Chronopharmacology of oral prednisolone in rats.

The chronopharmacology of oral prednisolone (PSL) was studied in rat models. Differences in the dosing-time-dependent toxicity were evaluated at four time points (3, 9, 15 and 21 HALO) in adult male Wistar rats and confirmed in an inbred strain of Lewis rats (MHC haplotype; RTIl) at two time points (9 and 21 HALO). The total body weight and that of the immunologic-related organs were maximally reduced when PSL was repeatedly administered during the late active phase (21 HALO). This chronotoxicity was independent of plasma concentrations of PSL, adrenocorticotropic hormone, and corticosterone. Repeated administration of PSL prolonged cardiac allograft survival in a DA (RTIa) -to-Lewis combination, and there was a tendency to be more effective in the 21 HALO trial. These results suggested that single dose therapy of PSL at the selected point of the day may be less harmful, protecting against allograft rejection.

The effects of a neutrophil elastase inhibitor (ONO-5046.Na) and neutrophil depletion using a granulotrap (G-1) column on lung reperfusion injury in dogs.

BACKGROUND: Activated neutrophils are reported to be closely involved in ischemia-reperfusion injury after lung transplantation. We investigated the beneficial effects of a new recombinant specific neutrophil elastase inhibitor, ONO-5046.Na, and an extracorporeal-type granulotrap (G-1) column on ischemia-reperfusion lung injury, by using an in situ warm lung ischemia model in dogs. METHODS: Warm ischemia was induced for 3 hours by clamping the pulmonary arteries and veins. The left main bronchus was bisected and reanastomosed prior to reperfusion. The left lung was collapsed for 3 hours. A total of 27 adult mongrel dogs were divided into three groups: the control group (n = 9) treated with a saline vehicle; the ONO group (n = 9), in which ONO-5046.Na was continuously administrated from before induced ischemia and to ending 2 hours after reperfusion; and the G-1 group (n = 9), in which a G-1 column was applied for 90 minutes starting 30 minutes before reperfusion under passive bypass support. RESULTS: Circulating neutrophils in the G-1 group decreased significantly (p<.05) compared to preischemia, and significantly decreased compared with the other groups after reperfusion. Oxygenation was improved actually and pulmonary vascular resistance was kept lower level after the administration of ONO-5046.Na. The increase of lung weight was significantly ameliorated in both the G-1 and ONO groups. In the histopathological study, lungs from the control group demonstrated diffuse alveolar edema, neutrophil infiltration, massive alveolar exudate and hemorrhage, and thickening of the interstitium. Lungs from the G-1 group showed mild swelling of the alveolar wall and neutrophil infiltration. Lungs from the ONO group showed virtually no abnormalities. CONCLUSION: This study demonstrated that a neutrophil elastase inhibitor and neutrophil depletion prevented lung reperfusion injury. These treatments may prevent ischemia and reperfusion injury in lung transplantation.