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As a result, this ONOSR product was shown to be hydrolysed at the site of administration to linearly release ONO into the adjacent tissue with a modest initial burst Fig. In addition, this product was shown to have a positive effect on bone regeneration [ 29 — 39 ] or nerve root angiogenesis [ 40 ], and have a protective effect against acute liver injury [ 41 ], skin injury [ 42 ] or renal tubulointerstitial fibrosis [ 43 ]. Of note, ONO is under the clinical study for treating medically refractory ulcerative colitis [ 44 ], though the result has not been reported.

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Another EP4 receptor agonist, EP4RAG, has been shown to have a protective effect against ischaemia—reperfusion myocardial injury [ 45 ], cardiac allograft transplantation-related inflammation [ 46 ] or experimental autoimmune myocarditis [ 47 ]. Despite several similar products to ONO, it appears that sustained-release form of prostagrandin agonist has been developed only in ONO to date. Therapeutic effects of ONOSR have been tested on a variety of cardiac pathologies, such as acute and chronic myocardial infarction MI , cardiomyopathy, cardiac allograft disease post-transplantation or myocarditis.

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As a result, ONOSR treatment showed positive effects on these pathologies by different mechanisms from other existing treatments that are used in the clinical settings, indicating that ONOSR is a potential new drug for a variety of cardiac diseases. In addition, border area between the infarct area and the area with sufficient blood supply confronts with persistent ischaemia that progressively widen the infarct region [ 51 ].

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  7. Treatment for the acute MI is therefore reperfusion of the ischaemic area to supply sufficient blood flow into the tissue [ 52 ]. It is, however, known that early reperfusion induces intracellular calcium overload, overproduction of superoxides and their derivatives and mitochondrial permeability transition pore opening in the cardiac myocytes, which consequently yields rapid cell death that often causes lethal ventricular arrhythmia, and importantly exacerbates inflammatory response in the reperfused area [ 53 , 54 ]. Despite a number of attempts, additional treatments that effectively reduce ischaemia—reperfusion cardiac injury have not been developed [ 53 ].

    Among the agents that activate myocyte receptors, such as adenosine [ 55 ], bradykinin [ 56 ], opioids [ 57 ], glucagon-like peptide 1 [ 58 ], atrial natriuretic peptide ANP [ 59 ], erythropoietin [ 60 ] or insulin [ 61 ], intravenous infusion of adenosine and ANP showed positive, but not substantial, additional therapeutic effects to direct percutaneous coronary intervention for acute MI.

    In addition, effects of the agents that act intracellularly, such as volatile anaesthetics [ 62 ], nitrates [ 63 ], atorvastatin [ 64 ], delcasertib [ 65 ], nicorandil [ 59 ] or cyclosporine [ 66 ], have not been proven by large randomised studies. There are a number of other potential agents that were or were not tested by large-scale human studies, such as phosphodiesterase-5 inhibitors [ 67 ], superoxide dismutase [ 68 ] or neutralising antibodies against adhesion molecules such as P-selectin, intercellular adhesion molecule-1 [ 69 ].

    In addition, delivery method of the agents needs to be optimised depending upon the underlying therapeutic mechanisms [ 68 , 69 ].

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    They directly injected ONOSR into the myocardium that was subjected to ischaemia by left coronary artery ligation in mice. They concluded that angiogenesis by ONOSR-induced up-regulation of multiple cytokines is the key therapeutic mechanisms of this treatment for acute MI [ 27 ]. In addition, the same team reported the angiogenesis-related positive effects of ONOSR on acute MI with reperfusion using a rat model in [ 70 ].

    It was thus concluded that accumulation of bone marrow-derived cells by ONOSR treatment is an alternative therapeutic mechanisms of this treatment, though role of the accumulated cells needs to be clarified. Noticeably, our group delivered ONOSR into the heart in an atelocollagen-based sheet form [ 20 ], since it was considered that direct injection of ONOSR into the myocardium may induce myocardial injury.

    However, further basic studies are necessary to thoroughly clarify the therapeutic mechanisms of this treatment for acute MI. Chronic cardiac failure is a result of previous or continuous insult against the heart, such as ischaemia, valvular pathologies or genetic abnormalities. On the other hand, treatments targeting responsible cellular and molecular processes for LV remodelling are under development as represented by cell transplantation therapy [ 9 , 10 , 12 ]. Treatment by ONOSR was also reported to induce similar therapeutic mechanisms to the cell transplantation therapy in chronic failing heart in pre-clinical studies as follows.

