ono-1301 and Disease-Models--Animal

Transplanting human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) tissue sheets effectively treat ischemic cardiomyopathy. Cardiac functional recovery relies on graft survival in which angiogenesis played an important part. ONO-1301 is a synthetic prostacyclin analog with proangiogenic effects. We hypothesized that transplantation of hiPSC-CM tissue sheets with slow-release ONO-1301 scaffold could promote hostgraft angiogenesis, enhance tissue survival and therapeutic effect.. We developed hiPSC-CM tissue sheets with ONO-1301 slow-release scaffold and evaluated their morphology, gene expression, and effects on angiogenesis. Three tissue sheet layers were transplanted into a rat myocardial infarction (MI) model. Left ventricular ejection fraction, gene expression in the MI border zone, and angiogenesis effects were investigated 4 weeks after transplantation.. In vitro assessment confirmed the slow-release of ONO-1301, and its pro-angiogenesis effects. In addition, in vivo data demonstrated that ONO-1301 administration positively correlated with graft survival. Cardiac tissue as thick as ∼900 μm was retained in the ONO (+) treated group. Additionally, left ventricular ejection fraction of the ONO (+) group was significantly enhanced, compared to ONO (-) group. The ONO (+) group also showed significantly improved interstitial fibrosis, higher capillary density, increased number of mature blood vessels, along with an enhanced supply of oxygen, and nutrients.. Slow-release ONO-1301 scaffold provided an efficient delivery method for thick hiPSC-CM tissue. ONO-1301 promotes angiogenesis between the host and graft and improves nutritional and oxygen supply, thereby enhancing the survival of transplanted cells, effectively improving ejection fraction, and therapeutic effects.

Topics: Angiogenesis Inducing Agents; Animals; Disease Models, Animal; Humans; Induced Pluripotent Stem Cells; Myocardial Infarction; Myocytes, Cardiac; Rats; Stroke Volume; Ventricular Function, Left

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by several pathologies including oxidative stress, apoptosis, neuroinflammation, and glutamate toxicity. Although multiple reports suggest that ischemia and hypoxia in the spinal cord plays a pivotal role in the pathogenesis of ALS, the precise role of hypoxia in disease progression remains unknown. In this study, we detected higher expression levels of Hypoxia-inducible factor 1-alpha (HIF-1α), a key regulator of cellular responses to hypoxia, in the spinal cord of ALS patients and in the transgenic mice overexpressing the familial ALS-associated G93A SOD1 mutation (mSOD1

Topics: Adenosine Triphosphate; Amyotrophic Lateral Sclerosis; Animals; Blotting, Western; Disease Models, Animal; Epoprostenol; Immunohistochemistry; Male; Mice; Mice, Inbred C57BL; Motor Neurons; Pyridines

We hypothesized that therapeutic efficacy may be augmented by a combination of placing a sheet immersed in ONO-1301SR, a slow-release synthetic prostacyclin agonist-inducing multiproangiogenic cytokines, over the left ventricle and a pedicled omental flap in a chronic myocardial infarct heart.. A minipig chronic myocardial infarction was generated by placing an ameroid constrictor ring around the left anterior descending artery for 4 weeks. The minipigs were then assigned into 4 groups of 6 each: sham, omental flap only, ONO-1301SR only, and ONO-1301SR combined with an omental flap (combined). Four weeks after treatment, therapeutic efficacy was evaluated histologically and via several modalities used in the clinical setting.. In an angiogram and pressure wire study, the combined group induced development of collateral arteries to decrease the resistance and increase the flow reserve of microvasculature in the left circumflex territory. In a. ONO-1301SR combined with a pedicled omental flap synergistically promoted myocardial angiogenesis, leading to function recovery in a porcine chronic myocardial infarction model.

