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Pain Medicine (Malden, Mass.) Apr 2020An expert panel convened to reach a consensus on common misconceptions surrounding buprenorphine, a Schedule III partial µ-opioid receptor agonist indicated for chronic... (Review)
Review
OBJECTIVE
An expert panel convened to reach a consensus on common misconceptions surrounding buprenorphine, a Schedule III partial µ-opioid receptor agonist indicated for chronic pain. The panel also provided clinical recommendations on the appropriate use of buprenorphine and conversion strategies for switching to buprenorphine from a full µ-opioid receptor agonist for chronic pain management.
METHODS
The consensus panel met on March 25, 2019, to discuss relevant literature and provide recommendations on interpreting buprenorphine as a partial µ-opioid receptor agonist, prescribing buprenorphine before some Schedule II, III, or IV options, perioperative/trauma management of patients taking buprenorphine, and converting patients from a full µ-opioid receptor agonist to buprenorphine.
RESULTS
The panel recommended that buprenorphine's classification as a partial µ-opioid receptor agonist not be clinically translated to mean partial analgesic efficacy. The panel also recommended that buprenorphine be considered before some Schedule II, III, or IV opioids in patients with a favorable risk/benefit profile on the basis of metabolic factors, abuse potential, and tolerability and that buprenorphine be continued during the perioperative/trauma period. In addition, switching patients from a full µ-opioid receptor agonist to buprenorphine should be considered with no weaning period at starting doses that are based on the previous opioid dose.
CONCLUSIONS
These recommendations provide a framework for clinicians to address most clinical scenarios regarding buprenorphine use. The overall consensus of the panel was that buprenorphine is a unique Schedule III opioid with favorable pharmacologic properties and a safety profile that may be desirable for chronic pain management.
Topics: Analgesics, Opioid; Buprenorphine; Chronic Pain; Drug Substitution; Humans; Practice Guidelines as Topic; Receptors, Opioid, mu
PubMed: 31917418
DOI: 10.1093/pm/pnz356 -
Peptides Mar 2023Long-acting analogues of the naturally occurring incretin, glucagon-like peptide-1 (GLP-1) and those modified to interact also with receptors for glucose-dependent... (Review)
Review
Long-acting analogues of the naturally occurring incretin, glucagon-like peptide-1 (GLP-1) and those modified to interact also with receptors for glucose-dependent insulinotropic polypeptide (GIP) have shown high glucose-lowering and weight-lowering efficacy when administered by once-weekly subcutaneous injection. These analogues herald an exciting new era in peptide-based therapy for type 2 diabetes (T2D) and obesity. Of note is the GLP-1R agonist semaglutide, available in oral and injectable formulations and in clinical trials combined with the long-acting amylin analogue, cagrilintide. Particularly high efficacy in both glucose- and weight lowering capacities has also been observed with the GLP-1R/GIP-R unimolecular dual agonist, tirzepatide. In addition, a number of long-acting unimolecular GLP-1R/GCGR dual agonist peptides and GLP-1R/GCGR/GIPR triagonist peptides have entered clinical trials. Other pharmacological approaches to chronic weight management include the human monoclonal antibody, bimagrumab which blocks activin type II receptors and is associated with growth of skeletal muscle, an antibody blocking activation of GIPR to which are conjugated GLP-1R peptide agonists (AMG-133), and the melanocortin-4 receptor agonist, setmelanotide for use in certain inherited obesity conditions. The high global demand for the GLP-1R agonists liraglutide and semaglutide as anti-obesity agents has led to shortage so that their use in T2D therapy is currently being prioritized.
Topics: Humans; Diabetes Mellitus, Type 2; Obesity; Glucagon-Like Peptide 1; Incretins; Gastric Inhibitory Polypeptide; Glucose; Glucagon-Like Peptide-1 Receptor
PubMed: 36608818
DOI: 10.1016/j.peptides.2023.170939 -
Nature Communications Feb 2022Premature ovarian failure (POF) is a leading cause of women's infertility without effective treatment. Here we show that intravenous injection of Ab4B19, an agonistic...
Premature ovarian failure (POF) is a leading cause of women's infertility without effective treatment. Here we show that intravenous injection of Ab4B19, an agonistic antibody for the BDNF receptor TrkB, penetrates into ovarian follicles, activates TrkB signaling, and promotes ovary development. In both natural aging and cyclophosphamide-induced POF models, treatment with Ab4B19 completely reverses the reduction of pre-antral and antral follicles, and normalizes gonadal hormone. Ab4B19 also attenuates gonadotoxicity and inhibits apoptosis in cyclophosphamide-induced POF ovaries. Further, treatment with Ab4B19, but not BDNF, restores the number and quality of oocytes and enhances fertility. In human, BDNF levels are high in granulosa cells and TrkB levels increase in oocytes as they mature. Moreover, BDNF expression is down-regulated in follicles of aged women, and Ab4B19 activates TrkB signaling in human ovary tissue ex vivo. These results identify TrkB as a potential target for POF with differentiated mechanisms, and confirms superiority of TrkB activating antibody over BDNF as therapeutic agents.