    Four weeks later, they performed direct epicardial injection of ONOSR into the infarct border area under LV electromechanical mapping guidance using a transcatheter system. As a result, ONOSR treatment enhanced collateral growth in relation to increased number of the capillaries, attenuated collagen fraction in the myocardial interstitium and reduced LV volume, indicating that this treatment reversed the LV remodelling. They discussed that intramyocardially delivered ONOSR directly acted on the residential fibroblasts to induce up-regulation of cardiotherapeutic factors such as VEGF or HGF, which in turn activated the regeneration process in the chronic MI heart [ 71 ].

    Our group generated a chronic MI model in canine by permanently ligating left coronary artery [ 22 ]. Importantly, this study showed increased myocardial blood flow by ONOSR treatment as assessed by 13 N-ammonia positron emission tomography study [ 22 ], indicating that pro-angiogenic effects of ONOSR augment myocardial blood flow to induce functional recovery in ischaemic cardiomyopathy Fig. Schematic representation of proposed mechanisms underlying ONOSR-immersed sheet placement therapy for treating damaged cardiac tissue.

    As a result, ONOSR-treated hamsters showed a preserved cardiac function in relation to reduced fibrous components and increased capillary network in the myocardial interstitium, suggesting a therapeutic potential of systemic delivery of ONOSR into the dilated cardiomyopathy-related chronic cardiac failure [ 72 ]. Our group directly delivered into the heart in order to maximise the therapeutic effects of this reagent and minimise systemic complications.

    However, the direct intramyocardial injection of ONOSR used in this report was concerned by inconsistent delivery of the reagent and injection-related myocardial injury. Therefore, in the subsequent study, ONOSR immersed into the atelocollagen sheet was simply placed on the LV surface of hamster model of dilated cardiomyopathy [ 21 ].

    This delivery method would achieve a consistent delivery of the reagent into the heart and minimum injury to the myocardium, whereas the myocardial territory that is affected by ONOSR might be theoretically limited. These two studies proved the concept that local delivery of ONOSR into the heart contributes to functional recovery and survival benefit in dilated cardiomyopathy-related chronic cardiac failure Fig. ONOSR was thus shown to have anti-inflammatory, pro-angiogenic and anti-fibrotic effects on acute and chronic cardiac pathologies via up-regulation of a variety of cardiotherapeutic cytokines and chemokines.

    Furthermore, positive effects of ONOSR were shown in other cardiac pathologies such as cardiac graft disease post-transplantation [ 73 ] or autoimmune myocarditis. This treatment was effective in chronic rejection as shown in the reduced myocardial fibrosis in a class II mismatch combination, but not effective in acute rejection in a full allomismatch combination, suggesting that ONOSR might be a potential new drug for chronic rejection post-cardiac allograft transplantation. Although positive effects of ONOSR treatment were proven on a variety of cardiac pathologies, such as acute MI, idiopathic dilated cardiomyopathy, ischaemic cardiomyopathy, cardiac allograft disease post-transplantation or fulminant myocarditis, it is a key of success of this treatment to optimise delivery method of ONO for each target pathology in clinical study.

    This section discusses suitable target pathology and delivery method of this reagent, and studies necessary for the first-in-human study. In addition, potential methods to enhance the therapeutic effects of ONO are discussed in the prospect of clinical application. It has been shown that both systemic and local delivery of the ONOSR potentially contributes to the therapeutic benefits for acute and chronic cardiac disease. However, optimal mode of the delivery in the clinical settings would be dependent upon the pathology and, most importantly, the standard treatment for the pathology in the routine clinical practice.

    Since the standard treatment for the acute MI is the prompt reperfusion of the occluded coronary arteries by percutaneous transcatheter approach, direct intramyocardial injection of ONOSR by transcatheter approach at the time of reperfusion may be ideal, although further basic studies using a large animal model are necessary. The standard treatment for ischaemic and non-ischaemic dilated cardiomyopathy is the intensive combination of medical and interventional treatments.

    Addition of subcutaneous ONOSR injection or oral ONO intake to the optimal medical management would augment the therapeutic effects of the standard medical treatment. Head-to-head comparison study for the therapeutic effects between placement over the heart and subcutaneous injection of ONOSR has not been reported. However, it may be theorised that enhanced effects will be achieved by the local placement which maximise ONO delivery into the targeted area with minimal systemic effects, since paracrinal actions of the effector cells are augmented in positive relation to the magnitude of the ONO stimuli [ 20 , 21 , 23 ].

    Once the target pathology and the delivery mode of the ONOSR treatment were decided, dose-optimisation study ideally using a large animal model is necessary to launch the clinical study. Degree of therapeutic effects and systemic complications such as hypotension, bleeding or diarrhoea, in addition to plasma and cardiac ONO level, need to be investigated depending upon the dose of ONOSR.