Topics: Angiogenic Proteins; Animals; Combined Modality Therapy; Coronary Circulation; Coronary Vessels; Delayed-Action Preparations; Disease Models, Animal; Microcirculation; Microvessels; Myocardial Ischemia; Neovascularization, Physiologic; Omentum; Pyridines; Recovery of Function; Signal Transduction; Surgical Flaps; Swine; Swine, Miniature; Time Factors; Ventricular Function, Left

Diabetic nephropathy is the most common pathological disorder predisposing patients to end-stage renal disease. Considering the increasing prevalence of type 2 diabetes mellitus worldwide, novel therapeutic approaches are urgently needed. ONO-1301 is a novel sustained-release prostacyclin analog that inhibits thromboxane A2 synthase. Here we examined the therapeutic effects of the intermittent administration of slow-release ONO-1301 (SR-ONO) on diabetic nephropathy in obese type 2 diabetes mice, as well as its direct effects on mesangial cells. The subcutaneous injection of SR-ONO (3mg/kg) every 3 wks did not affect the obesity or hyperglycemia in the db/db obese mice used as a model of type 2 diabetes, but it significantly ameliorated their albuminuria, glomerular hypertrophy, glomerular accumulation of type IV collagen, and monocyte/macrophage infiltration, and also the increase of TGF-β1, α-smooth muscle actin (α-SMA) and MCP-1 compared to vehicle treatment. In cultured mouse mesangial cells, ONO-1301 concentration-dependently suppressed the increases in TGF-β, type IV collagen, α-SMA, MCP-1 and fibronectin induced by high ambient glucose, at least partly through prostacyclin (PGI2) receptor-mediated signaling. Taken together, these results suggest the potential therapeutic efficacy of the intermittent administration of SR-ONO against type 2 diabetic nephropathy, possibly through protective effects on mesangial cells.

Topics: Actins; Animals; Blood Glucose; Cells, Cultured; Chemokine CCL2; Collagen Type IV; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Models, Animal; Lipids; Male; Mesangial Cells; Mice; Oxidative Stress; Pyridines; Tumor Necrosis Factor-alpha

The purpose of this study was to evaluate the angiogenic effect of topical application of three types of ONO-1301-loaded poly (lactide-co-glycolide) microspheres (ONO-1301 PLGA MS). ONO-1301 PLGA MS were prepared with PLGA 5010, 5020 and 5050 (with molecular weights of 10 K, 20 K and 50 K, respectively), using the solvent evaporation method. The lactide:glycolide ratio was fixed at 50:50; only the molecular weight was varied. The microspheres had an average diameter of almost 25 µm, and a loading efficiency of at least 70%. The sustained-release effect and its dependence on the molecular weight of the polymer used was confirmed in an in vitro drug-release test and by measuring subcutaneous plasma levels after administration of the three types of ONO-1301 PLGA MS to rats for 28 days. In the murine sponge model, the three types of ONO-1301 PLGA MS were administered to mice in a subcutaneously placed sponge and hemoglobin and hepatocyte growth factor (HGF) levels in the sponge were measured at predefined intervals up to 28 days. The hemoglobin and HGF levels obtained were significantly higher than those obtained after daily administration of ONO-1301 powder. Additional in vivo fluorescence imaging showed that PLGA MS remained in the sponge for 28 days. In conclusion, the three types of ONO-1301 PLGA MS prepared with PLGA three different molecular weight suppress the burst release, stimulate angiogenesis on topical application in a murine sponge model. This formulation may therefore be capable of improving the clinical picture in some types of vascular disease.

Topics: Administration, Topical; Angiogenesis Inducing Agents; Animals; Chemistry, Pharmaceutical; Delayed-Action Preparations; Disease Models, Animal; Drug Liberation; Epoprostenol; Lactic Acid; Male; Mice; Microspheres; Molecular Weight; Particle Size; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Pyridines; Rats

