ABSTRACT
BACKGROUND: Checkpoint inhibitors targeting the programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) pathway are effective therapies in a range of immunogenic cancer types. Blocking this pathway with an oral therapy could benefit patients through greater convenience, particularly in combination regimens, and allow flexible management of immune-mediated toxicities. METHODS: PD-L1 binding activity was assessed in engineered dimerization and primary cell target occupancy assays. Preclinical antitumor activity was evaluated in ex vivo and in vivo human PD-L1-expressing tumor models. Human safety, tolerability, pharmacokinetics, and biomarker activity were evaluated in an open-label, multicenter, sequential dose-escalation study in patients with advanced solid tumors. Biomarkers evaluated included target occupancy, flow cytometric immunophenotyping, plasma cytokine measurements, and T-cell receptor sequencing. RESULTS: GS-4224 binding caused dimerization of PD-L1, blocking its interaction with PD-1 and leading to reversal of T-cell inhibition and increased tumor killing in vitro and in vivo. The potency of GS-4224 was dependent on the density of cell surface PD-L1, with binding being most potent on PD-L1-high cells. In a phase 1 dose-escalation study in patients with advanced solid tumors, treatment was well tolerated at doses of 400-1,500 mg once daily. Administration of GS-4224 was associated with a dose-dependent increase in plasma GS-4224 exposure and reduction in free PD-L1 on peripheral blood T cells, an increase in Ki67 among the PD-1-positive T-cell subsets, and elevated plasma cytokines and chemokines. CONCLUSIONS: GS-4224 is a novel, orally bioavailable small molecule inhibitor of PD-L1. GS-4224 showed evidence of expected on-target biomarker activity, including engagement of PD-L1 and induction of immune-related pharmacodynamic responses consistent with PD-L1 blockade. TRIAL REGISTRATION NUMBER: NCT04049617.
Subject(s)
Immune Checkpoint Inhibitors , Neoplasms , Humans , Immune Checkpoint Inhibitors/therapeutic use , B7-H1 Antigen , Programmed Cell Death 1 Receptor , Neoplasms/drug therapy , T-Lymphocytes/metabolismABSTRACT
Hyperglucagonemia contributes to hyperglycemia in patients with type 1 diabetes (T1D); however, novel therapeutics that block glucagon action could improve glycemic control. This phase 2 study evaluated the safety and efficacy of volagidemab, an antagonistic monoclonal glucagon receptor (GCGR) antibody, as an adjunct to insulin therapy in adults with T1D. The primary endpoint was change in daily insulin use at week 12. Secondary endpoints included changes in hemoglobin A1c (HbA1c) at week 13, in average daily blood glucose concentration and time within target range as assessed by continuous blood glucose monitoring (CGM) and seven-point glucose profile at week 12, incidence of hypoglycemic events, the proportion of subjects who achieve HbA1c reduction of ≥0.4%, volagidemab drug concentrations and incidence of anti-drug antibodies. Eligible participants (n = 79) were randomized to receive weekly subcutaneous injections of placebo, 35 mg volagidemab or 70 mg volagidemab. Volagidemab produced a reduction in total daily insulin use at week 12 (35 mg volagidemab: -7.59 units (U) (95% confidence interval (CI) -11.79, -3.39; P = 0.040 versus placebo); 70 mg volagidemab: -6.64 U (95% CI -10.99, -2.29; P = 0.084 versus placebo); placebo: -1.27 U (95% CI -5.4, 2.9)) without meeting the prespecified significance level (P < 0.025). At week 13, the placebo-corrected reduction in HbA1c percentage was -0.53 (95% CI -0.89 to -0.17, nominal P = 0.004) in the 35 mg volagidemab group and -0.49 (95% CI -0.85 to -0.12, nominal P = 0.010) in the 70 mg volagidemab group. No increase in hypoglycemia was observed with volagidemab therapy; however, increases in serum transaminases, low-density lipoprotein (LDL)-cholesterol and blood pressure were observed. Although the primary endpoint did not meet the prespecified significance level, we believe that the observed reduction in HbA1c and tolerable safety profile provide a rationale for further randomized studies to define the long-term efficacy and safety of volagidemab in patients with T1D.
