ABSTRACT
Genetically engineered chondrocytes virally transduced with a transforming growth factor (TGF)-ß1 (TG-C [TissueGene-C]) expression vector have been shown to have potential benefits in the nonoperative management of knee osteoarthritis. Previous literature has reported on safe dosages of TG-C. Therefore, the purpose of this study was to evaluate the Phase II results and a 24-month efficacy of this injectable mixture compared with placebo in patients with Kellgren-Lawrence (K-L) grade III knee osteoarthritis. Specifically, we assessed (1) functional outcomes, (2) pain scores, (3) adverse events (AEs), and (4) magnetic resonance imaging (MRIs) findings. We performed a multicenter, double-blinded, placebo-controlled, and randomized study of adults who had K-L grade III knee osteoarthritis. A total of 102 patients were 2:1 randomized to TG-C at a dose of 3.0 × 107 cells, or placebo injections between May 1, 2011 and October 31, 2012. Outcomes analyzed were knee joint function, pain, quality of life, adverse events, and MRI findings using the whole-organ magnetic resonance imaging score (WORMS) system. There were significant improvements in the International Knee Documentation Committee (IKDC) and visual analogue scale (VAS) scores in the TG-C cohort, when compared with the placebo cohort at weeks 12, 52, 72, and 104 (p < 0.05). No severe AEs were observed. Common AEs were arthralgia, joint inflammation, and joint effusion which were similar between both cohorts. Whole-knee MRIs at 12 months showed less progression of cartilage damage, infrapatellar fat pad-synovitis, and effusion-synovitis in the TG-C cohort. Patients who received TG-C had significant improvements in IKDC and VAS scores. These patients also reported less severe and frequent pain. Additionally, fewer patients treated with TG-C showed progression of cartilage damage, as well as less progression of infrapatellar fat pad synovitis and effusion-synovitis. Furthermore, treatment with TG-C was generally well tolerated with minor AEs. Therefore, based on these results, TG-C appears to be a safe and effective modality for the management of K-L grade III osteoarthritis.
Subject(s)
Cell Transplantation/methods , Chondrocytes/metabolism , Chondrocytes/transplantation , Osteoarthritis, Knee/surgery , Transforming Growth Factor beta1/biosynthesis , Adult , Aged , Double-Blind Method , Female , Genetic Engineering , Humans , Injections, Intra-Articular , Knee Joint/diagnostic imaging , Knee Joint/surgery , Magnetic Resonance Imaging , Male , Middle Aged , Osteoarthritis, Knee/diagnostic imaging , Transduction, Genetic , Transforming Growth Factor beta1/metabolism , Transplantation, Homologous , Treatment OutcomeABSTRACT
INTRODUCTION: There has been a rapid increase in opioid-related morbidity and mortality worldwide, and the dangers of excessive opioid use have been observed in patients with chronic musculoskeletal pain, including those diagnosed with knee osteoarthritis. Pain management is an important component of nonoperative treatment in knee osteoarthritis and frequently entails the use of opioids. However, this management technique is not without risks, such as addiction, morbidity, and mortality. Therefore, the purpose of this study was to review the existing literature on the use of opioids in the management of knee osteoarthritis and compare the findings to a new injection management modality. Specifically, we assessed: 1) trends in opioid prescription; 2) patient-reported outcomes; 3) incidence of complications; 4) incidence of abuse and dependence; and 5) mortality related to opioid use in knee osteoarthritis. We then performed a sub-analysis comparing these findings to TG-C, a novel a 3:1 mixture of genetically engineered chondrocytes that has shown promising early phase I, II, and III results. MATERIALS AND METHODS: A literature search was performed utilizing the PubMed database with search terms including, but not limited to: "knee osteoarthritis," "total knee arthroplasty," "opioid," "annual trends," "outcomes," "complications," "dependence," "mortality," and "deaths". The initial search revealed 548 results, with an additional 182 sources added after reviewing associated references. After removing duplicates, 245 records were reviewed after which results were evaluated and stratified based on outcomes, yielding a total of 35 studies for final evaluation. Correlative and comparative analyses were performed evaluating trends in opioid prescription, patient-reported outcomes, incidence of complications, incidence of abuse and dependence, and mortality related to opioid use in knee