mice. Importantly, these improvements in insulin sensitivity and glucose dynamics were body-weight independent. Therefore, GCGR and GLP-1R signaling combine in GGG triagonism to improve insulin sensitivity mainly via suppression of hepatic glucose production. Disclosure T.Kim: None. S.Nason: None. J.Antipenko: None. K.M.Habegger: Consultant; Glyscend Inc., Research Support; Eli Lilly and Company, Novo Nordisk, Glyscend Inc., Stock/Shareholder; Glyscend Inc. Funding Eli Lilly and Company

1559-P: Glucagon Receptor–Mediated Improvements in Glycemia Are Dependent on Agonist Pharmacodynamics

Glucagon is considered the main glucose counter-regulatory hormone to insulin. Although, chronic glucagon receptor (GCGR) agonism induces hyperglycemia and glucose intolerance, it also improves insulin secretion and action. Surprisingly, we found chronic treatment with the selective, long-acting GCGR agonist, IUB288, improves ad libitum glycemia and glucose tolerance 4h after treatment. These glycemic improvements were associated with enhanced AKT phosphorylation, despite control-like insulin levels. We next tested if these results could be replicated with a short acting GCGR agonist. IUB94 displays improved aqueous solubility but maintains the short half-life and potency of native glucagon. 4h glucose excursion was monitored in lean mice after injection of IUB288, IUB94, or vehicle. We observed a transient rise in blood glucose (BG) 15min after either IUB288 or IUB94 compared to vehicle. Intriguingly, IUB288-treated mice exhibited improved BG from 120-240min, while BG in IUB94-treated mice was similar to vehicle controls. These data suggest that acute BG regulation is agonist-dependent yet, it remains unclear if pharmacodynamics or some inherent difference in potency is influencing the 4h BG. We next treated lean mice for 4d with vehicle or IUB288, measuring ad libitum glycemia over the final 24h period. IUB288-treated mice displayed improved glycemia 4h after the last injection and hyperglycemia after 12h, compared to vehicle-treated controls, suggesting chronic GCGR agonism is not exclusively hyperglycemic. Surprisingly, 4d IUB288 treatment in diet-induced obese (DIO) mice reduced ad libitum glycemia for a longer duration than observed in chow IUB288-treated mice. IUB288 treatment also increased glucose infusion rate, suppression of endogenous glucose production, and AKT phosphorylation during hyperinsulinemic-euglycemic clamps. These data provide insight into the potential therapeutic use of sustained-acting GCGR agonists against diabetes and obesity. Disclosure S.Nason: None. T.Kim: None. J.Antipenko: None. B.Yang: None. R.Dimarchi: None. K.M.Habegger: Consultant; Glyscend Inc., Research Support; Eli Lilly and Company, Novo Nordisk, Glyscend Inc., Stock/Shareholder; Glyscend Inc. Funding National Institutes of Health