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Clinical and Experimental Allergy :... Feb 2020GB001 is an oral antagonist of the prostaglandin D2 receptor that may inhibit recruitment and activation of airway eosinophils, reducing airway inflammation. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
GB001 is an oral antagonist of the prostaglandin D2 receptor that may inhibit recruitment and activation of airway eosinophils, reducing airway inflammation.
OBJECTIVE
To assess GB001 safety, efficacy and pharmacokinetics from a Phase 2 study and explore the association between type 2 biomarkers (fractional exhaled nitric oxide and blood eosinophils) and asthma control markers following GB001 administration.
METHODS
A randomized, placebo-controlled, double-blind study evaluating 36 patients with mild-to-moderate atopic asthma. Patients receiving fluticasone propionate ≤500 mcg/day or equivalent were randomized (2:1) to GB001 (30 mg) or placebo once daily for 28 days. Safety, pharmacokinetics, forced expiratory volume in 1 second, asthma control questionnaire and rescue medication use were assessed. Clinical outcomes were analysed post hoc by baseline fractional exhaled nitric oxide (<35 and ≥35 ppb) and blood eosinophil (<250 and ≥250 cells/µL) subgroups.
RESULTS
GB001 was well tolerated and rapidly absorbed with a 14.5-hour terminal half-life. Overall, GB001 demonstrated greater improvement relative to placebo in forced expiratory volume in 1 second at Day 28 (102 mL [95% CI: -110, 314]). Greater effects on forced expiratory volume in 1 second were observed in the high baseline fractional exhaled nitric oxide and blood eosinophil subgroups (207 mL [95% CI: -283, 698];133 mL [95% CI: -422, 687], respectively). These effects were observed as early as Day 2 (229 mL [95% CI: -170, 628]; 163 mL [95% CI: -223, 550] for the high baseline fractional exhaled nitric oxide and blood eosinophil subgroups, respectively) and were sustained through treatment completion.
CONCLUSION AND CLINICAL RELEVANCE
GB001 was well tolerated, with the estimated half-life supporting once-daily (QD) dosing. GB001 may have a rapid and sustained effect on lung function, particularly in patients with type 2 phenotype. Further studies are needed to confirm these findings.
Topics: Adolescent; Adult; Anti-Asthmatic Agents; Asthma; Biomarkers; Breath Tests; Double-Blind Method; Female; Humans; Male; Middle Aged; Receptors, Immunologic; Receptors, Prostaglandin
PubMed: 31659803
DOI: 10.1111/cea.13524 -
Molecular Human Reproduction Jan 2021Non-hormonal therapeutic strategies for endometriosis are needed. The aim of this study was to characterize the effects of prostaglandin (PG)E2 receptor inhibitors to...
Non-hormonal therapeutic strategies for endometriosis are needed. The aim of this study was to characterize the effects of prostaglandin (PG)E2 receptor inhibitors to explore their potential as novel therapeutic strategies for endometriosis. The expression of PGE2 receptors (EP2 and EP4) in donated tissues from human ovarian endometriosis, adenomyosis and peritoneal endometriosis was examined using immunohistochemistry. Human endometriotic stromal cells (ESC) isolated from ovarian endometriotic tissue and peritoneal macrophages were treated with EP2 and EP4 antagonists. cAMP accumulation and the effect of EP antagonists were measured using cAMP assays. DNA synthesis in ESC was detected using bromodeoxyuridine incorporation analysis. Interleukin (IL)-6 and IL-8 protein levels in ESC supernatants were measured using ELISAs. mRNA expression level for aromatase by ESC, and selected cytokines by peritoneal macrophages was measured using RT-PCR. EP2 and EP4 receptors were expressed in cells derived from control and diseased tissue, ovarian endometriotic, adenomyotic and peritoneal lesions. A selective EP2 antagonist reduced DNA synthesis, cAMP accumulation and IL-1β-induced proinflammatory cytokine secretion and aromatase expression. A selective EP4 antagonist negated IL-1β-induced IL-6 secretion and aromatase expression. In peritoneal macrophages, EP expression was elevated in endometriosis samples but the EP4 antagonist reduced cAMP levels and expression of vascular endothelial growth factor, chemokine ligand 2 and chemokine ligand 3 mRNA. EP2 and EP4 are functioning in endometriosis lesions and peritoneal macrophages, and their selective antagonists can reduce EP-mediated actions, therefore, the EP antagonists are potential therapeutic agents for controlling endometriosis.