Subject(s)
Antibodies, Monoclonal, Humanized , Diabetes Mellitus, Type 1 , Receptors, Glucagon , Adult , Antibodies, Monoclonal, Humanized/adverse effects , Blood Glucose , Blood Glucose Self-Monitoring , Diabetes Mellitus, Type 1/drug therapy , Double-Blind Method , Glucagon , Glycated Hemoglobin/analysis , Glycated Hemoglobin/therapeutic use , Humans , Insulin/therapeutic use , Lipoproteins, LDL/therapeutic use , Receptors, Glucagon/antagonists & inhibitors , Transaminases/therapeutic use , Treatment OutcomeABSTRACT
Andecaliximab (ADX) is a monoclonal antibody that inhibits matrix metalloproteinase 9 (MMP9), an extracellular enzyme involved in matrix remodeling, tumor growth, and metastasis. In preclinical models, MMP9 inhibitors have been shown to enhance the cytotoxic effects of chemotherapeutic agents and to suppress distant metastasis. In this phase Ib, multicenter study, the safety and efficacy of ADX combined with S-1 plus cisplatin (SP) or S-1 plus oxaliplatin (SOX) as a first-line treatment were evaluated in Japanese patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. ADX was administrated at a dose of 800 mg every 2 weeks for the SP cohort and 1200 mg every three weeks for the SOX cohort. As of December 2019, 16 patients were enrolled (six patients in the SP cohort and 10 patients in the SOX cohort). Peripheral sensory neuropathy (69%), anorexia (63%), nausea (56%), and decreased neutrophil counts (44%) were the most common adverse events (AEs). The grade 3 or higher AEs attributed to ADX were stomatitis and abnormal hepatic function (each one patient) in the SP cohort and decreased neutrophil counts (two patients) in the SOX cohort. The objective response rate in 11 patients with measurable target lesions was 73% (8/11), based on the investigator's evaluation. Median progression-free survival was11.9 months (90% confidence interval, 5.6-16.6), and median overall survival was not reached. In conclusion, ADX combined with S-1 plus platinum demonstrated a manageable safety profile and promising clinical activity in the first-line treatment of patients with advanced gastric or GEJ adenocarcinoma.Clinical Trial Registration information: ClinicalTrials.gov Identifier: NCT02862535 (11/08/2016) and protocol ID: GS-US-296-1884.
Subject(s)
Adenocarcinoma , Antineoplastic Agents , Stomach Neoplasms , Adenocarcinoma/pathology , Antibodies, Monoclonal, Humanized , Antineoplastic Agents/pharmacology , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cisplatin , Drug Combinations , Esophageal Neoplasms , Esophagogastric Junction/pathology , Humans , Japan , Matrix Metalloproteinase 9/therapeutic use , Oxaliplatin/pharmacology , Platinum/therapeutic use , Stomach Neoplasms/pathologyABSTRACT
BACKGROUND: Matrix metalloproteinase 9 (MMP9) is implicated in protumorigenic processes. Targeting either stromal or epithelial MMP9 reduces the incidence of metastasis. Andecaliximab is a monoclonal antibody that targets MMP9 with high affinity and selectivity. However, no study has examined whether the inhibition of T-cell programmed death 1 (PD-1) in the presence of andecaliximab increases activated lymphocyte infiltration into the tumor, thereby increasing antitumor activity more than that in anti-PD-1 monotherapy. In this study, we assessed the safety, pharmacokinetics (PK), exploratory biomarkers, and preliminary efficacy of andecaliximab as monotherapy and in combination with nivolumab in Japanese patients with advanced or recurrent gastric or gastroesophageal junction (GEJ) adenocarcinoma. METHODS: This phase 1b study comprised four cohorts enrolling Japanese patients with gastric or GEJ adenocarcinoma. This paper concerns cohorts 1 and 4; cohorts 2 and 3 will be reported subsequently. Cohort 1 enrolled patients with human epidermal growth factor receptor 2 (HER2)-negative tumors (n=8) who received andecaliximab monotherapy (800 mg by intravenous infusion every 2 weeks (Q2W)), and cohort 4 enrolled patients irrespective of their HER2 status (n=10) who received 800 mg of andecaliximab in combination with nivolumab Q2W. Safety, dose-limiting toxicities (DLTs), PK, pharmacodynamics, and biomarkers were assessed in both cohorts. RESULTS: PK of andecaliximab in Japanese patients with gastric or GEJ adenocarcinoma was similar to that reported in non-Japanese patients with advanced solid tumors. Andecaliximab monotherapy and in combination with nivolumab demonstrated no DLTs in cohort 1 and 4, respectively. Toxicities were manageable and well tolerated in both cohorts. The median progression-free survival was 1.4 months (90% CI, 0.5 to 5.4) and 4.6 months (90% CI, 0.9 to not reached) in cohorts 1 and 4, respectively. The objective response rate was 50% (90% CI, 22% to 78%) in cohort 4, and in some patients, the combination therapy was effective regardless of the biomarker status. CONCLUSIONS: The andecaliximab-nivolumab combination demonstrated a manageable safety profile and promising clinical activity in patients with advanced gastric adenocarcinoma.NCT02862535.