    One approach would be combination with the treatments that contribute to cardiac function by a different mechanism from ONOSR, while the other approach may be combination with treatments whose mechanisms are similar to ONOSR. Our group developed hybrid therapy by combination of ONOSR delivery and cardiac support mesh net device placement [ 22 ]. It has been shown that placement of cardiac support net over the ventricles mechanically reduces diastolic LV wall stress to inhibit progression of the LV remodelling, whereas clinical studies of cardiac support net for treating chronically failing heart failed to show survival benefits despite positive effects on the LV volume [ 76 ].

    This inconsistent result of cardiac support net device would be explained by a lack of biological effects in this treatment. In contrast, ONOSR contributes to recovery of cardiac function by the biological effects, not by mechanical effects. It was therefore theorised that combination of ONOSR and cardiac support net placement would augment the therapeutic effects of either treatment. To test this hypothesis, our laboratory developed a hybrid device consisting of biodegradable polyglycolic acid-based cardiac support net and ONOSR-immersed atelocollagen sheet for treating a canine chronic MI model [ 22 ].

    As a result, the hybrid device elicited a greater reversal of the MI-inducing LV remodelling than either single treatment, indicating the potential of this device for chronic cardiac failure [ 22 ]. One may claim that head-to-head comparison study in the therapeutic effects of the two treatments would be clinically important. Rather, addition of the ONOSR placement therapy to the cell transplantation therapy may prolong the regenerative effects for the cardiac tissue, depending upon expression of IP receptor and subsequent intracellular signalling in the transplanted cells.

    Further studies are necessary to test this hypothesis. This unique character of the omentum was applied to develop a treatment for cardiac ischaemic disease by mobilising to the cardiac surface in a pedicle fashion [ 75 , 80 ]. Of note, it was reported that omentum covering over the chronic MI-heart with local sustained-delivery of basic fibroblast growth factor bFGF , but not without bFGF, induced a new vascular network formation between the pedicle omentum and the heart [ 75 ].

    It is thus theorised that the omentum covering with local delivery of ONOSR might be effective in augmenting regional blood flow in the ischaemic cardiac tissue via formation of new vascular networks in the heart. In fact, use of this reagent was reported to be effective in pulmonary arterial hypertension PAH , pulmonary fibrosis or chronic kidney disease.

    Moreover, the effects of ONOSR as a potent protective cytokines-inducer might be applied to other pathologies, such as cerebral, liver or pancreatic pathologies. This section summarises previous reports and potential target of ONOSR treatment for extracardiac pathologies. In addition, this section discusses a potential of ONOSR in combination with medical devices, to accumulate further knowledge and information regarding this unique product, exploring further applications.

    In fact, Kataoka et al. Subsequently, Obata et al. The same group reported in that oral administration of ONO was therapeutic in monocrotaline-induced PAH rats [ 86 ]. Moreover, Murakami et al. In addition, Kimura et al. As a result, they proved the anti-inflammatory and the reverse remodelling effects of ONOSR on chronic house dust mite-induced asthma model in mice. These results might warrant a potential of ONOSR treatment for PAH or asthma, of which chronic inflammation is involved in the development of the pathologies, in clinical practice. Further basic studies should be focused on optimisation of the dose of ONOSR or the administration mode of ONOSR, such as a single subcutaneous injection, intermittent injections, or oral intake.

    It may be proposed that intravenous injection of ONOSR would induce entrapment of the product in the pulmonary arterioles or capillaries to achieve sustained release of the ONO, although intravenous injection may carry a substantial risk of pulmonary embolism that further exacerbates PAH or associated lung pathologies. Progression of chronic kidney disease is known to be regulated by chronic inflammatory and fibrotic process in the tubulointerstitium of the kidney. Anti-inflammatory effects of ONO on nephritis was first reported by Hayashi et al.

    Subsequently, Yamasaki et al. In addition, Nasu et al. Although standard treatment of cerebral ischaemia is early reperfusion, additional medical treatments that ameliorate ischaemia—reperfusion injury would further improve the outcome of the intervention. The same groups reported in that repeated ONOSR administration reduced ischaemic damage of rats that were subjected to middle cerebral artery occlusion [ 94 ]. Acute liver injury is a life-threatening disorder, initiated by a burst inflammation, followed by a complex inflammatory process.

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    Date is from the failure date, the smaller the amount of lost computation to since the recovered pro- r brightwell, r riesen, p g bridges, and d arnold. In addition, extracellularly released factors by ono have been shown to enhance a tube-like formation of human umbilical vein endothelial cells huvecs co-cultured with normal human dermal fibroblasts nhdf in vitro [27], indicating a pro-angiogenic property of ono in addition, it was. Effective date subtitle c—quality health insurance coverage for all americans part i—health insurance market reforms sec amendment qualified health plan defined sec essential health benefits requirements sec special rules sec related definitions.

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