A novel cardiovascular systems model to quantify drugs effects on the inter-relationship between contractility and other hemodynamic variables.

The use of systems-based pharmacological modeling approaches to characterize mode-of-action and concentration-effect relationships for drugs on specific hemodynamic variables has been demonstrated. Here, we (i) expand a previously developed hemodynamic system model through integration of cardiac output (CO) with contractility (CTR) using pressure-volume loop theory, and (ii) evaluate the contribution of CO data for identification of system-specific parameters, using atenolol as proof-of-concept drug. Previously collected experimental data was used to develop the systems model, and included measurements for heart rate (HR), CO, mean arterial pressure (MAP), and CTR after administration of atenolol (0.3-30 mg/kg) from three in vivo telemetry studies in conscious Beagle dogs. The developed cardiovascular (CVS)-contractility systems model adequately described the effect of atenolol on HR, CO, dP/dtmax, and MAP dynamics and allowed identification of both system- and drug-specific parameters with good precision. Model parameters were structurally identifiable, and the true mode of action can be identified properly. Omission of CO data did not lead to a significant change in parameter estimates compared to a model that included CO data. The newly developed CVS-contractility systems model characterizes short-term drug effects on CTR, CO, and other hemodynamic variables in an integrated and quantitative manner. When the baseline value of total peripheral resistance is predefined, CO data was not required to identify drug- and system-specific parameters. Confirmation of the consistency of system-specific parameters via inclusion of data for additional drugs and species is warranted. Ultimately, the developed model has the potential to be of relevance to support translational CVS safety studies.

Design of Intermittent Control for Cortisol Secretion Under Time-Varying Demand and Holding Cost Constraints.

OBJECTIVE: We take the release of stress hormone cortisol as a part of an intermittent control feedback system in contrast to the existing continuous models. By modeling cortisol secretion as an impulsive system, we design an impulsive controller as opposed to a continuous controller for adjusting cortisol levels while maintaining the blood cortisol levels within bounds that satisfy circadian demand and cost constraints. METHODS: We develop an analytical approach along with an algorithm for identifying both the timing and amplitude of the control. RESULTS: The model and the algorithm are tested by two examples to illustrate that the proposed approach achieves impulsive control and that the obtained blood cortisol levels render the circadian rhythm and the ultradian rhythm consistent with the known physiology of cortisol secretion. CONCLUSIONS: The approach successfully achieves the desired circadian impulsive control, which has great potential to be used in personalizing the medications in order to control the cortisol levels optimally. SIGNIFICANCE: This type of bioinspired intermittent controllers can be employed for designing noncontinuous controllers in treating Addisonian disease, which is caused by the adrenal deficiency.

Impulsive model of endocrine regulation with a local continuous feedback.

Whereas development of mathematical models describing the endocrine system as a whole remains a challenging problem, visible progress has been demonstrated in modeling its subsystems, or axes. Models of hormonal axes portray only the most essential interactions between the hormones and can be described by low-order systems of differential equations. This paper analyzes the properties of a novel model of a hypothalamic-pituitary axis, portraying the interactions in a chain of a release hormone (secreted by the hypothalamus), a tropic hormone (produced by the pituitary gland) and an effector hormone (secreted by a target gland). This model, unlike previously published ones, captures two prominent features of neurohormonal regulation systems, namely, the pulsatile (episodic) production of the release hormone and a complex non-cyclic feedback mechanism that maintains the involved hormone concentrations within certain biological limits. At the same time, the discussed model is analytically tractable; in particular, the existence of a so-called 1-cycle featured by a single pulse over one period is proven mathematically.

Parameter-robustness analysis for a biochemical oscillator model describing the social-behaviour transition phase of myxobacteria.

We develop a tool based on bifurcation analysis for parameter-robustness analysis for a class of oscillators and, in particular, examine a biochemical oscillator that describes the transition phase between social behaviours of myxobacteria. Myxobacteria are a particular group of soil bacteria that have two dogmatically different types of social behaviour: when food is abundant they live fairly isolated forming swarms, but when food is scarce, they aggregate into a multicellular organism. In the transition between the two types of behaviours, spatial wave patterns are produced, which is generally believed to be regulated by a certain biochemical clock that controls the direction of myxobacteria's motion. We provide a detailed analysis of such a clock and show that, for the proposed model, there exists some interval in parameter space where the behaviour is robust, i.e. the system behaves similarly for all parameter values. In more mathematical terms, we show the existence and convergence of trajectories to a limit cycle, and provide estimates of the parameter under which such a behaviour occurs. In addition, we show that the reported convergence result is robust, in the sense that any small change in the parameters leads to the same qualitative behaviour of the solution.