1988
DOI: 10.1016/0160-5402(88)90052-6
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The anesthetized ferret, an in vivo model for evaluating inotropic activity: Effects of milrinone and anagrelide

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1989
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Cited by 12 publications
(4 citation statements)
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“…The use of in vivo genetic models has been described both for predicting clinical efficacy [37] and carcinogenicity [38]; these technologies hold promise for the generation of mechanistic information vital to issue management and risk assessment. Finally, the evaluation of alternative in vivo models may also allow the earlier identification of human-specific toxicities [39,40].…”
Section: In Vivo Safety Assessmentmentioning
confidence: 99%
“…The use of in vivo genetic models has been described both for predicting clinical efficacy [37] and carcinogenicity [38]; these technologies hold promise for the generation of mechanistic information vital to issue management and risk assessment. Finally, the evaluation of alternative in vivo models may also allow the earlier identification of human-specific toxicities [39,40].…”
Section: In Vivo Safety Assessmentmentioning
confidence: 99%
“…In a model of hemorrhagic shock conducted in anesthetized beagle dogs, oral administration of 1 at doses ranging from 0.2 to 5.0 mg/kg inhibited the elevation in screen filtration pressure that was the read-out for the model in a dose-related fashion. In anesthetized ferrets, intraduodenal administration of 1 was associated with a reduction in mean arterial blood pressure that reached a plateau of ∼30%, a small elevation of heart rate, and a dose-dependent increase in cardiac contractile force …”
mentioning
confidence: 99%
“…Anagrelide ( 1 ) is a potent inhibitor of blood platelet aggregation (BPA) in platelet-rich plasma (PRP) from rats, dogs, rhesus monkeys, and humans that protects against activation induced by a broad range of physiologically relevant stimuli, including adenosine diphosphate (ADP), collagen, arachidonic acid, and thrombin, with EC 50 values of <1 μg/mL. , BL-3459 ( 2 ), the prototype 1,2,3,5-tetrahydroimidazo­[2,1- b ]­quinazolin-2-one, was discovered 50 years ago at Bristol Laboratories in Syracuse, New York when J. Stuart Fleming and his team conducted a phenotypic screening campaign that used ADP-induced rabbit PRP to identity effective platelet aggregation inhibitors. , Although 2 was subjected to extensive preclinical profiling, development was ultimately suspended following the observation of microcrystals of the 7-hydroxy metabolite in the livers of dogs during preclinical toxicology studies, a finding that led to the selection of 1 , where the 7-position is blocked, for clinical evaluation. , As a potent and broad-spectrum inhibitor of rabbit and human BPA in PRP, 1 was readily distinguished from the most prominent antiplatelet agents at that time, aspirin, sulfinpyrazone, and dipyridamole, each of which exhibited inhibitory activity toward a much narrower range of stimuli (Table ). Following oral dosing of 1 to rats and dogs, BPA measured ex vivo in response to collagen or ADP was inhibited with ED 50 values ranging from 0.29 to 4.86 mg/kg, with the half-lives of the biological effect amounting to 7 h in the rat and 19 h in the dog .…”
mentioning
confidence: 99%
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