The cardiac support device supports the heart and mechanically reduces left ventricular (LV) diastolic wall stress. Although it has been shown to halt LV remodeling in dilated cardiomyopathy, its therapeutic efficacy is limited by its lack of biological effects. In contrast, the slow-release synthetic prostacyclin agonist ONO-1301 enhances reversal of LV remodeling through biological mechanisms such as angiogenesis and attenuation of fibrosis. We therefore hypothesized that ONO-1301 plus a cardiac support device might be beneficial for the treatment of ischemic cardiomyopathy.. Twenty-four dogs with induced anterior wall infarction were assigned randomly to 1 of 4 groups at 1 week postinfarction as follows: cardiac support device alone, cardiac support device plus ONO-1301 (hybrid therapy), ONO-1301 alone, or sham control.. At 8 weeks post-infarction, LV wall stress was reduced significantly in the hybrid therapy group compared with the other groups. Myocardial blood flow, measured by positron emission tomography, and vascular density were significantly higher in the hybrid therapy group compared with the cardiac support device alone and sham groups. The hybrid therapy group also showed the least interstitial fibrosis, the greatest recovery of LV systolic and diastolic functions, assessed by multidetector computed tomography and cardiac catheterization, and the lowest plasma N-terminal pro-B-type natriuretic peptide levels (P < .05).. The combination of a cardiac support device and the prostacyclin agonist ONO-1301 elicited a greater reversal of LV remodeling than either treatment alone, suggesting the potential of this hybrid therapy for the clinical treatment of ischemia-induced heart failure.

Topics: Animals; Anterior Wall Myocardial Infarction; Biomarkers; Cardiomyopathies; Cardiovascular Agents; Chemistry, Pharmaceutical; Combined Modality Therapy; Coronary Circulation; Delayed-Action Preparations; Disease Models, Animal; Dogs; Fibrosis; Heart Ventricles; Heart-Assist Devices; Natriuretic Peptide, Brain; Peptide Fragments; Prostaglandins I; Prosthesis Design; Pyridines; Recovery of Function; Time Factors; Ventricular Function, Left; Ventricular Remodeling

Cardiac functional deterioration in dilated cardiomyopathy (DCM) is known to be reversed by intramyocardial up-regulation of multiple cardioprotective factors, whereas a prostacyclin analog, ONO1301, has been shown to paracrinally activate interstitial cells to release a variety of protective factors. We here hypothesized that intramyocardial delivery of a slow-releasing form of ONO1301 (ONO1301SR) might activate regional myocardium to up-regulate cardiotherapeutic factors, leading to regional and global functional recovery in DCM.. ONO1301 elevated messenger RNA and protein level of hepatocyte growth factor, vascular endothelial growth factor, and stromal-derived factor-1 of normal human dermal fibroblasts in a dose-dependent manner in vitro. Intramyocardial delivery of ONO1301SR, which is ONO1301 mixed with polylactic and glycolic acid polymer (PLGA), but not that of PLGA only, yielded significant global functional recovery in a canine rapid pacing-induced DCM model, assessed by echocardiography and cardiac catheterization (n = 5 each). Importantly, speckle-tracking echocardiography unveiled significant regional functional recovery in the ONO1301-delivered territory, consistent to significantly increased vascular density, reduced interstitial collagen accumulation, attenuated myocyte hypertrophy, and reversed mitochondrial structure in the corresponding area.. Intramyocardial delivery of ONO1301SR, which is a PLGA-coated slow-releasing form of ONO1301, up-regulated multiple cardiotherapeutic factors in the injected territory, leading to region-specific reverse left ventricular remodeling and consequently a global functional recovery in a rapid-pacing-induced canine DCM model, warranting a further preclinical study to optimize this novel drug-delivery system to treat DCM.