osteoarthritis. Additionally, for each of the aims studied, a summative discussion relating study findings to clinical practice was performed. Outcomes from phase II and III trials of genetically engineered chondrocytes (GEC) injections were also analyzed with a focus on pain reduction. RESULTS: Nearly all studies report markedly increasing trends in opioid prescriptions, with some studies showing significant incremental increases in prescription rates (31 vs. 40%) over time. Additionally, projection models predict-based on current rates of prescribing opioids-that by 2030, prescriptions will triple from 1.1 million in 2015 to 3.0 million in 2030. Along with this, mean oral morphine equivalent dosages will also increase by 22% over a 15-year period. When evaluating patient-reported outcomes, multiple studies have found no significant differences in patient-reported pain outcomes between opioid and non-opioid users (p>0.05). In fact, many studies even report poorer outcomes in patients who used opioids prior to surgical interventions. Opioid use was found to also be associated with increased referrals to pain management, longer in-hospital stays, and poorer Knee Society scores after total knee arthroplasty (TKA) (p<0.05). Furthermore, some studies report as high as 42% of patients continue to use opioids after the initial 90-day postoperative period, and epidemiologic data for the United States reveals an over 20x increase in opioid-related deaths from 0.3 to 6.2 per 100,000 between 1999 and 2016. Our sub-analysis revealed that GEC injections were found to significantly improve reductions in visual analog scale (VAS) pain (-37.2 vs. -23.4 mm, p<0.05) and International Knee Documentation Committee (IKDC) scores (23.0 vs. 12.7, p<0.05) between study and control cohorts, indicating this injection modality to potentially be a successful non-opioid based management technique that is safe and effective. DISCUSSION: The effects of the opioid epidemic on patients with knee osteoarthritis are severe. Excessive opioid use in these patients leads to poorer patient satisfactions as well as increased morbidities and mortalities. Therefore, there is a real need for alternative nonoperative treatment options that effectively reduce pain, and promising results from studies on the efficacy GEC injections demonstrate that they may be an answer to the opioid epidemic observed among osteoarthritis patients.
Subject(s)
Analgesics, Opioid/therapeutic use , Arthralgia/drug therapy , Arthroplasty, Replacement, Knee/adverse effects , Opioid-Related Disorders/prevention & control , Osteoarthritis, Knee/complications , Pain, Postoperative/drug therapy , Arthralgia/etiology , Humans , Opioid-Related Disorders/etiology , Pain, Postoperative/etiologyABSTRACT
BACKGROUND: Invossa™ (TissueGene-C) is a cell and gene therapy for osteoarthritis. It is composed of primary human chondrocytes (hChonJ cells) and irradiated human chondrocytes modified to express TGF-ß1 (hChonJb#7 cells). The hChonJ cells were isolated from a polydactyly donor, and TGF-ß1 cDNA was delivered to the cells, generating hChonJb#7 cells. Since the cells are allogeneic, the concern of immune response against cells has been raised. In this study, we investigated the immunogenicity of allogenic human chondrocyte, hChonJ cells. METHODS: The immunological properties of hChonJ cells were investigated through the analysis of surface marker expression and the effect on allogeneic T cell proliferation. Flow cytometry and RT-PCR analysis were performed to analyze the surface marker expression related to immune response, such as major histocompatibility complex (MHC) class I, class II, T cell co-stimulatory molecules and T cell co-inhibitory molecules. A mixed lymphocyte reaction (MLR) was conducted to evaluate how allogeneic T cells would respond to hChonJ cells. RESULTS: We observed that hChonJ cells did not express MHC class II and T cell co-stimulatory molecules, but expressed T cell co-inhibitory molecule PD-L2. IFN-γ treatment induced the expression of PD-L1, and up-regulated the expression of PD-L2. Also, we observed that hChonJ cells did not stimulate T cell proliferation from a MHC-mismatched donor. Further, they could suppress the proliferation of activated T cells. We also observed that the blockade of PD-L1 and/or PD-L2 with specific neutralizing antibody could lead to the restoration of allo-reactive T cell proliferation. CONCLUSIONS: We showed that hChonJ cells were not immunogenic but immunosuppressive, and that this phenomenon was mediated by co-inhibitory molecules PD-L1 and PD-L2 on hChonJ cells in a contact-dependent manner.