Subject(s)
Adenocarcinoma/pathology , Antibodies, Monoclonal, Humanized/therapeutic use , Esophagogastric Junction/pathology , Stomach Neoplasms/drug therapy , Adult , Aged , Antibodies, Monoclonal, Humanized/pharmacology , Cohort Studies , Female , Humans , Japan , Male , Middle AgedABSTRACT
BACKGROUND: Matrix metalloproteinase-9 (MMP9) selectively cleaves extracellular matrix proteins contributing to tumor growth and an immunosuppressive microenvironment. This study evaluated andecaliximab (ADX), an inhibitor of MMP9, in combination with nivolumab (NIVO), for the treatment of advanced gastric cancer. METHODS: Phase 2, open-label, randomized multicenter study evaluating the efficacy, safety, and pharmacodynamics of ADX+NIVO versus NIVO in patients with pretreated metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and adverse events (AEs). We explored the correlation of efficacy outcomes with biomarkers. RESULTS: 144 patients were randomized; 141 were treated: 81% white, 69% male, median age was 61 years in the ADX+NIVO group and 62 years in the NIVO-alone group. The ORR was 10% (95% CI 4 to 19) in the ADX+NIVO group and 7% (95% CI 2 to 16) in the NIVO-alone group (OR: 1.5 (95% CI 0.4 to 6.1; p=0.8)). There was no response or survival benefit associated with adding ADX. AE rates were comparable in both treatment groups; the most common AEs were fatigue, decreased appetite, nausea, and vomiting. Programmed cell death ligand 1, interferon-γ (IFN), and intratumoral CD8+ cell density were not associated with treatment response or survival. The gene signature most correlated with shorter survival was the epithelial-to-mesenchymal gene signature; high transforming growth factor (TGF)-ß fibrosis score was negatively associated with OS (p=0.036). Gene expression analysis of baseline tumors comparing long-(1+ years) and short-term (<1 year) survivors showed that GRB7 was associated with survival beyond 1 year. Human epidermal growth factor receptor 2 (HER2)-positive disease was associated with significantly longer survival (p=0.0077). Median tumor mutation burden (TMB) was 2.01; patients with TMB ≥median had longer survival (p=0.0025) and improved PFS (p=0.016). Based on a model accounting for TMB, TGF-ß fibrosis, and HER2, TMB was the main driver of survival in this patient population. CONCLUSION: Combination of ADX+NIVO had a favorable safety profile but did not improve efficacy compared with NIVO alone in patients with pretreated metastatic gastric or GEJ adenocarcinoma. HER2 positivity, higher TMB or GRB7, and lower TGF-ß were associated with improved outcomes. TRIAL REGISTRATION NUMBER: NCT02864381 or GS-US-296--2013.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/genetics , Gene Expression Regulation, Neoplastic , Stomach Neoplasms/mortality , Adult , Aged , Antibodies, Monoclonal, Humanized/administration & dosage , Female , Follow-Up Studies , Humans , Male , Middle Aged , Nivolumab/administration & dosage , Prognosis , Stomach Neoplasms/drug therapy , Stomach Neoplasms/genetics , Stomach Neoplasms/pathology , Survival Rate , Transcriptome , Young AdultABSTRACT
PURPOSE: Andecaliximab (ADX) is a monoclonal antibody that inhibits matrix metalloproteinase 9, an extracellular enzyme involved in matrix remodeling, tumor growth, and metastases. A phase I and Ib study of modified oxaliplatin, leucovorin, and fluorouracil (mFOLFOX6) with ADX revealed encouraging antitumor activity in patients with gastric or gastroesophageal junction (GEJ) adenocarcinoma. MATERIALS AND METHODS: This phase III, randomized, double-blinded, placebo (PBO)-controlled multicenter study investigated the efficacy and safety of mFOLFOX6 with and without ADX in patients with untreated human epidermal growth factor receptor 2-negative gastric or GEJ adenocarcinoma. Random assignment was 1:1 to mFOLFOX6 + ADX or mFOLFOX6 + PBO. ADX/PBO 800 mg was infused on days 1 and 15 of each 28-day cycle. Protocol therapy was given until disease progression or intolerance. The primary end point was overall survival (OS), and secondary end points were progression-free survival (PFS), objective response rate (RECIST 1.1), and safety. RESULTS: Between September 2015 and May 2017, 432 patients were randomly assigned, 218 to ADX and 214 to PBO. The median OS was 12.5 versus 11.8 months in the ADX and PBO groups, respectively. The median PFS was 7.5 versus 7.1 months in the ADX and PBO groups, respectively. The objective response rate was 51% in the ADX group and 41% in the PBO group. Among the subgroup analyses, patients of age ≥ 65 years had an improved OS and PFS with ADX versus PBO; the P values and CIs were not adjusted for multiplicity. There were no meaningful differences in the safety profile of the ADX versus PBO groups. CONCLUSION: The addition of ADX to mFOLFOX6 did not improve OS in unselected patients with untreated human epidermal growth factor receptor 2-negative gastric or GEJ adenocarcinoma.