Topics: Animals; Cardiac Catheterization; Cardiac Pacing, Artificial; Cardiomyopathy, Dilated; Cardiovascular Agents; Cell Line; Chemistry, Pharmaceutical; Cytokines; Delayed-Action Preparations; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Drug Carriers; Echocardiography, Doppler; Fibroblasts; Heart Failure; Humans; Injections, Intramuscular; Lactic Acid; Microscopy, Electron; Mitochondria, Heart; Myocardium; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Pyridines; Recovery of Function; RNA, Messenger; Stroke Volume; Time Factors; Up-Regulation; Ventricular Function, Left; Ventricular Remodeling

A prostacyclin analogue, ONO-1301, is reported to upregulate beneficial proteins, including stromal cell derived factor-1 (SDF-1). We hypothesized that the sustained-release delivery of ONO-1301 would enhance SDF-1 expression in the acute myocardial infarction (MI) heart and induce bone marrow cells (BMCs) to home to the myocardium, leading to improved cardiac function in mice.. ONO-1301 significantly upregulated SDF-1 secretion by fibroblasts. BMC migration was greater to ONO-1301-stimulated than unstimulated conditioned medium. This increase was diminished by treating the BMCs with a CXCR4-neutralizing antibody or CXCR4 antagonist (AMD3100). Atelocollagen sheets containing a sustained-release form of ONO-1301 (n = 33) or ONO-1301-free vehicle (n = 48) were implanted on the left ventricular (LV) anterior wall immediately after permanent left-anterior descending artery occlusion in C57BL6/N mice (male, 8-weeks-old). The SDF-1 expression in the infarct border zone was significantly elevated for 1 month in the ONO-1301-treated group. BMC accumulation in the infarcted hearts, detected by in vivo imaging after intravenous injection of labeled BMCs, was enhanced in the ONO-1301-treated hearts. This increase was inhibited by AMD3100. The accumulated BMCs differentiated into capillary structures. The survival rates and cardiac function were significantly improved in the ONO-1301-treated group (fractional area change 23±1%; n = 22) compared to the vehicle group (19±1%; n = 20; P = 0.004). LV anterior wall thinning, expansion of infarction, and fibrosis were lower in the ONO-1301-treated group.. Sustained-release delivery of ONO-1301 promoted BMC recruitment to the acute MI heart via SDF-1/CXCR4 signaling and restored cardiac performance, suggesting a novel mechanism for ONO-1301-mediated acute-MI heart repair.

Topics: Animals; Bone Marrow Cells; Bone Marrow Transplantation; Cell Differentiation; Cell Movement; Chemokine CXCL12; Disease Models, Animal; Epoprostenol; Humans; Male; Mice; Myocardial Infarction; Myocardium; Pyridines; Receptors, CXCR4; Signal Transduction; Ventricular Remodeling

Chronic injury and inflammation in the liver are associated with the development of liver fibrosis. Expressions of transforming growth factor-β1 (TGF-β1) and hepatocyte growth factor (HGF) participate in the development and suppression, respectively, of liver fibrosis. Here, we investigated the effect of ONO-1301, a synthetic prostaglandin I2/IP receptor agonist, on liver fibrosis and on changes in the hepatic expressions of genes that regulate the progression of fibrosis in mice. Liver fibrosis was caused by the repetitive administration of CCl4 for 12 weeks, with ONO-1301 being administered during the last 4 weeks. The expressions of fibrogenic genes: TGF-β1, connective tissue growth factor, α-smooth muscle actin, type-I collagen, and type-III collagen were upregulated by chronic liver injury, which was associated with the expansion of myofibroblasts and the development of liver fibrosis. Treatment with ONO-1301 increased hepatic HGF mRNA expression, but decreased the expressions of TGF-β1, connective tissue growth factor, α-smooth muscle actin, and type-I and type-III collagen, which was associated with the suppression of myofibroblast expansion and liver fibrosis. Neutralizing antibody for HGF significantly attenuated the suppressive action of ONO-1301 on liver fibrosis and fibrogenic gene expressions. The therapeutic action of ONO-1301 on liver fibrosis may have occurred partly through HGF-mediated pathways.