Topics: Adult; Animals; Female; Humans; Male; Mice; Middle Aged; Young Adult; Aging; Apoptosis; Brain-Derived Neurotrophic Factor; Cell Line, Tumor; Cyclophosphamide; Disease Models, Animal; Fertility; Fertility Agents, Female; Membrane Glycoproteins; Organ Culture Techniques; Ovary; Primary Ovarian Insufficiency; Receptor, trkB
PubMed: 35177657
DOI: 10.1038/s41467-022-28611-2 -
Cell Feb 2021Ligand-gated ion channels mediate signal transduction at chemical synapses and transition between resting, open, and desensitized states in response to neurotransmitter...
Ligand-gated ion channels mediate signal transduction at chemical synapses and transition between resting, open, and desensitized states in response to neurotransmitter binding. Neurotransmitters that produce maximum open channel probabilities (Po) are full agonists, whereas those that yield lower than maximum Po are partial agonists. Cys-loop receptors are an important class of neurotransmitter receptors, yet a structure-based understanding of the mechanism of partial agonist action has proven elusive. Here, we study the glycine receptor with the full agonist glycine and the partial agonists taurine and γ-amino butyric acid (GABA). We use electrophysiology to show how partial agonists populate agonist-bound, closed channel states and cryo-EM reconstructions to illuminate the structures of intermediate, pre-open states, providing insights into previously unseen conformational states along the receptor reaction pathway. We further correlate agonist-induced conformational changes to Po across members of the receptor family, providing a hypothetical mechanism for partial and full agonist action at Cys-loop receptors.
Topics: Animals; Binding Sites; Cell Line; Cryoelectron Microscopy; Glycine; HEK293 Cells; Humans; Imaging, Three-Dimensional; Ion Channel Gating; Maleates; Models, Molecular; Mutant Proteins; Mutation; Neurotransmitter Agents; Protein Domains; Receptors, Glycine; Styrene; Zebrafish; gamma-Aminobutyric Acid
PubMed: 33567265
DOI: 10.1016/j.cell.2021.01.026 -
Blood Reviews May 2022Thrombopoietin regulates platelet production through activation of the thrombopoietin receptor (TPO-R). TPO-R agonists (TPO-RAs) are available to treat thrombocytopenia... (Review)
Review
Thrombopoietin regulates platelet production through activation of the thrombopoietin receptor (TPO-R). TPO-R agonists (TPO-RAs) are available to treat thrombocytopenia in chronic immune thrombocytopenia (ITP), chronic liver disease (CLD) patients who are undergoing a procedure, severe aplastic anemia (SAA), and hepatitis C virus (HCV) infection. There are four TPO-RAs approved in the US and Europe: romiplostim (ITP), eltrombopag (ITP, SAA, HCV), avatrombopag (ITP, CLD), and lusutrombopag (CLD). It is important to understand pharmacological characteristics of these agents when evaluating treatment options. Avatrombopag interacts with the transmembrane domain of the TPO-RA and does not compete with endogenous thrombopoietin for TPO-R binding. Structural differences between avatrombopag and other TPO-RAs may impart differential downstream effects on cell signaling pathways, potentially resulting in clinically relevant differences in outcome. Avatrombopag has a favorable pharmacological profile with similar exposure in Japanese, Chinese, or Caucasian patients and no drug-drug interactions, food interactions, or potential for chelation.
Topics: Anemia, Aplastic; Hepatitis C; Humans; Liver Diseases; Receptors, Thrombopoietin; Thiazoles; Thiophenes; Thrombopoietin
PubMed: 34815110
DOI: 10.1016/j.blre.2021.100909 -
Cancer Immunology Research Aug 2022Activation of the stimulator of interferon genes (STING) pathway promotes antitumor immunity but STING agonists have yet to achieve clinical success. Increased...