Topics: Adult; Azetidines; Benzamides; Cells, Cultured; Chemokines; Cyclic AMP; DNA Replication; Endometriosis; Endometrium; Female; Humans; Macrophages, Peritoneal; Protein Biosynthesis; Real-Time Polymerase Chain Reaction; Receptors, Prostaglandin; Receptors, Prostaglandin E, EP2 Subtype; Receptors, Prostaglandin E, EP4 Subtype; Stromal Cells
PubMed: 33543288
DOI: 10.1093/molehr/gaaa077 -
American Journal of Physiology. Renal... Apr 2021Local or systemic inflammation can severely impair urinary bladder functions and contribute to the development of voiding disorders in millions of people worldwide.... (Review)
Review
Local or systemic inflammation can severely impair urinary bladder functions and contribute to the development of voiding disorders in millions of people worldwide. Isoprostanes are inflammatory lipid mediators that are upregulated in the blood and urine by oxidative stress and may potentially induce detrusor overactivity. The aim of the present study was to investigate the effects and signal transduction of isoprostanes in human and murine urinary bladders in order to provide potential pharmacological targets in detrusor overactivity. Contraction force was measured with a myograph in murine and human urinary bladder smooth muscle (UBSM) ex vivo. Isoprostane 8-iso-PGE and 8-iso-PGF evoked dose-dependent contraction in the murine UBSM, which was abolished in mice deficient in the thromboxane prostanoid (TP) receptor. The responses remained unaltered after removal of the mucosa or incubation with tetrodotoxin. Smooth muscle-specific deletion of Gα protein or inhibition of Rho kinase by Y-27632 decreased the contractions. In Gα-knockout mice, responses were reduced and in the presence of Y-27632 abolished completely. In human UBSM, the TP agonist U-46619 evoked dose-dependent contractions. Neither atropine nor the purinergic receptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid decreased the effect, indicating that TP receptors directly mediate detrusor muscle contraction. 8-iso-PGE and 8-iso-PGF evoked dose-dependent contraction in the human UBSM, and these responses were abolished by the TP antagonist SQ-29548 and were decreased by Y-27632. Our results indicate that isoprostanes evoke contraction in murine and human urinary bladders, an effect mediated by the TP receptor. The G-Rho-Rho kinase pathway plays a significant role in mediating the contraction and therefore may be a potential therapeutic target in detrusor overactivity. Voiding disorders affect millions of people worldwide. Inflammation can impair urinary bladder functions and contribute to the development of detrusor overactivity. The effects and signal transduction of inflammatory lipid mediator isoprostanes were studied in human and murine urinary bladders ex vivo. We found that isoprostanes evoke contraction, an effect mediated by thromboxane prostanoid receptors. The G-Rho-Rho kinase signaling pathway plays a significant role in mediating the contraction and therefore may be a potential therapeutic target.
Topics: Animals; Humans; Isoprostanes; Muscle, Smooth, Vascular; Prostaglandin Antagonists; Prostaglandins; Receptors, Prostaglandin; Receptors, Thromboxane
PubMed: 33491563
DOI: 10.1152/ajprenal.00400.2020 -
Journal of the American Heart... Nov 2019Background Muscular dystrophy (MD) causes a progressive cardiomyopathy characterized by diffuse fibrosis, arrhythmia, heart failure, and early death. Activation of the...
Background Muscular dystrophy (MD) causes a progressive cardiomyopathy characterized by diffuse fibrosis, arrhythmia, heart failure, and early death. Activation of the thromboxane-prostanoid receptor (TPr) increases calcium transients in cardiomyocytes and is proarrhythmic and profibrotic. We hypothesized that TPr activation contributes to the cardiac phenotype of MD, and that TPr antagonism would improve cardiac fibrosis and function in preclinical models of MD. Methods and Results Three different mouse models of MD (mdx/utrn double knockout, second generation mdx/mTR double knockout, and delta-sarcoglycan knockout) were given normal drinking water or water containing 25 mg/kg per day of the TPr antagonist ifetroban, beginning at weaning. After 6 months (10 weeks for mdx/utrn double knockout), mice were evaluated for cardiac and skeletal muscle function before euthanization. There was a 100% survival rate of ifetroban-treated mice to the predetermined end point, compared with 60%, 43%, and 90% for mdx/utrn double knockout, mdx/mTR double knockout, and delta-sarcoglycan knockout mice, respectively. TPr antagonism improved cardiac output in mdx/utrn double knockout and mdx/mTR mice, and normalized fractional shortening, ejection fraction, and other parameters in delta-sarcoglycan knockout mice. Cardiac fibrosis in delta-sarcoglycan knockout was reduced with TPr antagonism, which also normalized cardiac expression of claudin-5 and neuronal nitric oxide synthase proteins and multiple signature genes of Duchenne MD. Conclusions TPr antagonism reduced cardiomyopathy and spontaneous death in mouse models of Duchenne and limb-girdle MD. Based on these studies, ifetroban and other TPr antagonists could be novel therapeutics for treatment of the cardiac phenotype in patients with MD.
Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Cardiomyopathies; Disease Models, Animal; Female; Male; Mice; Mice, Inbred mdx; Mice, Knockout; Muscular Dystrophy, Duchenne; Oxazoles; Prostaglandin Antagonists; Random Allocation; Receptors, Thromboxane
PubMed: 31662020
DOI: 10.1161/JAHA.118.011902 -
Arthritis Research & Therapy Apr 2019Lupus nephritis (LN) is a representative manifestation in systemic lupus erythematosus (SLE). Some studies have shown that myeloid-derived suppressor cells (MDSCs) play...
INTRODUCTION
Lupus nephritis (LN) is a representative manifestation in systemic lupus erythematosus (SLE). Some studies have shown that myeloid-derived suppressor cells (MDSCs) play a vital role in the regulation of the SLE process. MDSC infiltration in the kidney as well as inflammation and oxidative stress provokes the acceleration and deterioration of LN. Nuclear factor E2-related factor 2 (Nrf2) is thought to be a major regulator of the antioxidant response. Baicalein is a flavonoid with known anti-inflammatory effects and antioxidant response. However, the effects of baicalein on MDSCs, inflammation, and oxidative stress are not evaluated in the development of pristane-induced LN in mice.
METHODS
The renoprotective effect of baicalein was detected in a pristane-induced lupus mice model. NLRP3 inflammasome activation and NF-κB phosphorylation as well as reactive oxygen species (ROS) production and Nrf2 activation were examined. The percentages and function changes of MDSCs were measured. The possible mechanisms of the underlying effects of baicalein on ROS production and signaling pathways of Nrf2/heme-oxygenase (HO)-1, NLRP3 inflammasome, and NF-κB phosphorylation in lipopolysaccharide (LPS)-primed MDSCs were analyzed.
RESULTS
Baicalein reduced proteinuria and attenuated renal function impairment and renal histopathology including intrinsic cell proliferation, cellular crescents, and podocyte injury as well as glomerulonephritis activity in lupus mice. Moreover, baicalein downregulated the activation of NLRP3 inflammasome and levels of ROS or NF-κB phosphorylation, and it enhanced Nrf2 activation. Of note, baicalein inhibited the expansion of MDSCs and improved the function of MDSCs in lupus mice. Through analyzing LPS-primed MDSCs in vitro, baicalein was found to exhibit cytoprotective effects coincident with the induction of Nrf2/HO-1 signaling and the suppression of the NLRP3 inflammasome.
CONCLUSION
The data show that baicalein alleviates the symptoms of pristane-induced LN and suggest that the alleviation may be attributed to inhibition of MDSC expansion and regulation of the balance of the Nrf2/HO-1 signal and NLRP3 expression in MDSCs.
Topics: Animals; Dose-Response Relationship, Drug; Female; Flavanones; Heme Oxygenase-1; Immunosuppressive Agents; Lupus Nephritis; Membrane Proteins; Mice; Mice, Inbred BALB C; Myeloid-Derived Suppressor Cells; NF-E2-Related Factor 2; Prostaglandin Antagonists; Reactive Oxygen Species; Terpenes
PubMed: 31023362
DOI: 10.1186/s13075-019-1876-0 -
Journal of Neuroimmune Pharmacology :... Mar 2013Multiple lines of evidence indicate that regional brain eicosanoid signaling is important in initiation and progression of neurodegenerative conditions that have... (Review)
Review
Multiple lines of evidence indicate that regional brain eicosanoid signaling is important in initiation and progression of neurodegenerative conditions that have neuroinflammatory pathologic component, such as AD. We hypothesized that PGE(2) receptor subtype 1 (EP1) signaling (linked to intracellular Ca(2+) release) regulates Aβ peptide neurotoxicity and tested this in two complementary in vitro models: a human neuroblastoma cell line (MC65) producing Aβ(1-40) through conditional expression of the APP C-terminal portion, and murine primary cortical neuron cultures exposed to Aβ(1-42). In MC65 cells, EP1 receptor antagonist SC-51089 reduced Aβ neurotoxicity ~50 % without altering high molecular weight Aβ immunoreactive species formation. Inositol-3-phosphate receptor antagonist 2-aminoethoxy-diphenyl borate offered similar protection. SC-51089 largely protected the neuron cultures from synthetic Aβ(1-42) neurotoxicity. Nimodipine, a Ca(2+) channel blocker, was completely neuroprotective in both models. Based on these data, we conclude that suppressing neuronal EP1 signaling may represent a promising therapeutic approach to ameliorate Aβ peptide neurotoxicity.