Subject(s)
Chondrocytes/immunology , Immune Tolerance/physiology , Immunity, Cellular/physiology , Immunogenetic Phenomena/physiology , Cells, Cultured , Coculture Techniques , Flow Cytometry/methods , Humans , Immunomodulation/physiologyABSTRACT
Guided by co-crystal structural information obtained from a different series we were exploring, a scaffold morphing and SBDD approach led to the discovery of the 1,4-disubstituted indazole series as a novel class of GKAs that potently activate GK in enzyme and cell assays. anti-diabetic OGTT efficacy was demonstrated with 29 in a rodent models of type 2 diabetes.
Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Drug Discovery , Enzyme Activators/pharmacology , Glucokinase/metabolism , Indazoles/pharmacology , Administration, Oral , Allosteric Regulation/drug effects , Animals , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Type 2/metabolism , Dose-Response Relationship, Drug , Enzyme Activators/administration & dosage , Enzyme Activators/chemistry , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Ether-A-Go-Go Potassium Channels/metabolism , Glucose Tolerance Test , Humans , Indazoles/administration & dosage , Indazoles/chemistry , Mice , Mice, Inbred C57BL , Mice, Obese , Models, Molecular , Molecular Structure , Potassium Channel Blockers/pharmacology , Structure-Activity RelationshipABSTRACT
Multiple therapies have been developed to slow down the progression of knee osteoarthritis (OA), with the aim of avoiding or delaying TKA. One such potential method is cell-mediated gene therapy, which utilizes allogeneic human chondrocytes modified to express transforming growth factor-ß1. Using magnetic resonance imaging (MRI), we evaluated patients who underwent treatment with this injection in a Phase II study and assessed structural changes in: (1) bone marrow edema lesions, (2) cartilage defect depth and surface area, (3) articular bone surface and osteophytes, and (4) meniscus structure and signal, as well as changes in (5) joint fluid, (6) periarticular inflammation, and (7) synovial inflammation. Twenty-seven patients (6 men and 21 women) who had late-stage OA were randomized 1:1 to receive a 3:1 mixture of nontransduced chondrocytes and genetically engineered chondrocytes, at doses of 6 × 106 cells (group 1) or 1.8 × 107 cells (group 2). MRI was performed at baseline (preinjection), and at 6 and 12 months postinjection. The whole-organ MRI score system was used to assess the aforementioned changes. Treatment was considered to be successful if patients experienced an improvement in or no change in their scores, indicating that the disease had not progressed. All patients in both cohorts individually demonstrated an improvement or no change in one or more of the assessment parameters. At 6 months, the low-dose cohort demonstrated worsening in mean scores in one parameter (bone surface and osteophytes), while the high-dose cohort demonstrated no worsening in mean scores. At 12 months, the low-dose cohort had worsening in the mean score in a subset of one parameter (cartilage signal intensity), and the high-dose cohort demonstrated worsening in mean scores in two parameters (bone surface osteophytes and periarticular inflammation). This is the first study to evaluate MRI changes in patients treated with this injection. These findings provide an impetus for further research on this topic, as well as a starting point for Phase III testing.
Subject(s)
Chondrocytes/transplantation , Knee Joint/diagnostic imaging , Magnetic Resonance Imaging , Osteoarthritis, Knee/diagnostic imaging , Osteoarthritis, Knee/therapy , Aged , Cartilage Diseases/pathology , Cell- and Tissue-Based Therapy , Chondrocytes/metabolism , Female , Genetic Therapy , Humans , Knee Joint/pathology , MaleABSTRACT
Guided by co-crystal structures of compounds 15, 22 and 30, an SBDD approach led to the discovery of the 6-methyl pyridone series as a novel class of GKAs that potently activate GK in enzyme and cell assays. Anti-diabetic OGTT efficacy was demonstrated with 54 in a mouse model of type 2 diabetes.
