ACTA ENDOCRINOLOGICA (BUC)

Using mathematical and clinical trial pharmacokinetics for Cabergoline (a dopaminergic agonist used in hyperprolactinaemia and long-term treatment of nonfunctioning tumours), a new ?hyperfractionation? effect is proven. This effect leads to higher steady state plasma concentrations of drug by fractionating multiple dose regimens in more frequent doses of smaller individual amounts. We generalize this effect by formulating a general mathematical condition for any drug to benefit from hyperfractionation. The effect is important in the long-term treatment of non-functioning tumours as one tries to achieve higher steady state plasma concentrations by using small individual doses in order to insure tolerability. This effect is more complex than the accumulation effect known in pharmacokinetics as a one parameter effect (frequency). Hyperfractionation is a two parameter effect for multiple dose regimens (frequency, dose amount).

The stress driven cortisol dynamics of the Hippocampal-Hypothalamic-(Anterior) Pituitary-Adrenal (HHPA) axis with its negative feedback loops from the adrenals to pituitary and hypothalamus, in particular relation with hippocampus, have been the focus of the last few years boom of papers\r\nusing various distinctive mathematical models, simulations, stability analyses and optimal control of these models. These many quantitative approaches led to discovering unknown connections between cortisol feedback loop dysfunctions and stress disorders (post-traumatic stress\r\ndisorder (PTSD), depression, chronic fatigue syndrome (CFS)), adrenal suppression and atrophy, Alzheimer (AD)\r\nand hypocampal cognitive dysfunctions (memory loss) leading to new drug treatment strategies. We assemble here together and unify these results, including our own early work, in order to create an integrative mathematical system theory framework for HHPA & HPA and stress driven cortisol dynamics in which various clinical disorders appear as various quantifiable negative feedback loop dysfunctions and drug therapies correcting these disorders appear as feedback model based treatments: a neuroendocrine system theory for cortisol ?feedback pathology? and its existing and future possible ?feedback therapies?.