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Esophagogastric Junction/drug effects , Stomach Neoplasms/drug therapy , Adenocarcinoma/pathology , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/administration & dosage , Double-Blind Method , Esophagogastric Junction/pathology , Female , Fluorouracil/administration & dosage , Follow-Up Studies , Humans , Leucovorin/administration & dosage , Male , Middle Aged , Oxaliplatin/administration & dosage , Prognosis , Stomach Neoplasms/pathology , Survival Rate , Young AdultABSTRACT
BACKGROUND: Matrix metalloproteinase 9 (MMP9) expression in the tumor microenvironment is implicated in multiple protumorigenic processes. Andecaliximab (GS-5745), a monoclonal antibody targeting MMP9 with high affinity and selectivity, was evaluated in combination with gemcitabine and nab-paclitaxel in patients with advanced pancreatic adenocarcinoma. PATIENTS AND METHODS: This phase I study was completed in two parts: part A was a dose-finding, monotherapy phase that enrolled patients with advanced solid tumors, and part B examined andecaliximab in combination with chemotherapy in specific patient cohorts. In the cohort of patients with pancreatic adenocarcinoma (n = 36), andecaliximab 800 mg every 2 weeks was administered in combination with gemcitabine and nab-paclitaxel. Patients were treated until unacceptable toxicity, withdrawal of consent, disease progression, or death. Efficacy, safety, and biomarker assessments were performed. RESULTS: Andecaliximab combined with gemcitabine and nab-paclitaxel appeared to be well tolerated and did not demonstrate any unusual toxicities in patients with pancreatic adenocarcinoma. The most common treatment-emergent adverse events were fatigue (75.0%), alopecia (55.6%), peripheral edema (55.6%), and nausea (50.0%). Median progression-free survival was 7.8 months (90% confidence interval, 6.9-11.0) with an objective response rate of 44.4% and median duration of response of 7.6 months. Maximal andecaliximab target binding, defined as undetectable, andecaliximab-free MMP9 in plasma, was observed. CONCLUSION: Andecaliximab in combination with gemcitabine and nab-paclitaxel demonstrates a favorable safety profile and clinical activity in patients with advanced pancreatic adenocarcinoma. IMPLICATIONS FOR PRACTICE: The combination of andecaliximab, a novel, first-in-class inhibitor of matrix metalloproteinase 9, with gemcitabine and nab-paclitaxel in patients with advanced pancreatic adenocarcinoma provided a median progression-free survival of 7.8 months and objective response rate of 44.4%. The majority of systemic biomarkers related to matrix metalloproteinase 9 activity and immune suppression increased at 2 months, whereas biomarkers related to tumor burden decreased. Although this study demonstrates promising results with andecaliximab plus chemotherapy in patients with advanced pancreatic adenocarcinoma, andecaliximab was not associated with a survival benefit in a phase III study in patients with advanced gastric/gastroesophageal junction carcinoma.
Subject(s)
Adenocarcinoma , Pancreatic Neoplasms , Adenocarcinoma/drug therapy , Albumins , Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Deoxycytidine/analogs & derivatives , Humans , Paclitaxel/therapeutic use , Pancreatic Neoplasms/drug therapy , Treatment Outcome , Tumor Microenvironment , GemcitabineABSTRACT
Under extreme conditions or by genetic modification, pancreatic α-cells can regenerate and be converted into ß-cells. This regeneration holds substantial promise for cell replacement therapy in diabetic patients. The discovery of clinical therapeutic strategies to promote ß-cell regeneration is crucial for translating these findings into clinical applications. In this study, we reported that treatment with REMD 2.59, a human glucagon receptor (GCGR) monoclonal antibody (mAb), lowered blood glucose without inducing hypoglycemia in normoglycemic, streptozotocin-induced type 1 diabetic (T1D) and non-obesity diabetic mice. Moreover, GCGR mAb treatment increased the plasma glucagon and active glucagon-like peptide-1 levels, induced pancreatic ductal ontogenic α-cell neogenesis, and promoted α-cell proliferation. Strikingly, the treatment also increased the ß-cell mass in these two T1D models. Using α-cell lineage-tracing mice, we found that the neogenic ß-cells were likely derived from α-cell conversion. Therefore, GCGR mAb-induced α- to ß-cell conversion might represent a pre-clinical approach for improving diabetes therapy.