Topics: Amyloid beta-Peptides; Animals; Blotting, Western; Calcium Channel Blockers; Cell Line, Tumor; Cells, Cultured; Coloring Agents; Dinoprostone; Humans; Hydrazines; Mice; Mice, Inbred C57BL; Neurons; Neurotoxicity Syndromes; Nimodipine; Oxazepines; Peptide Fragments; Prostaglandin Antagonists; Receptors, Prostaglandin E, EP1 Subtype; Tetrazolium Salts; Thiazoles
PubMed: 22718277
DOI: 10.1007/s11481-012-9380-1 -
British Journal of Clinical Pharmacology Jul 2019To investigate presence or absence of clinically relevant drug interactions (pharmacokinetic and safety/tolerability) of OBE022 with standard-of-care medicines for... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
To investigate presence or absence of clinically relevant drug interactions (pharmacokinetic and safety/tolerability) of OBE022 with standard-of-care medicines for preterm labour, enabling coadministration and further clinical development.
METHODS
Part A: open-label, randomized, 3-period crossover assessing coadministration of single doses of OBE022 (1100 mg) and MgSO . Part B: open-label, single-sequence crossover assessing the interactions following administration of OBE022 (1000 mg/day) at steady state coadministered with single doses of atosiban, nifedipine and betamethasone. Twenty-five healthy nonpregnant women of reproductive age were enrolled (Part A: n = 12; Part B: n = 13).
RESULTS
OBE022, alone or in combination with standard-of-care medications, was well tolerated. Headache and dizziness were the most frequently reported adverse events; dizziness occurred more often with the nifedipine/OBE022 combination. There were no clinically significant pharmacokinetic interactions when coadministered with MgSO . Co-administration had no notable effect on atosiban exposure. Atosiban reduced exposure to OBE002 (peak concentration [C ] 22%, area under the concentration-time curve [AUC] 19%). Coadministration with betamethasone slightly increased betamethasone exposure (C + 18%, AUC +27%) and OBE002 exposure (C + 35%, AUC +15%). These changes were not considered clinically significant. Coadministration with nifedipine slightly increased OBE002 exposure (C + 29%, AUC +24%) and markedly increased nifedipine exposure (C by 2-fold and AUC by 2-fold), which may be clinically significant.
CONCLUSIONS
The use of OBE022, a PGF2α antagonist prodrug, in combination with standard-of-care medicines may provide new treatment alternatives for preterm labour. All tested combinations were well tolerated. Nifedipine doses could potentially be reduced or staggered when coadministered with OBE022.
Topics: Adolescent; Adult; Area Under Curve; Betamethasone; Cross-Over Studies; Drug Interactions; Esters; Female; Humans; Magnesium Sulfate; Middle Aged; Nifedipine; Receptors, Prostaglandin; Sulfones; Thiazolidines; Tocolytic Agents; Vasotocin; Young Adult
PubMed: 30891820
DOI: 10.1111/bcp.13925 -
Birth Defects Research. Part C, Embryo... Dec 2013Fetal circulation has characteristic features, being morphologically and functionally different from extrauterine circulation. The ductus arteriosus plays a fundamental... (Review)
Review
Fetal circulation has characteristic features, being morphologically and functionally different from extrauterine circulation. The ductus arteriosus plays a fundamental role in directing the blood flow to fetal inferior body parts. Basically, the ductus arteriosus directs 80-85% of the right ventricular output arising from the superior vena cava, coronary sinus, and a small part from the inferior vena cava to descending aorta. Its histological structure is made up predominantly by a thick muscular layer, differently from the aorta and the pulmonary artery, which increases with gestational age. The fibers have a circumferential orientation, especially at the external layers, facilitating and making effective ductal constriction. These factors may generate lumen alterations which may cause fetal and neonatal complications, such as heart failure, hydrops, neonatal pulmonary hypertension, and even death. Classically, maternal administration of indomethacin and/or other antiinflammatory drugs interfere in prostaglandins metabolism, causing ductal constriction. However, many cases of fetal ductal constriction, as well as of persistent neonatal pulmonary artery hypertension, remain without an established etiology, being referred as "idiopathic." In recent years, a growing body of evidence has shown that herbs, fruits, nuts, and a wide diversity of substances commonly used in daily diets have definitive effects upon the metabolic pathway of inflammation, with consequent inhibition of prostaglandins synthesis. This antiinflammatory action, especially of polyphenols, when ingested during the third trimester of pregnancy, may influence the dynamics of fetal ductus arteriosus flow. The goal of this review is to present these new observations and findings, which may influence dietary orientation during pregnancy.
