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For specific conditions, higher doses have been studiedfor instance, some trials in heart failure have used 100300 mg daily, whilst migraine prevention studies have investigated doses up to 300400 mg daily

doi: 10.1074/jbc.M010677200 64 HanDLernerAGVande WalleLUptonJPXuWHagenAet al

Naloxone and its quaternary derivative, naloxone methiodide, have differing affinities for mu, delta, and kappa opioid receptors in mouse brain homogenates

Indeed, drug resistance is also related to increase discharge (efflux) of anticancer drugs due to the overexpression of the efflux transporters

However, preclinical studies demonstrate therapeutic effects with once-daily or even less frequent administration, suggesting tissue distribution, receptor binding, or cellular signaling effects extend beyond plasma clearance