ABSTRACT
Mice were treated with a fully human monoclonal glucagon receptor antagonistic antibody REMD2.59 following myocardial infarction or pressure overload. REMD2.59 treatment blunted cardiac hypertrophy and fibrotic remodeling, and attenuated contractile dysfunction at 4 weeks after myocardial infarction. In addition, REMD2.59 treatment at the onset of pressure overload significantly suppressed cardiac hypertrophy and chamber dilation with marked preservation of cardiac systolic and diastolic function. Initiation of REMD2.59 treatment 2 weeks after pressure overload significantly blunted the progression of cardiac pathology. These results provide the first in vivo proof-of-concept evidence that glucagon receptor antagonism is a potentially efficacious therapy to ameliorate both onset and progression of heart failure.
ABSTRACT
BACKGROUND: In heart failure the myocardium becomes insulin resistant which negatively influences cardiac energy metabolism and function, while increasing cardiac insulin signalling improves cardiac function and prevents adverse remodelling in the failing heart. Glucagon's action on cardiac glucose and lipid homeostasis counteract that of insulin's action. We hypothesised that pharmacological antagonism of myocardial glucagon action, using a human monoclonal antibody (mAb A) against glucagon receptor (GCGR), a G-protein coupled receptor, will enhance insulin sensitivity and improve cardiac energy metabolism and function post myocardial infarction (MI). METHODS: Male C57BL/6 mice were subjected to a permanent left anterior descending coronary artery ligation to induce MI, following which they received either saline or mAb A (4 mg kg-1 week-1 starting at 1 week post-MI) for 3 weeks. RESULTS: Echocardiographic assessment at 4 weeks post-MI showed that mAb A treatment improved % ejection fraction (40.0 ± 2.3% vs 30.7 ± 1.7% in vehicle-treated MI heart, p < 0.05) and limited adverse remodelling (LV mass: 129 ± 7 vs 176 ± 14 mg in vehicle-treated MI hearts, p < 0.05) post MI. In isolated working hearts an increase in insulin-stimulated glucose oxidation was evident in the mAb A-treated MI hearts (1661 ± 192 vs 924 ± 165 nmol g dry wt-1 min-1 in vehicle-treated MI hearts, p < 0.05), concomitant with a decrease in ketone oxidation and fatty acid oxidation rates. The increase in insulin stimulated glucose oxidation was accompanied by activation of the IRS-1/Akt/AS160/GSK-3ß pathway, an increase in GLUT4 expression and a reduction in pyruvate dehydrogenase phosphorylation. This enhancement in insulin sensitivity occurred in parallel with a reduction in cardiac branched chain amino acids content (374 ± 27 vs 183 ± 41 µmol g protein-1 in vehicle-treated MI hearts, p < 0.05) and inhibition of the mTOR/P70S6K hypertrophic signalling pathway. The MI-induced increase in the phosphorylation of transforming growth factor ß-activated kinase 1 (p-TAK1) and p38 MAPK was also reduced by mAb A treatment. CONCLUSIONS: mAb A-mediated cardioprotection post-myocardial infarction is associated with improved insulin sensitivity and a selective enhancement of glucose oxidation via, at least in part, enhancing branched chain amino acids catabolism. Antagonizing glucagon action represents a novel and effective pharmacological intervention to alleviate cardiac dysfunction and adverse remodelling post-myocardial infarction.
Subject(s)
Antibodies, Monoclonal/pharmacology , Insulin Resistance , Myocardial Infarction/drug therapy , Myocardium/metabolism , Receptors, Glucagon/antagonists & inhibitors , Stroke Volume/drug effects , Ventricular Function, Left/drug effects , Animals , Blood Glucose/drug effects , Blood Glucose/metabolism , Disease Models, Animal , Energy Metabolism/drug effects , Isolated Heart Preparation , Male , Mice, Inbred C57BL , Myocardial Infarction/metabolism , Myocardial Infarction/physiopathology , Receptors, Glucagon/metabolism , Recovery of Function , Signal Transduction/drug effects , Ventricular Remodeling/drug effectsABSTRACT
The antidiabetic potential of glucagon receptor antagonism presents an opportunity for use in an insulin-centric clinical environment. To investigate the metabolic effects of glucagon receptor antagonism in type 2 diabetes, we treated Leprdb/db and Lepob/ob mice with REMD 2.59, a human monoclonal antibody and competitive antagonist of the glucagon receptor. As expected, REMD 2.59 suppresses hepatic glucose production and improves glycemia. Surprisingly, it also enhances insulin action in both liver and skeletal muscle, coinciding with an increase in AMP-activated protein kinase (AMPK)-mediated lipid oxidation. Furthermore, weekly REMD 2.59 treatment over a period of months protects against diabetic cardiomyopathy. These functional improvements are not derived simply from correcting the systemic milieu; nondiabetic mice with cardiac-specific overexpression of lipoprotein lipase also show improvements in contractile function after REMD 2.59 treatment. These observations suggest that hyperglucagonemia enables lipotoxic conditions, allowing the development of insulin resistance and cardiac dysfunction during disease progression.