Subject(s)
Diabetes Mellitus, Experimental/enzymology , Drug Design , Enzyme Activators/pharmacology , Glucokinase/metabolism , Hypoglycemic Agents/pharmacology , Pyridones/pharmacology , Animals , Crystallography, X-Ray , Diabetes Mellitus, Experimental/drug therapy , Disease Models, Animal , Enzyme Activation/drug effects , Enzyme Activators/administration & dosage , Enzyme Activators/chemistry , Glucose Tolerance Test , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/chemistry , Mice , Mice, Inbred C57BL , Mice, Obese , Models, Molecular , Molecular Structure , Pyridones/administration & dosage , Pyridones/chemistry , Structure-Activity RelationshipABSTRACT
Protein kinases Aurora A, B, and C play essential roles during mitosis and cell division, are frequently elevated in cancer, and represent attractive targets for therapeutic intervention. TAK-901 is an investigational, multitargeted Aurora B kinase inhibitor derived from a novel azacarboline kinase hinge-binder chemotype. TAK-901 exhibited time-dependent, tight-binding inhibition of Aurora B, but not Aurora A. Consistent with Aurora B inhibition, TAK-901 suppressed cellular histone H3 phosphorylation and induced polyploidy. In various human cancer cell lines, TAK-901 inhibited cell proliferation with effective concentration values from 40 to 500 nmol/L. Examination of a broad panel of kinases in biochemical assays revealed inhibition of multiple kinases. However, TAK-901 potently inhibited only a few kinases other than Aurora B in intact cells, including FLT3 and FGFR2. In rodent xenografts, TAK-901 exhibited potent activity against multiple human solid tumor types, and complete regression was observed in the ovarian cancer A2780 model. TAK-901 also displayed potent activity against several leukemia models. In vivo biomarker studies showed that TAK-901 induced pharmacodynamic responses consistent with Aurora B inhibition and correlating with retention of TAK-901 in tumor tissue. These preclinical data highlight the therapeutic potential of TAK-901, which has entered phase I clinical trials in patients within a diverse range of cancers.
Subject(s)
Carbolines/pharmacology , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Sulfones/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Aurora Kinase A , Aurora Kinase B , Aurora Kinases , Biomarkers , Carbolines/chemistry , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Enzyme Activation/drug effects , Histones/metabolism , Humans , Kinetics , Mice , Phosphorylation/drug effects , Protein Binding , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/metabolism , Rats , Sulfones/chemistry , Xenograft Model Antitumor AssaysABSTRACT
The discovery of two classes of heterocyclic dipeptidyl peptidase IV (DPP-4) inhibitors, pyrimidinones and pyrimidinediones, is described. After a single oral dose, these potent, selective, and noncovalent inhibitors provide sustained reduction of plasma DPP-4 activity and lowering of blood glucose in animal models of diabetes. Compounds 13a, 27b, and 27j were selected for development.
