To advance the systems approach in pharmacology, experimental models and computational methods need to be integrated from early drug discovery onward. Here, we propose outside‐in model development,... Show moreTo advance the systems approach in pharmacology, experimental models and computational methods need to be integrated from early drug discovery onward. Here, we propose outside‐in model development, a model identification technique to understand and predict the dynamics of a system without requiring prior biological and/or pharmacological knowledge. The advanced data required could be obtained by whole vertebrate, high‐throughput, low‐resource dose‐exposure‐effect experimentation with the zebrafish larva. Combinations of these innovative techniques could improve early drug discovery. Show less
According to the amyloid cascade hypothesis, accumulation of beta-amyloid (Aβ) peptides initiates the pathological cascade in Alzheimer's disease (AD). Early in the disease process, before clinical... Show moreAccording to the amyloid cascade hypothesis, accumulation of beta-amyloid (Aβ) peptides initiates the pathological cascade in Alzheimer's disease (AD). Early in the disease process, before clinical symptoms, an increase in Aβ concentrations leads to formation of toxic Aβ oligomers. These oligomers drive the neurodegeneration in AD brain. An important therapeutic strategy is to lower Aβ concentration in the CNS. Theoretically, this can prevent all subsequent pathological processes. Aβ is the final product of sequential proteolytic cleavages of the precursor protein APP. The drug effects on the individual pathways of APP processing are hard to predict, because these are regulated by a complex biochemical network. In this research, a 'systems pharmacology' approach was applied, integrating available knowledge of biology and pharmacology of system reactions into mathematical models. The APP-system-pharmacology-model provides important information about the APP processing pathways: (i) Aβ production inhibition leads to a relatively greater decrease in Aβ oligomers compared to monomers (ii) dissociation of oligomers contributes to the drug effect; (iii) Aβ42 is the major Aβ variant that contributes to the oligomer pool; (iv) inhibition of the enzyme GS stimulates alternative processing of APP by feedback. The APP-system-pharmacology-model can be of value in development of therapeutic interventions for AD. Show less
Brink, W.J. van den; Elassaiss, J.; Gonzalez Amoros, B.; Harms, A.C.; Graaf, P.H. van der; Hankemeier, T.; Lange, E.C.M. de 2017
A recently developed system-pharmacological model for the dynamics of receptor tyrosine kinases is used to compare di erent targets for drug action: one aiming at binding endogenous ligand needed... Show moreA recently developed system-pharmacological model for the dynamics of receptor tyrosine kinases is used to compare di erent targets for drug action: one aiming at binding endogenous ligand needed for phosphorylation and another binding re- ceptors at their kinase domains and thus preventing them to generate phosphory- lation. We obtain quantitative estimates for the e ectivity of the inhibitor which demonstrate the influence of drug-properties such as dose, a nity to target and drug-elimination rates. Show less
Cardiovascular safety issues related to changes in blood pressure, arise frequently in drug development. In the thesis __Towards predictive cardiovascular safety __ a systems pharmacology approach_... Show moreCardiovascular safety issues related to changes in blood pressure, arise frequently in drug development. In the thesis __Towards predictive cardiovascular safety __ a systems pharmacology approach__, a system-specific model is described to quantify drug effects on the interrelationship between mean arterial pressure, cardiac output, heart rate, stroke volume and total peripheral resistance in rats. The developed model can be used to quantify and predict the dynamic changes in the cardiovascular system (CVS) and elucidate the mechanism of action of novel compounds. An ultimate application of this system-specific CVS model would be to facilitate the anticipation of the clinical response based on preclinical data for newly developed compounds. Furthermore, the developed system-specific CVS model was combined with receptor models to quantify and predict the cardiovascular effects of the sphingosine 1-phosphate (S1P) receptor agonists, fingolimod-phosphate (fingolimod-P)and siponimod, in rats. This systems pharmacology model provided a quantitative understanding of the cardiovascular effects of fingolimod-P and siponimod and can be applied to predict the cardiovascular effects of other S1P receptor agonists with different selectivity profiles in rats. Ultimately, it may constitute a basis for prediction of cardiovascular effects of S1P receptor agonists in humans Show less
Parkinson__s disease is a progressive neurodegenerative disease, which is composed of many components, each caused by interplay of a number of genetic and nongenetic causes. As the blood-brain... Show moreParkinson__s disease is a progressive neurodegenerative disease, which is composed of many components, each caused by interplay of a number of genetic and nongenetic causes. As the blood-brain barrier (BBB) is a key player in the relationship between plasma and brain pharmacokinetics, the influences of disease states on BBB functionality in the various stages of the disease is important in order to judge on drug effects. This warrants a systems pharmacology approach to the development of novel drug treatments of Parkinson__s disease. Animal models of disease are an essential asset in this research. The research described in this thesis shows that the intracerebral rotenone rat model is a chronic and progressive animal model for Parkinson__s disease, displaying alpha-synuclein immunoreactivity and aggregation in several cases. The model has also shown that no changes were found in passive BBB permeability, nor in BBB transport modes of L-DOPA. However, a diseased condition was present as indicated by the clear effect of rotenone on the levels and elimination rates of DOPAC and HVA in brain that provided information on decreased dopamine concentrations at the diseased brain side. Altogether, it can be concluded that the intracerebral rotenone rat model is an animal model which is suitable as a tool in systems pharmacology research on Parkinson__s disease. Show less