Subject(s)
Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/physiopathology , Glucose/metabolism , Heart/physiopathology , Receptors, Glucagon/antagonists & inhibitors , Adenylate Kinase/metabolism , Animals , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/enzymology , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/enzymology , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/physiopathology , Diabetic Cardiomyopathies/complications , Diabetic Cardiomyopathies/pathology , Diabetic Cardiomyopathies/prevention & control , Disease Models, Animal , Enzyme Activation/drug effects , Gluconeogenesis/drug effects , Glucose Tolerance Test , Hyperglycemia/complications , Hyperglycemia/metabolism , Hyperglycemia/pathology , Insulin/pharmacology , Lipid Metabolism/drug effects , Lipids/toxicity , Liver/metabolism , Mice , Receptors, Glucagon/metabolismABSTRACT
The aim of the current study (Clinical trial reg. no. NCT02715193, clinicaltrials.gov) was to study the efficacy and safety of REMD-477, a glucagon receptor antagonist, in type 1 diabetes. This was a randomized controlled trial in which 21 patients with type 1 diabetes were enrolled. Glycaemic control and insulin use were evaluated in outpatient and inpatient settings, before and after a single 70-mg dose of REMD-477 (half-life 7-10 days) or placebo. Inpatient insulin use was 26% (95% CI, 47%, 4%) lower 1 day after dosing with REMD-477 than with placebo (P = .02). Continuous glucose monitoring during post-treatment days 6 to 12 showed that average daily glucose was 27 mg/dL lower (P < .001), percent time-in-target-range (70-180 mg/dL) was ~25% greater (~3.5 h/d) (P = .001), and percent time-in-hyperglycaemic-range (> 180 mg/dL) was ~40% lower (~4 h/d) (P = .001) in the REMD-477 group than in the placebo group, without a difference in percent time-in-hypoglycaemic-range (<70 mg/dL). No serious adverse events were reported. Glucagon receptor antagonism decreases insulin requirements and improves glycaemic control in patients with type 1 diabetes.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Diabetes Mellitus, Type 1/drug therapy , Hyperglycemia/prevention & control , Hypoglycemia/prevention & control , Hypoglycemic Agents/therapeutic use , Insulin/administration & dosage , Receptors, Glucagon/antagonists & inhibitors , Adult , Antibodies, Blocking/administration & dosage , Antibodies, Blocking/adverse effects , Antibodies, Blocking/therapeutic use , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal, Humanized , Blood Glucose/analysis , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 1/metabolism , Double-Blind Method , Drug Administration Schedule , Drug Therapy, Combination , Drugs, Investigational/adverse effects , Drugs, Investigational/therapeutic use , Female , Humans , Hypoglycemia/chemically induced , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/adverse effects , Injections, Subcutaneous , Insulin/therapeutic use , Male , Monitoring, Ambulatory , Proof of Concept Study , Receptors, Glucagon/metabolismABSTRACT
INTRODUCTION: Vietnam is a tropical country so fungal diseases including dermatophytosis may be prevalent, but epidemiological profiles of agents responsible for the infection have rarely been reported. OBJECTIVE: To find out the distribution of dermatophytes among patients living in a central province of Vietnam. METHODS: We examined dermatophyte infections in patients with lesions suspected of dermatophytosis referred to the Nghean provincial leprosy and dermatology centre from August 2015 to August 2016. The speciation of dermatophyte was performed by conventional and molecular approaches. RESULTS: One hundred and thirty-six patients (90 males and 46 females) were included. Those aged from 11 to 30 contribute 59.1%. The most common agent found was Trichophyton rubrum (66.9%), followed by T. interdigitale (12.5%), T. tonsurans (9.6%), Microsporum incurvatum (8.1%), and the less frequent species were M. canis (2.2%) and T. violaceum (0.7%). Epidermophyton floccosum was not reported. T. rubrum were more common in men (74.4%) than in women (52.2%), while T. interdigitale and M. incurvatum were more common in women (21.7 and 15.2%) than in men (7.8 and 4.4%). Patients infected with Microsporum spp. had small-sized lesions for only 3 months, while those affected by Trichophyton spp. had large-sized lesions with longer duration. CONCLUSION: Trichophyton species are the predominant agents of infection in Nghean province, while Epidermophyton species is absent. Additional investigations are required to clarify the epidemiological profile of dermatophytes in Vietnam.