Topics: Actins; Animals; Disease Models, Animal; Female; Fibrosis; Gene Expression Profiling; Gene Expression Regulation; Hepatocyte Growth Factor; Liver Cirrhosis; Mice; Myofibroblasts; Pyridines

Remodeling of the left ventricle (LV) in idiopathic dilated cardiomyopathy (IDCM) is known to be associated with multiple pathologic changes that endogenous factors, such as hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF), protect against. Although a clinically relevant delivery method of these factors has not been established, ONO1301, a synthetic prostacyclin agonist, has been shown to upregulate multiple cardioprotective factors, including HGF and VEGF, in vivo. We thus hypothesized that ONO1301 may reverse LV remodeling in the DCM heart.. ONO1301 dose-dependently added to the normal human dermal fibroblasts and human coronary artery smooth muscle cells in vitro, to measure the expression of HGF, VEGF, stromal cell-derived factor (SDF)-1, and granulocyte-colony stimulating factor (G-CSF), assessed by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay. δ-Sarcoglycan-deficient J2N-k hamsters, which is an established DCM model, were treated by epicardial implantation of an atelocollagen sheet with or without ONO1301 immersion or sham operation.. ONO1301 dose-dependently upregulated expression of these 4 factors in vitro. ONO1301 treatment, which induced dominant elevation of ONO1301 levels for 2 weeks, significantly preserved cardiac performance and prolonged survival compared with the other groups. This treatment significantly upregulated expressions of cardioprotective factors and was associated with increased capillaries, attenuated fibrosis, and upregulation of α-sarcoglycan in the DCM heart.. ONO1301 atelocollagen-sheet implantation reorganized cytoskeletal proteins, such as α-sarcoglycan, increased capillaries, reduced fibrosis, and was associated with upregulated expression of multiple cardioprotective factors, leading to preservation of cardiac performance and prolongation of survival in the δ-sarcoglycan-deficient DCM hamster.

Topics: Animals; Animals, Genetically Modified; Cardiomyopathy, Dilated; Cells, Cultured; Chemokine CXCL12; Collagen; Coronary Vessels; Cricetinae; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Carriers; Fibroblasts; Fibrosis; Granulocyte Colony-Stimulating Factor; Heart Ventricles; Hepatocyte Growth Factor; Humans; Muscle, Smooth, Vascular; Myocardium; Myocytes, Smooth Muscle; Neovascularization, Physiologic; Pyridines; Regeneration; Sarcoglycans; Time Factors; Vascular Endothelial Growth Factor A; Ventricular Remodeling

Injury to the heart can result in cardiomyocyte hypertrophy, fibrosis, and cell death. Myocarditis sometimes progresses to dilated cardiomyopathy. We previously reported that ONO-1301, a synthetic prostacyclin agonist with thromboxane-synthase inhibitory activity, promotes production of hepatocyte growth factor (HGF) from various cell types and ameliorates ischemia-induced left ventricle dysfunction in the mouse, rat and pig. Here, we investigated the therapeutic efficacy of ONO-1301 in a rat model of myosin-induced experimental autoimmune myocarditis, in which the heart transits from an acute inflammatory phase to a chronic dilated cardiomyopathy phase. Four weeks after myosin injection to Lewis rats, ONO-1301 (6 mg/kg/day) was orally administered for 4 weeks (ONO-1301 group). Hemodynamic parameters and plasma brain natriuretic peptide (BNP) level were significantly improved by ONO-1301. Histological analysis revealed that capillary density in the myocardium was significantly increased by ONO-1301. ONO-1301 increased circulating endothelial progenitor cells (EPC) as determined by FACS analysis. These beneficial effects of ONO-1301 were partially abrogated by a neutralizing anti-HGF antibody (8 mg/kg/dose). These findings indicate beneficial effects of ONO-1301 in a rat experimental autoimmune myocarditis model.