Activation of the stimulator of interferon genes (STING) pathway promotes antitumor immunity but STING agonists have yet to achieve clinical success. Increased understanding of the mechanism of action of STING agonists in human tumors is key to developing therapeutic combinations that activate effective innate antitumor immunity. Here, we report that malignant pleural mesothelioma cells robustly express STING and are responsive to STING agonist treatment ex vivo. Using dynamic single-cell RNA sequencing of explants treated with a STING agonist, we observed CXCR3 chemokine activation primarily in tumor cells and cancer-associated fibroblasts, as well as T-cell cytotoxicity. In contrast, primary natural killer (NK) cells resisted STING agonist-induced cytotoxicity. STING agonists enhanced migration and killing of NK cells and mesothelin-targeted chimeric antigen receptor (CAR)-NK cells, improving therapeutic activity in patient-derived organotypic tumor spheroids. These studies reveal the fundamental importance of using human tumor samples to assess innate and cellular immune therapies. By functionally profiling mesothelioma tumor explants with elevated STING expression in tumor cells, we uncovered distinct consequences of STING agonist treatment in humans that support testing combining STING agonists with NK and CAR-NK cell therapies.
Topics: Cell Line, Tumor; Cell- and Tissue-Based Therapy; Humans; Immunotherapy, Adoptive; Killer Cells, Natural; Membrane Proteins; Mesothelioma, Malignant; Receptors, Chimeric Antigen
PubMed: 35678717
DOI: 10.1158/2326-6066.CIR-22-0017 -
Pharmaceutical Research Jun 2022Semaglutide, a peptidic GLP-1 receptor agonist, has been clinically approved for treatment of type 2 diabetes mellitus and is available in subcutaneous and oral dosage... (Review)
Review
Therapeutic Potential of Semaglutide, a Newer GLP-1 Receptor Agonist, in Abating Obesity, Non-Alcoholic Steatohepatitis and Neurodegenerative diseases: A Narrative Review.
INTRODUCTION
Semaglutide, a peptidic GLP-1 receptor agonist, has been clinically approved for treatment of type 2 diabetes mellitus and is available in subcutaneous and oral dosage form. Diabetes, insulin resistance, and obesity are responsible for the pathological manifestations of non-alcoholic steatohepatitis (NASH). Similarly, insulin resistance in brain is also responsible for neurodegeneration and impaired cognitive functions.
BACKGROUND
Observations from phase-3 clinical trials like SUSTAIN and PIONEER indicated anti-obesity potential of semaglutide, which was established in STEP trials. Various pre-clinical and phase-2 studies have indicated the therapeutic potential of semaglutide in non-alcoholic steatohepatitis and neurodegenerative disorders like Parkinson's and Alzheimer's disease.
DISCUSSION
Significant weight reduction ability of semaglutide has been demonstrated in various phase-3 clinical trials, for which recently semaglutide became the first long-acting GLP-1 receptor agonist to be approved by the United States Food and Drug Administration for management of obesity. Various pre-clinical and clinical studies have revealed the hepatoprotective effect of semaglutide in NASH and neuroprotective effect in Parkinson's and Alzheimer's disease.
CONCLUSION
Many GLP-1 receptor agonists have shown hepatoprotective and neuroprotective activity in animal and human trials. As semaglutide is an already clinically approved drug, successful human trials would hasten its inclusion into therapeutic treatment of NASH and neurodegenerative diseases. Semaglutide improves insulin resistance, insulin signalling pathway, and reduce body weight which are responsible for prevention or progression of NASH and neurodegenerative diseases.
Topics: Alzheimer Disease; Animals; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Hypoglycemic Agents; Insulin Resistance; Neurodegenerative Diseases; Non-alcoholic Fatty Liver Disease; Obesity; Parkinson Disease
PubMed: 35650449
DOI: 10.1007/s11095-022-03302-1 -
Journal of Medicinal Chemistry Jun 2022Peptide agonists of the glucagon-like peptide-1 receptor (GLP-1R) have revolutionized diabetes therapy, but their use has been limited because they require injection....
Peptide agonists of the glucagon-like peptide-1 receptor (GLP-1R) have revolutionized diabetes therapy, but their use has been limited because they require injection. Herein, we describe the discovery of the orally bioavailable, small-molecule, GLP-1R agonist PF-06882961 (danuglipron). A sensitized high-throughput screen was used to identify 5-fluoropyrimidine-based GLP-1R agonists that were optimized to promote endogenous GLP-1R signaling with nanomolar potency. Incorporation of a carboxylic acid moiety provided considerable GLP-1R potency gains with improved off-target pharmacology and reduced metabolic clearance, ultimately resulting in the identification of danuglipron. Danuglipron increased insulin levels in primates but not rodents, which was explained by receptor mutagensis studies and a cryogenic electron microscope structure that revealed a binding pocket requiring a primate-specific tryptophan 33 residue. Oral administration of danuglipron to healthy humans produced dose-proportional increases in systemic exposure (NCT03309241). This opens an opportunity for oral small-molecule therapies that target the well-validated GLP-1R for metabolic health.