Subject(s)
Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Pyrimidinones/chemical synthesis , Animals , Binding Sites , Biological Availability , Crystallography, X-Ray , Cytochrome P-450 Enzyme Inhibitors , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Dogs , Macaca fascicularis , Models, Molecular , Pyrimidinones/chemistry , Pyrimidinones/pharmacology , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The aim of the present research was to characterize the pharmacokinetic, pharmacodynamic, and efficacy profiles of alogliptin, a novel quinazolinone-based dipeptidyl peptidase-4 (DPP-4) inhibitor. Alogliptin potently inhibited human DPP-4 in vitro (mean IC(50), ~ 6.9 nM) and exhibited > 10,000-fold selectivity for DPP-4 over the closely related serine proteases DPP-2, DPP-8, DPP-9, fibroblast activation protein/seprase, prolyl endopeptidase, and tryptase (IC(50) > 100,000 nM). Absolute oral bioavailability of alogliptin in rats, dogs, and monkeys was 45%, 86%, and 72% to 88%, respectively. After a single oral dose of alogliptin, plasma DPP-4 inhibition was observed within 15 min and maximum inhibition was > 90% in rats, dogs, and monkeys; inhibition was sustained for 12 h in rats (43%) and dogs (65%) and 24 h in monkeys (> 80%). From E(max) modeling, 50% inhibition of DPP-4 activity was observed at a mean alogliptin plasma concentration (EC(50)) of 3.4 to 5.6 ng/ml (10.0 to 16.5 nM) in rats, dogs, and monkeys. In Zucker fa/fa rats, a single dose of alogliptin (0.3, 1, 3, and 10 mg/kg) inhibited plasma DPP-4 (91% to 100% at 2 h and 20% to 66% at 24 h), increased plasma GLP-1 (2- to 3-fold increase in AUC(0-20 min)) and increased early-phase insulin secretion (1.5- to 2.6-fold increase in AUC(0-20 min)) and reduced blood glucose excursion (31%-67% decrease in AUC(0-90 min)) after oral glucose challenge. Alogliptin (30 and 100 mg/kg) had no effect on fasting plasma glucose in normoglycemic rats. In summary, these data suggest that alogliptin is a potent and highly selective DPP-4 inhibitor with demonstrated efficacy in Zucker fa/fa rats and potential for once-daily dosing in humans.
Subject(s)
Dipeptidyl-Peptidase IV Inhibitors , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Glucose Metabolism Disorders/drug therapy , Hypoglycemic Agents/pharmacology , Piperidines/pharmacology , Uracil/analogs & derivatives , Administration, Oral , Animals , Biological Availability , Blood Glucose/drug effects , Dipeptidyl Peptidase 4 , Dipeptidyl-Peptidase IV Inhibitors/administration & dosage , Dipeptidyl-Peptidase IV Inhibitors/pharmacokinetics , Disease Models, Animal , Dogs , Dose-Response Relationship, Drug , Drug Administration Schedule , Glucagon-Like Peptide 1/blood , Glucose Metabolism Disorders/enzymology , Glucose Metabolism Disorders/physiopathology , Humans , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/pharmacokinetics , Insulin/blood , Insulin Resistance , Macaca fascicularis , Male , Piperidines/administration & dosage , Piperidines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Rats, Zucker , Uracil/administration & dosage , Uracil/pharmacokinetics , Uracil/pharmacologyABSTRACT
The mitochondrial Na(+)-Ca(2+) exchanger (mNCE) mediates efflux of Ca(2+) from mitochondria in exchange for influx of Na(+). We show that inhibition of the mNCE enhances mitochondrial oxidative metabolism and increases glucose-stimulated insulin secretion in rat islets and INS-1 cells. The benzothiazepine CGP37157 inhibited mNCE activity in INS-1 cells (50% inhibition at IC(50) = 1.5 micro mol/l) and increased the glucose-induced rise in mitochondrial Ca(2+) ([Ca(2+)](m)) 2.1 times. Cellular ATP content was increased by 13% in INS-1 cells and by 49% in rat islets by CGP37157 (1 micro mol/l). Krebs cycle flux was also stimulated by CGP37157 when glucose was present. Insulin secretion was increased in a glucose-dependent manner by CGP37157 in both INS-1 cells and islets. In islets, CGP37157 increased insulin secretion dose dependently (half-maximal efficacy at EC(50) = 0.06 micro mol/l) at 8 mmol/l glucose and shifted the glucose dose response curve to the left. In perifused islets, mNCE inhibition had no effect on insulin secretion at 2.8 mmol/l glucose but increased insulin secretion by 46% at 11 mmol/l glucose. The effects of CGP37157 could not be attributed to interactions with the plasma membrane sodium calcium exchanger, L-type calcium channels, ATP-sensitive K(+) channels, or [Ca(2+)](m) uniporter. In hyperglycemic clamp studies of Wistar rats, CGP37157 increased plasma insulin and C-peptide levels only during the hyperglycemic phase of the study. These results illustrate the potential utility of agents that affect mitochondrial metabolism as novel insulin secretagogues.