Topics: Administration, Oral; Animals; Autoimmune Diseases; Cardiomyopathy, Dilated; Disease Models, Animal; Endothelial Cells; Hemodynamics; Male; Myocarditis; Myosins; Natriuretic Peptide, Brain; Pyridines; Rats; Rats, Inbred Lew; Stem Cells

The purpose of this study was to prepare the ONO-1301 loaded poly(lactide-co-glycolide) microsphere (ONO-1301 PLGA MS) and to evaluate neuroprotective effects for short-term memory by a single subcutaneous injection of ONO-1301 PLGA MS on repeated induction of cerebral ischemia (2 × 10-min with a 1-min interval) in rat. Drug release profiles from ONO-1301 PLGA MS in vitro and in vivo were evaluated. The extent of ischemic injury was assessed behaviourally using the passive avoidance test and histopathologically by evaluating hippocampal CA1 pyramidal damage on day 42 after ischemia. Experiments in vitro showed that the release of ONO-1301 from ONO-1301 PLGA MS was sustained for approximately 3 weeks with maintenance of steady plasma levels. The neuroprotective effect was shown by treatment with ONO-1301 PLGA MS from 2 days after induction of ischemia behaviourally and histopathologically. These results suggest that ONO-1301 PLGA MS can limit short-term learning injury following global cerebral ischemia.

Topics: Animals; Brain Ischemia; CA1 Region, Hippocampal; Delayed-Action Preparations; Disease Models, Animal; Drug Compounding; Epoprostenol; Hippocampus; Lactic Acid; Male; Memory Disorders; Memory, Short-Term; Microspheres; Particle Size; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Pyridines; Rats; Rats, Wistar; Time Factors; Treatment Outcome

Tubulointerstitial injuries are crucial histological alterations that predict the deterioration of renal function in chronic kidney disease. ONO-1301, a novel sustained-release prostacyclin analog, accompanied by thromboxane synthase activity, exerts therapeutic effects on experimental pulmonary hypertension, lung fibrosis, cardiomyopathy, and myocardial ischemia, partly associated with the induction of hepatocyte growth factor (HGF). In the present study, we examined the therapeutic efficacies of ONO-1301 on tubulointerstitial alterations induced by unilateral ureteral obstruction (UUO). After inducing unilateral ureteral obstruction in C57/BL6J mice, a single injection of sustained-release ONO-1301 polymerized with poly (D,L-lactic-co-glycolic acid) sustained-release ONO-1301 (SR-ONO) significantly suppressed interstitial fibrosis, accumulation of types I and III collagen, increase in the number of interstitial fibroblast-specific protein-1 (FSP-1)(+) cells, and interstitial infiltration of monocytes/macrophages (F4/80(+)) in the obstructed kidneys (OBK; day 7). Treatment with SR-ONO significantly suppressed the increase of the renal levels of profibrotic factor TGF-β and phosphorylation of Smad2/3, and elevated the renal levels of HGF in the OBK. In cultured mouse proximal tubular epithelial cells (mProx24), ONO-1301 significantly ameliorated the expression of fibroblast-specific protein-1 and α-smooth muscle actin as well as phosphorylation of Smad3 and increased the expression of zonula occludens-1 and E-cadherin in the presence of TGF-β1 as detected by immunoblot and immunocytochemistry, partly dependent on PGI(2) receptor-mediated signaling. Administration of rabbit anti-HGF antibodies, but not the control IgG, partly reversed the suppressive effects of SR-ONO on tubulointerstitial injuries in the OBK. Taken together, our findings suggest the potential therapeutic efficacies of ONO-1301 in suppressing tubulointerstitial alterations partly mediated via inducing HGF, an antifibrotic factor counteracting TGF-β.