Subject(s)
Arthrodermataceae/isolation & purification , Dermatomycoses/epidemiology , Microsporum/isolation & purification , Trichophyton/isolation & purification , Adolescent , Adult , Child , Dermatomycoses/microbiology , Epidermophyton , Female , Humans , Male , Microsporum/classification , Skin/microbiology , Trichophyton/classification , Tropical Climate , Vietnam/epidemiology , Young AdultABSTRACT
We have identified a new role for the matrix enzyme lysyl oxidase-like-2 (LOXL2) in the creation and maintenance of the pathologic microenvironment of cancer and fibrotic disease. Our analysis of biopsies from human tumors and fibrotic lung and liver tissues revealed an increase in LOXL2 in disease-associated stroma and limited expression in healthy tissues. Targeting LOXL2 with an inhibitory monoclonal antibody (AB0023) was efficacious in both primary and metastatic xenograft models of cancer, as well as in liver and lung fibrosis models. Inhibition of LOXL2 resulted in a marked reduction in activated fibroblasts, desmoplasia and endothelial cells, decreased production of growth factors and cytokines and decreased transforming growth factor-beta (TGF-beta) pathway signaling. AB0023 outperformed the small-molecule lysyl oxidase inhibitor beta-aminoproprionitrile. The efficacy and safety of LOXL2-specific AB0023 represents a new therapeutic approach with broad applicability in oncologic and fibrotic diseases.
Subject(s)
Amino Acid Oxidoreductases/antagonists & inhibitors , Amino Acid Oxidoreductases/drug effects , Amino Acid Oxidoreductases/genetics , Amino Acid Oxidoreductases/metabolism , Aminopropionitrile/pharmacology , Animals , Antibodies, Monoclonal/pharmacology , Breast Neoplasms/pathology , Cell Line, Tumor , Female , Humans , Lactones/pharmacology , Mice , Mice, Nude , Neoplasm Metastasis/pathology , Neoplasm Metastasis/prevention & control , Polyenes/pharmacology , RNA, Small Interfering/genetics , Transcription, Genetic , Transfection , Transplantation, HeterologousABSTRACT
Particularly in small brain biopsies, it might be difficult to distinguish reactive astrogliosis from low-grade or infiltration zones of high-grade astrocytomas. So far no immunohistochemical marker allows a reliable distinction. Recently, the over-expression of Wilms' tumor gene product WT1 was reported in astrocytic tumor cells. However, no sufficient data on WT1 expression in normal or reactive astrocytes are available. Therefore, we investigated WT1 expression in paraffin-embedded brain sections from 28 controls, 48 cases with astrogliosis of various etiology and 219 astrocytomas [World Health Organization (WHO) grades I-IV] by immunohistochemistry. In normal brains and in astrogliosis, expression of WT1 was restricted to endothelial cells. In astrocytomas, WT1-positive tumor cells were found in pilocytic astrocytomas (66.7% of cases), diffuse astrocytomas (52.7%) WHO grade II (52.7%), anaplastic astrocytomas (83.4%) and glioblastomas (98.1%). Overall, the majority of all astrocytic neoplasms (84.5%) expressed WT1. Establishing a cut-off value of 0% immunoreactive tumor cells served to recognize neoplastic astrocytes with 100% specificity and 68% sensitivity and was associated with positive and negative predictive values of 1 and 0.68, respectively. Therefore, WT1 expression in astrocytes indicates a neoplastic origin and might represent an important diagnostic tool to differentiate reactive from neoplastic astrocytes by immunohistochemistry.
Subject(s)
Astrocytes/metabolism , Astrocytoma/metabolism , Brain Neoplasms/metabolism , Gliosis/metabolism , WT1 Proteins/biosynthesis , Adult , Aged , Astrocytes/pathology , Astrocytoma/pathology , Biomarkers, Tumor/analysis , Brain Neoplasms/pathology , Endothelial Cells/metabolism , Female , Gene Expression , Gliosis/pathology , Humans , Immunohistochemistry , Male , Middle AgedABSTRACT
Long wavelength voltage-sensitive dyes (VSDs) called Pittsburgh (PGH) dyes were recently synthesized by coupling various heterocyclic groups to a styryl-thiophene intermediate forming extended, partially rigid chromophores. Unlike most styryl VSDs, dyes with a sulfonic acid anchor directly attached to the chromophore showed no solvatochromic absorption shifts. The limited water solubility of many long wavelength VSDs requires the use of surfactants to transport the dye through physiological saline solutions and effectively label biological membranes. Here, we tested the chemical substitution of the sulfonic acid moiety with polyethyleneglycol (PEG) chains, ranging from MW 750 to 5000, to overcome the poor solubility of VSDs while retaining their properties as VSDs. The chemical synthesis of PGH dyes and their PEG derivatives are described. The PEG derivatives were soluble in aqueous solutions (>1 mM) and still reported membrane potential changes. In frog and mouse hearts, the voltage sensitivity (DeltaF/F per action potential) and spectral properties of PEG dyes were the same as the sulfonated analogues. Thus, the solubility of VSDs can be considerably improved with small polyethyleneglycol chains and can provide an effective approach to improve staining of excitable tissues and optical recordings of membrane potential.
