To clarify the preventive effects of ONO-3144, a free radical scavenger, on stroke-prone spontaneously hypertensive rats (SHRSP) and free radicals related to the hypertensive disorders.METHODSDrugs with powdered chow were administered orally to the rats from 2- to 14-month-old. Body weight, blood pressure, rectal temperature, oxygen consumption rate, thyroid hormones, lipids, platelet number, ocular fundus, autopsy, and life span were investigated.RESULTSONO-3144 did not affect the growth, blood pressure, concentrations of thyroid hormones and lipids in the blood, but decreased the rectal temperature and oxygen consumption rate. ONO-3144 also prevented the platelet number decrease, sclerotic change of retinal artery, edematous and hypertrophic changes in parenchymal and circulatory organs. Both the average life-span and the longest life time of SHRSP given 40 mg/kg ONO-3144 were longer than those of normotensive rats and no administration hypertensive rats.CONCLUSIONThe oxidative f ree radicals closely relate to hypertension-induced pathophysiological changes in SHRSP, and ONO-3144 prevents the changes of those disorders, and then brings longevity.

01 Jan 1995·Journal of Nippon Medical School

Endotoxin-induced lung injury. The roles of leukocytes and oxidants, and the efficacies of steroids and antioxidants.

Article

Author: Matsuda, Noriko ; Miyashita, Masao ; Matsuda, Takeshi ; Onda, Masahiko

Previous work in our laboratory has shown the relation between leukocytes (WBC) and the generation of oxidants in endotoxin (LPS) shock. The purpose of this study was to find out if WBC-derived oxidants can produce acute lung injury in guinea pigs given LPS. We alos evaluated the efficacies of steroids and antioxidants against the initial changes in LPS-induced lung injury. One group of guinea pigs (200-250 g, male) received 0.7 mg/kg (LD50, 24 hrs.) of E. coli LPS in the peritoneal cavity (group I). The animals in group II received 30 mg/kg of methylprednisolone (MP), followed by intraperitoneal LPS. The animals in group III were given 30 mg/kg of 2-aminomethyl-4-tert-butyl-6-propionylphenol hydrochloride (ONO-3144), a known as antioxidant (OH radical scavenger), and then an injection of LPS. The animals were killed at following time course: 30, 60 or 180 minutes after the LPS injection. Hematological examinations (WBC counts), total cell counts and differential counts in bronchoalveolar lavage (BAL) fluid were done along with light microscopic studies. Superoxide dismutase (SOD) activity, catalase activity and malonaldehyde (MDA) produced as a result of lipid peroxidation in the lung were measured and correlated with histological changes. Survival ratios of the three groups were compared. The results obtained were: 1) Significant leukopenia occurred in all groups. 2) In group I, WBC, especially eosinophils, were recovered by BAL and the total cell number of the BAL fluid had increased by 180 minutes after LPS injection, but MP or ONO-3144 treatment inhibited the migration of WBC (eosinophils and neutrophils) into alveolar lumen after LPS injection. 3) Histologic examinations revealed diffuse edema, hemorrhage, and marked leukocyte infiltration in the alveoli in group I, but not in group II or III. 4) SOD activity in all group diminished below the control level. Catalase activity had significantly increased by 180 minutes after LPS injection in group I, but not in group II or III. MDA had increased remarkably by 60 minutes after injection of LPS in group I, but MP or ONO-3144 treatment prevented such increases. 5) Animals in group II and III survived significantly longer than those in the other group. In conclusion, these findings suggest that LPS provokes WBC-mediated vascular damage in the lung and steroids or antioxidants can minimize the injury and prevent edema formation. Steroids might be useful for achieving quantifiable changes in LPS-induced WBC chemotaxis to the lung and for decreasing oxidant-induced lung injury.

01 Dec 1990·Journal of Cardiovascular PharmacologyQ4 · MEDICINE

Prevention of Myocardial Reperfusion Injury in Experimental Coronary Revascularization Following Ischemic Arrest by a Novel Antiinflammatory Drug, ONO-3144

Q4 · MEDICINE

Article

Author: Engelman, Richard M. ; Iyengar, Jaisimha ; Das, Dipak K. ; Kimura, Yutaka

The cardioprotective effects of a novel antiinflammatory drug, ONO-3144 (ONO), on ischemic-reperfused myocardium were investigated using an in situ pig heart model. Heart was subjected to 2 h of regional ischemia, with the final 1 h having superimposed global cardioplegic arrest followed by 1 h of reperfusion. ONO (20 microM) was administered after the arrest at the onset of reperfusion. Left ventricular developed pressure (LVDP), maximum rate of rise of left ventricular pressure (LV dp/dt), and left ventricular end-diastolic pressure (LVEDP) were measured under isovolumic conditions to assess cardiac contractility and compliance. ONO improved LVDP and LV dp/dt, and reduced LVEDP after 60 min of reperfusion compared to control. This drug also improved segment shortening and end-diastolic length significantly after 15 and 60 min of reperfusion. Slight improvements in oxygen consumption and creatine kinase (CK) release were also noted. In addition, ONO reduced lipid peroxidation and thromboxane formation but enhanced the production of prostaglandins. In vitro studied demonstrated ONO to be effective scavengers for both hydroxyl (OH.) and hypohalite (OCL.) radicals. The results suggest that myocardial reperfusion injury that developed after ischemic arrest was reduced significantly by ONO. This drug inhibited such injury, probably by directly scavenging potentially harmful radicals such as OH. and OCI., which are generated in ischemic-reperfused myocardium.

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Indication	Highest Phase	Country/Location	Organization	Date
Myocardial Ischemia	Phase 3	JP	Ono Pharmaceutical Co., Ltd.	-

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