Topics: Animals; Collagen; Disease Models, Animal; Fibrosis; Kidney; Kidney Diseases; Mice; Phosphorylation; Pyridines; Smad2 Protein; Transforming Growth Factor beta1; Ureteral Obstruction

ONO-1301 is a novel drug that acts as a prostacyclin agonist with thromboxane A(2) (TxA(2)) synthase inhibitory activity. We investigated the effect of ONO-1301 on development of airway allergic inflammation.. Mice sensitized and challenged to ovalbumin (OVA) received ONO-1301, OKY-046 (TxA(2) synthase inhibitor), beraprost, a prostacyclin receptor (IP) agonist, ONO-1301 plus CAY10449 (selective IP antagonist) or vehicle during the challenge period. Twenty-four hours after the OVA challenge, airway hyperresponsiveness (AHR) to methacholine was assessed and bronchoalveolar lavage was performed. Lung specimens were excised for goblet cell staining and analysis of lung dendritic cells (DCs). Bone marrow-derived dendritic cells (BMDCs) were generated, in the presence or absence of drugs, for analysis of DC function.. Mice that received ONO-1301 showed significantly lower AHR, airway eosinophilia, T-helper type 2 cytokine levels, mucus production and lung DCs numbers than vehicle-treated mice. These effects of ONO-1301 were mostly reversed by CAY10449. BMDCs treated with ONO-1301 alone showed lower DC functions, such as expression of costimulatory factors or stimulation to spleen T cells.. These data suggest that ONO-1301 may suppress AHR and airway allergic inflammation through modulation of DCs, mainly mediated through the IP receptor. This agent may be effective as an anti-inflammatory drug in the treatment of asthma.

Topics: Animals; Bronchial Hyperreactivity; Dendritic Cells; Disease Models, Animal; Epoprostenol; Female; Inflammation; Methacrylates; Mice; Mice, Inbred BALB C; Ovalbumin; Pyridines; Thromboxane-A Synthase; Thromboxanes

It was reported that administration of angiogenic growth factors can augment collateral growth in ischemic tissues. It is assumed that angiogenic effects of cell transplantation may be mainly mediated by secretion of angiogenic cytokines. We tested feasibility of clinical use of ONO-1301, a synthetic small molecule that stimulates secretion of growth factors from various cell types, to treat patients with chronic myocardial ischemia.. Effects of ONO-1301 on fibroblasts and endothelial cells were evaluated in vitro. We examined the efficacy of local delivery of ONO-1301 in models of rat hindlimb ischemia and swine chronic ischemic myocardium.. ONO-1301 stimulated hepatocyte growth factor secretion from human fibroblasts. ONO-1301 promoted vascular-like tube formation by endothelial cells in vitro. Direct injection of a slow-release form of ONO-1301 (SR-ONO) to rat hindlimb ischemic muscle enhanced perfusion recovery. In a swine cardiac ischemia model, direct injection of SR-ONO into the ischemic myocardium significantly augmented collateral formation (SR-ONO vs. control; 1.7+/-0.2 vs. 1.0+/-0.2 Rentrop score), with improved local ventricular wall motion, reduced enlargement of left ventricular diastolic volume (49.5+/-1.9 mL vs. 59.7+/-4.2 mL) and increased cardiac index (4.2+/-0.1 vs. 3.4+/-0.2 L/min/m(2)). Histological analysis revealed that SR-ONO suppressed fibrosis in ischemic tissue (collagen volume fraction; 7.5+/-1.1% vs. 12.8+/-2.2%) and enhanced neovascularization (capillary density, 275.6 vs. 159.3/mm(2); arterioles 36.6 vs. 25.5 /mm(2)).. Local delivery of SR-ONO might be effective for therapeutic angiogenesis and propose that local administration of slow-release of synthetic small molecules represents new strategy for therapeutic angiogenesis.

Topics: Animals; Cells, Cultured; Collateral Circulation; Delayed-Action Preparations; Disease Models, Animal; Endothelium, Vascular; Fibroblasts; Hepatocyte Growth Factor; Hindlimb; Laser-Doppler Flowmetry; Male; Microcirculation; Myocardial Ischemia; Neovascularization, Pathologic; Prostaglandins I; Pyridines; Rats; Rats, Sprague-Dawley; Swine