Topics: Constriction; Diet; Ductus Arteriosus; Female; Fetus; Humans; Indomethacin; Maternal Exposure; Polyphenols; Pregnancy; Pregnancy Trimester, Third; Prenatal Exposure Delayed Effects; Prostaglandin Antagonists; Randomized Controlled Trials as Topic
PubMed: 24339037
DOI: 10.1002/bdrc.21051 -
Proceedings of the Royal Society of... Sep 1973
Topics: Animals; Arthritis, Rheumatoid; Aspirin; Colic; Complement System Proteins; Glomerular Filtration Rate; Glomerulonephritis; Gold; Hematuria; Hexosephosphates; Humans; Hypertension; Immunoglobulin G; Kidney Diseases; Nephrotic Syndrome; Penicillamine; Peptic Ulcer; Phenacetin; Prostaglandin Antagonists; Proteinuria; Rats; Urinary Tract Infections
PubMed: 4805093
DOI: No ID Found -
Biological & Pharmaceutical Bulletin 2011The prophylactic use of anti-allergic drugs has been proposed to be effective in the treatment of seasonal allergic rhinitis in humans. However, there is little...
Prophylactic effects of the histamine H1 receptor antagonist epinastine and the dual thromboxane A2 receptor and chemoattractant receptor-homologous molecule expressed on Th2 cells antagonist ramatroban on allergic rhinitis model in mice.
The prophylactic use of anti-allergic drugs has been proposed to be effective in the treatment of seasonal allergic rhinitis in humans. However, there is little information regarding the prophylactic effect of thromboxane A(2) (TXA(2)) receptor antagonist on allergic rhinitis. Recent studies revealed that a TXA(2) receptor antagonist ramatroban could block the prostaglandin D(2) (PGD(2)) receptor and chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). In the present study, we investigated the prophylactic effects of the histamine H(1) receptor antagonist epinastine and the TXA(2) receptor antagonist ramatroban and seratrodast on mouse models of allergic rhinitis. Female BALB/c mice were sensitized by an intraperitoneal injection of ovalbumin and alum on days 0, 5, 14 and 21. Seven days later, mice were sensitized by intranasal application of ovalbumin thrice a week. Drugs were administered once a day from day 22. The severity of allergic rhinitis was assessed by determining the extent of 2 nasal allergic symptoms (sneezing and nasal rubbing). Histamine sensitivity and eosinophil infiltration into the nasal mucosa were also determined. Epinastine and ramatroban significantly reduced nasal symptoms and the number of eosinophils in the nasal mucosa. Seratrodast showed no effect on nasal symptoms and eosinophil infiltration into the nasal mucosa. In addition, histamine sensitivity was reduced by epinastine and ramatroban. These results indicate that epinastine and ramatroban induce the prophylactic effect on allergic rhinitis.
Topics: Animals; Anti-Allergic Agents; Behavior, Animal; Benzoquinones; Carbazoles; Dibenzazepines; Disease Models, Animal; Eosinophils; Female; Heptanoic Acids; Histamine; Histamine H1 Antagonists; Imidazoles; Mice; Mice, Inbred BALB C; Nasal Mucosa; Prostaglandin Antagonists; Receptors, Immunologic; Receptors, Prostaglandin; Receptors, Thromboxane A2, Prostaglandin H2; Rhinitis, Allergic, Seasonal; Severity of Illness Index; Sneezing; Sulfonamides; Th2 Cells
PubMed: 21467637
DOI: 10.1248/bpb.34.507