Topics: Animals; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Peptides
PubMed: 35647711
DOI: 10.1021/acs.jmedchem.1c01856 -
MAbs 2023The clinical development of 4-1BB agonists for cancer immunotherapy has raised substantial interest during the past decade. The first generation of 4-1BB agonistic... (Review)
Review
The clinical development of 4-1BB agonists for cancer immunotherapy has raised substantial interest during the past decade. The first generation of 4-1BB agonistic antibodies entering the clinic, urelumab (BMS-663513) and utomilumab (PF-05082566), failed due to (liver) toxicity or lack of efficacy, respectively. The two antibodies display differences in the affinity and the 4-1BB receptor epitope recognition, as well as the isotype, which determines the Fc-gamma-receptor (FcγR) crosslinking activity. Based on this experience a very diverse landscape of second-generation 4-1BB agonists addressing the liabilities of first-generation agonists has recently been developed, with many entering clinical Phase 1 and 2 studies. This review provides an overview focusing on differences and their scientific rationale, as well as challenges foreseen during the clinical development of these molecules.
Topics: Humans; Tumor Necrosis Factor Receptor Superfamily, Member 9; Receptors, IgG; Epitopes; Neoplasms; Immunotherapy
PubMed: 36727218
DOI: 10.1080/19420862.2023.2167189 -
Journal of Hepatology May 2021While cholangiocarcinomas (CCAs) commonly express programmed cell death 1 (PD-1) and its ligand (PD-L1), they respond poorly to immune checkpoint inhibitors (ICIs). We...
BACKGROUND & AIMS
While cholangiocarcinomas (CCAs) commonly express programmed cell death 1 (PD-1) and its ligand (PD-L1), they respond poorly to immune checkpoint inhibitors (ICIs). We aimed to determine whether stimulating antigen-presenting cells, including macrophages and dendritic cells, using a CD40 agonist could improve this response.
METHODS
We compared treatment responses in subcutaneous, orthotopic, and 2 plasmid-based murine intrahepatic CCA (iCCA) models. Mice were treated for 4 weeks with weekly IgG control, a CD40 agonistic antibody, anti-PD-1, or the combination of both (anti-CD40/PD-1). Flow cytometric (FACS) analysis of lymphocytes and myeloid cell populations (including activation status) was performed. We used dendritic cell knockout mice, and macrophage, CD4 and CD8 T cell depletion models to identify effector cells. Anti-CD40/PD-1 was combined with chemotherapy (gemcitabine/cisplatin) to test for improved therapeutic efficacy.
RESULTS
In all 4 models, anti-PD-1 alone was minimally efficacious. Mice exhibited a moderate response to CD40 agonist monotherapy. Combination anti-CD40/PD-1 therapy led to a significantly greater reduction in tumor burden. FACS demonstrated increased number and activation of CD4 and CD8 T cells, natural killer cells, and myeloid cells in tumor and non-tumor liver tissue of tumor-bearing mice treated with anti-CD40/PD-1. Depletion of macrophages, dendritic cells, CD4+ T cells, or CD8+ T cells abrogated treatment efficacy. Combining anti-CD40/PD-1 with gemcitabine/cisplatin resulted in a significant survival benefit compared to gemcitabine/cisplatin alone.
CONCLUSION
CD40-mediated activation of macrophages and dendritic cells in iCCA significantly enhances response to anti-PD-1 therapy. This regimen may enhance the efficacy of first-line chemotherapy.
LAY SUMMARY
Checkpoint inhibition, a common form of immune therapy, is generally ineffective for the treatment of cholangiocarcinoma. These tumors suppress the infiltration and function of surrounding immune cells. Stimulating immune cells such as macrophages and dendritic cells via the CD40 receptor activates downstream immune cells and enhances the response to checkpoint inhibitors.
Topics: Animals; Antimetabolites, Antineoplastic; CD40 Antigens; Cell Line, Tumor; Cholangiocarcinoma; Cisplatin; Dendritic Cells; Deoxycytidine; Drug Collateral Sensitivity; Immune Checkpoint Inhibitors; Liver Neoplasms; Lymphocytes, Tumor-Infiltrating; Macrophage Activation; Macrophage-Activating Factors; Mice; Mice, Knockout; Tumor Microenvironment; Gemcitabine
PubMed: 33276030
DOI: 10.1016/j.jhep.2020.11.037