ABSTRACT
Photosafety evaluation is becoming important during the drug development process in pharmaceutical companies. Both in vitro and in vivo test systems have been developed for the evaluation of phototoxic potential of chemicals. In the present study, we conducted an in vivo phototoxicity test using BALB/c mice. The mice were treated with sparfloxacin, lomefloxacin, or a quinoline derivative orally followed by the irradiation of simulated sunlight, and resulting phototoxic reactions of the ears were assessed. Sparfloxacin and lomefloxacin, but not the quinoline derivative, are well known to cause photoirritation in humans. All three drugs exhibited positive reaction in the 3T3 neutral red uptake phototoxicity test (3T3 NRU PT). In the in vivo test, sparfloxacin and lomefloxacin exhibited positive skin reaction in mice, but the quinoline derivative did not. The results of in vivo phototoxicity test in the mice coincided with phototoxic potential of these drugs in humans. The exposure levels of sparfloxacin or lomefloxacin at the minimum effective dose that exhibited phototoxic reaction in the mice were comparable with those in humans treated with the recommended therapeutic dose.
Subject(s)
Dermatitis, Phototoxic/etiology , Drug Evaluation, Preclinical/methods , Photosensitizing Agents/toxicity , 3T3 Cells/drug effects , 3T3 Cells/radiation effects , Animals , Antitubercular Agents/pharmacokinetics , Antitubercular Agents/toxicity , Dermatitis, Phototoxic/metabolism , Dermatitis, Phototoxic/pathology , Disease Models, Animal , Dose-Response Relationship, Drug , Ear, External/drug effects , Ear, External/metabolism , Female , Fibroblasts/drug effects , Fibroblasts/radiation effects , Fluoroquinolones/pharmacokinetics , Fluoroquinolones/toxicity , Humans , Mice , Mice, Inbred BALB C , Photosensitizing Agents/classification , Photosensitizing Agents/pharmacokinetics , Quinolines/pharmacokinetics , Quinolines/toxicity , Radiography , Skin/diagnostic imaging , Skin/drug effects , Skin/pathology , Ultraviolet RaysABSTRACT
The effect of a selective inducible nitric oxide synthase inhibitor, ONO-1714 ((1S,5S,6R,7R)-7-chloro-3-imino-5-methyl-2-azabicyclo[4.1.0]heptane hydrochloride), on hemodialysis-related hypotension was investigated using a canine model of renal dysfunction. Renal dysfunction was induced in dogs by complete bilateral ligation of renal arteries. On performing hemodialysis with ultrafiltration, the blood pressure of the renal dysfunction dogs gradually decreased and persisted at reduced levels until completion. ONO-1714 ameliorated the hemodialysis-induced hypotension in the renal dysfunction dogs at a dose that did not influence blood pressure in non-hemodialysis dogs with normal renal function. The above findings indicated that ONO-1714 may elicit beneficial effects on hemodialysis-related hypotension.
Subject(s)
Amidines/therapeutic use , Heterocyclic Compounds, 2-Ring/therapeutic use , Hypotension/drug therapy , Kidney Diseases/drug therapy , Kidney Diseases/physiopathology , Nitric Oxide Synthase/antagonists & inhibitors , Renal Dialysis/methods , Amidines/pharmacology , Animals , Dogs , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Heterocyclic Compounds, 2-Ring/pharmacology , Hypotension/enzymology , Kidney Diseases/enzymology , Kidney Function Tests , Male , Nitric Oxide Synthase/metabolism , Nitric Oxide Synthase Type IIABSTRACT
To clarify the role of nitric oxide (NO) in hemodialysis (HD)-related hypotension, the relationship between plasma NO metabolites (NOx) and blood pressure changes, and the effect of N(G)-monomethyl-L-arginine (L-NMMA), a NO synthase inhibitor, on changes in blood pressure were evaluated in an experimental renal dysfunctional dog model. In order to create a renal dysfunction model, gentamicin was administered to male beagles in which 7 of 8 renal artery branches had been ligated. Normal renal functional and dysfunctional dogs underwent 3 hr of HD per day for 3 days. HD induced a transient decrease in mean blood pressure in the normal renal functional dogs. In renal dysfunctional dogs, a continuous hypotension occurred with a gradual increase in the plasma NOx concentration during HD. Although L-NMMA prevented the fall in blood pressure, it did not significantly change the plasma NOx concentration during HD. These results suggest that NO contributes to HD-related hypotension in renal dysfunctional dogs but the plasma NOx concentration does not reflect the change in blood pressure.