Subject(s)
Coloring Agents/chemistry , Polyethylene Glycols/chemistry , Sulfonic Acids/chemistry , Water/chemistry , Electricity , SolubilityABSTRACT
BACKGROUND: Gamma-hydroxybutyrate (GHB) is a common drug of abuse that can produce serious toxicity, particularly when used with other sedatives. We examined the individual and combined effects of GHB and ethanol in human volunteers. METHODS: Sixteen healthy adults (7 men) were given 50 mg/kg GHB (Xyrem), 0.6 g/kg ethanol in 2 doses, alone and combined in a double-blind, placebo-controlled, crossover study. Plasma concentrations, heart rate (HR), blood pressure (BP), and oxygen saturation (O2sat) were serially monitored for 24 hours. RESULTS: Adverse events included 2 instances of hypotension and 6 episodes of vomiting with GHB-plus-ethanol ingestion. Oxygen saturation was decreased by GHB and ethanol individually, and maximally decreased by the drugs combined (max -2.1% +/- 0.3%, P < 0.0001 vs placebo). Compared with baseline, systolic and diastolic BP were significantly decreased, and HR was increased by ethanol but not affected by GHB alone (maximum systolic BP change -15.7 +/- 3.0 mm Hg, P = 0.0006; maximum HR change 13.5 +/- 2.3 beats per minute, P = 0.006). Ethanol coingestion resulted in 16% higher GHB maximal plasma concentration and 29% longer elimination half-life, indicating possible enhanced bioavailability or reduced clearance of GHB caused by ethanol, however, these effects were not statistically significant. CONCLUSIONS: Modest doses of GHB do not affect hemodynamic function, but O2sat was decreased. Gamma-hydroxybutyrate-plus-ethanol resulted in more adverse effects, including gastrointestinal disturbances, hypotension, and decreased O2sat, but only minimal pharmacokinetic interactions were observed.
Subject(s)
Central Nervous System Depressants/pharmacology , Ethanol/pharmacology , Sodium Oxybate/pharmacology , Adult , Blood Pressure/drug effects , Central Nervous System Depressants/adverse effects , Central Nervous System Depressants/blood , Central Nervous System Depressants/pharmacokinetics , Cross-Over Studies , Double-Blind Method , Drug Interactions , Ethanol/adverse effects , Ethanol/blood , Ethanol/pharmacokinetics , Female , Heart Rate/drug effects , Humans , Male , Oxygen/blood , Reference Values , Skin Temperature/drug effects , Sodium Oxybate/adverse effects , Sodium Oxybate/blood , Sodium Oxybate/pharmacokinetics , Vomiting/chemically inducedABSTRACT
Gamma-hydroxybutyric acid (GHB) is used as an illicit drug and is implicated in drug-facilitated sexual assault, but it also has some therapeutic uses. Detection of GHB in urine is important for forensic testing and could be of clinical benefit in overdose management. Urine GHB concentration-time profiles have not been well-characterized or correlated with doses used therapeutically. GHB levels were measured by gas chromatography-mass spectrometry in urine collected over 24 h from 16 adults administered single doses of 50 mg/kg GHB (Xyrem) alone and combined with 0.6 g/kg ethanol. Peak GHB urine concentrations averaged 150-200 mg/L and occurred in the 0-3 h urine collection. Significant variability in GHB urine levels between individuals was observed. Caucasians had lower urine concentrations than other races/ethnicities (p = 0.03). Men had lower GHB levels than women in the first 3 h after dosing (p = 0.038). Coingestion of ethanol did not significantly affect renal clearance of GHB, but urine GHB concentrations were lower in the first 3 h when ethanol and GHB were coingested (p = 0.039). At a proposed cut-off of 10 mg/L to distinguish endogenous versus exogenous GHB levels, 12.5% of the samples collected from 3 to 6 h, 81.3% of samples collected from 6 to 12 h, and 100% of urine specimens collected from 12 to 24 h were below this level. We conclude that the detection time for GHB in urine may be shorter than the previously reported 12-h window in some people taking therapeutic doses of GHB.