Understanding the Hysteresis Loop Conundrum in Pharmacokinetic / Pharmacodynamic Relationships

This is the published version. Copyright 2014 Canadian Society for Pharmaceutical SciencesHysteresis loops are phenomena that sometimes are encountered in the analysis of pharmacokinetic and pharmacodynamic relationships spanning from pre-clinical to clinical studies. When hysteresis occurs it provides insight into the complexity of drug action and disposition that can be encountered. Hysteresis loops suggest that the relationship between drug concentration and the effect being measured is not a simple direct relationship, but may have an inherent time delay and disequilibrium, which may be the result of metabolites, the consequence of changes in pharmacodynamics or the use of a non-specific assay or may involve an indirect relationship. Counter-clockwise hysteresis has been generally defined as the process in which effect can increase with time for a given drug concentration, while in the case of clockwise hysteresis the measured effect decreases with time for a given drug concentration. Hysteresis loops can occur as a consequence of a number of different pharmacokinetic and pharmacodynamic mechanisms including tolerance, distributional delay, feedback regulation, input and output rate changes, agonistic or antagonistic active metabolites, uptake into active site, slow receptor kinetics, delayed or modified activity, time-dependent protein binding and the use of racemic drugs among other factors. In this review, each of these various causes of hysteresis loops are discussed, with incorporation of relevant examples of drugs demonstrating these relationships for illustrative purposes. Furthermore, the effect that pharmaceutical formulation has on the occurrence and potential change in direction of the hysteresis loop, and the major pharmacokinetic / pharmacodynamic modeling approaches utilized to collapse and model hysteresis are detailed

Effect of Mozart's music (Romanze-Andante of "Eine Kleine Nacht Musik", sol major, K525) stimulus on common carp (Cyprinus carpio L.) physiology under different light conditions

It is well known that music could have relaxing and antidepressant effects on humans, other mammals and birds. The present study aimed to evaluate music effects on common carp Cyprinus carpio growth and physiology, under different light conditions. Therefore, common carp (130.9 ± 0.67 g) was reared, in recirculating water system, under constant darkness (D) or normally illuminated conditions (L) for 12 weeks. Classical music was transmitted underwater and music treatments consisted of no music at all (control groups, C) and three music transmissions either of 30 min duration at 1.5 h intervals (M30) or of 60 min duration at 1 h intervals (M60). Obtained results showed that light conditions had a negative effect on fish growth (L-C versus D-C, P < 0.01), but when 30 min music was transmitted (L-M30) growth was improved and equal to D-C. Fish groups presenting reduced growth exhibited significantly increased brain neurotransmitters levels, indicating the occurrence of stressful conditions. Also, music transmission significantly affected carcass and liver fatty acid composition. Present results showed that music could be regarded as a stress relieving or inducing factor. Possible use of music as a growth and product quality promoter, as well as a means to ensure fish welfare under intensive fish farming is discussed. © 2006 Elsevier B.V. All rights reserved