Impairment of cardiac function in cardiomyopathy has been postulated to be related to decreased blood flow and increased collagen synthesis. Administration of growth factors was reported to attenuate left ventricular (LV) remodeling and dysfunction in animal models of dilated cardiomyopathy. We previously reported that ONO-1301, a synthetic prostacyclin agonist with thromboxane-synthase inhibitory activity, promotes production of hepatocyte growth factor and vascular endothelial growth factor from various cell types and ameliorate ischemia-induced LV dysfunction in mice and pigs. We evaluated therapeutic efficacy of ONO-1301 in the Syrian hamster (TO-2), a model of genetically determined dilated cardiomyopathy. Either vehicle or a slow releasing form of ONO-1301 (ONO-1301-PLGA, 10mg/kg/3 weeks) was administered subcutaneously every 3 weeks to TO-2 hamsters from 24 to 32 weeks of age (n=12 for each group). Age-matched F1B hamsters were used as a control. Plasma concentration of HGF was elevated in ONO-1301-PLGA group (p<0.05). Echocardiographic study demonstrated that LV fractional shortening was significantly improved in the ONO-1301-PLGA group (25+/-4%, p<0.01) compared with that in the vehicle group (19+/-2%). Cardiac fibrosis was significantly reduced by ONO-1301-PLGA (p<0.05) as determined by Azan-Mallory staining. Capillary density of left ventricle was markedly reduced in TO-2 hamsters. ONO-1301-PLGA significantly increased capillary density in TO-2 group (p<0.05). ONO-1301 improved LV dysfunction and reduced cardiac fibrosis in the hamster model of dilated cardiomyopathy. ONO-1301 might hold a therapeutic potential in the treatment of dilated cardiomyopathy.

Topics: Animals; Cardiomyopathy, Dilated; Cricetinae; Delayed-Action Preparations; Disease Models, Animal; Drug Carriers; Enzyme Inhibitors; Fibrosis; Lactic Acid; Male; Myocardium; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Pyridines; Thromboxane-A Synthase; Ventricular Dysfunction, Left

Although prostacyclin is recognized as a therapeutic breakthrough for pulmonary hypertension, it needs continuous infusion because of its short action. Therefore, we developed a new drug delivery system for prostacyclin. We prepared ONO-1301MS, a novel sustained-release prostacyclin analog polymerized with poly(d,l-lactic-co-glycolic acid) (PLGA) microspheres.. We examined whether ONO-1301MS attenuates monocrotaline (MCT)-induced pulmonary hypertension in rats, and attempted to elucidate the underlying mechanisms responsible for the beneficial effects of ONO-1301MS.. After MCT injection, rats were randomized to receive a single subcutaneous injection of 100 mg/kg ONO-1301MS or vehicle.. We prepared ONO-1301MS, which was polymerized with PLGA to release ONO-1301 for 3 weeks. A single administration of ONO-1301MS achieved sustained elevation of its circulating level and plasma cyclic adenosine 3',5'-monophosphate level for 3 weeks, and attenuated an increase in a metabolite of thromboxane A(2) level. Rats had developed pulmonary hypertension 3 weeks after MCT injection; however, treatment with ONO-1301MS significantly attenuated the increases in right ventricular systolic pressure and right ventricular weight to body weight ratio. ONO-1301MS significantly inhibited hypertrophy of pulmonary arteries. Phosphorylation of extracellular signal-regulated protein kinase (ERK) in the lung was significantly increased in the control group, whereas this increase was markedly attenuated by treatment.. We developed a new drug delivery system for prostacyclin using PLGA and ONO-1301. A single injection of ONO-1301MS resulted in sustained activity for 3 weeks, and attenuated pulmonary hypertension, partly through its antiproliferative effect on vascular smooth muscle cells via inhibition of ERK phosphorylation.

Topics: Animals; Antihypertensive Agents; Delayed-Action Preparations; Disease Models, Animal; Drug Compounding; Epoprostenol; Extracellular Signal-Regulated MAP Kinases; Hemodynamics; Hypertension, Pulmonary; Injections, Subcutaneous; Male; Microspheres; Monocrotaline; Pyridines; Rats; Rats, Wistar; Thromboxane-A Synthase