Physiologically Based Pharmacokinetic Modelling: A Sub-Compartmentalized Model of Tissue Distribution

We present a sub-compartmentalized model of drug distribution in tissue that extends existing approaches based on the well-stirred tissue model. It is specified in terms of differential equations that explicitly account for the drug concentration in erythrocytes, plasma, interstitial and cellular space. Assuming, in addition, steady state drug distribution and by lumping the different sub-compartments, established models to predict tissue-plasma partition coefficients can be derived in an intriguingly simple way. This direct link is exploited to explicitly construct and parameterize the sub-compartmentalized model for moderate to strong bases, acids, neutrals and zwitterions. The derivation highlights the contributions of the different tissue constituents and provides a simple and transparent framework for the construction of novel tissue distribution models

Supervised Resistance Training Results in Changes in Postural Control in Patients With Multiple Sclerosis

Postural disturbances are one of the first reported symptoms in patients with Multiple Sclerosis (MS). The purpose of this study was to investigate the effect of supervised resistance training on postural control in MS patients. Postural control was assessed using amount of sway variability [Root Mean Square (RMS)] and temporal structure of sway variability [Lyapunov Exponent (LyE)] from 15 MS patients. Posture was evaluated before and after completion of three months of resistance training. There were significant differences between MS patients pretraining and healthy controls for both LyE (p = .000) and RMS (p = .002), but no differences between groups after training. There was a significant decrease in RMS (p = .025) and a significant increase in LyE (p = .049) for MS patients pre- to posttraining. The findings suggested that postural control of MS patients could be affected by a supervised resistance training intervention

Software Supported Modelling in Pharmacokinetics

A powerful new software concept to physiologically based pharmacokinetic (PBPK) modelling of drug disposition is presented. It links the inherent modular understanding in pharmacology with orthogonal design principles from software engineering. This concept allows for flexible and user-friendly design of pharmacokinetic whole body models, data analysis, hypotheses testing or extrapolation. The typical structure of physiologically-based pharmacokinetic models is introduced. The resulting requirements from a modelling and software engineering point of view and its realizations in the software tool MEDICI-PK [9] are described. Finally, an example in the context of drug-drug interaction studies is given that demonstrates the advantage of defining a whole-body pharmacokinetic model in terms of the underlying physiological processes quite impressively: A system of 162 ODEs is automatically compiled based on the specification of 7 local physiological processes only

Postural control strategy during standing is altered in patients with multiple sclerosis

Disturbances in balance are one of the first reported symptoms of Multiple Sclerosis (MS), yet limited research has been performed to classify the postural control deficits in this population. This study investigated the variability present in the sway patterns during quiet standing in patients with MS (PwMS) and healthy controls. Subjects were assessed (eyes open, closed) standing on a force platform. Variability of the sway patterns was quantified using a measure of amount of variability (root mean square; RMS) and two measures of temporal structure of variability (Lyapunov Exponent – LyE; Approximate Entropy – ApEn). RMS results revealed significantly higher amount of variability in the sway patterns of PwMS. PwMS also exhibit increased regularity (decreased ApEn) and decreased divergence (decreased LyE) during standing compared to healthy controls. Removing vision resulted in significantly decreased divergence (decreased LyE) in the MS subject group. These changes in the temporal structure correspond well with the theoretical model of the optimal movement variability hypothesis and the results support using variability measures to understand the mechanisms that underline postural control in PwMS and possibly other neurodegenerative disease pathologies

Coordination of trunk and foot acceleration during gait is affected by walking velocity and fall history in elderly adults

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.Background: Falling is a significant concern for many elderly adults but identifying individuals at risk of falling is difficult, and it is not clear how elderly adults adapt to challenging walking. Aims: The aim of the current study was to determine the effects of walking at non-preferred speeds on the coordination between foot and trunk acceleration variability in healthy elderly adults with and without fall history compared to healthy young adults. Methods: Subjects walked on a treadmill at 80% to 120% of their preferred walking speed while trunk and foot accelerations were recorded with wireless inertial sensors. Variability of accelerations were measured by root mean square, range, sample entropy, and Lyapunov exponent. The gait stability index was calculated using each variability metric in the frontal and sagittal plane by taking the ratio of trunk acceleration variability divided by foot acceleration variability. Results: Healthy young adults demonstrated larger trunk accelerations relative to foot accelerations at faster walking speeds compared to elderly adults, but both young and elderly adults show similar adaption to their acceleration regularity. Between group differences showed that elderly adult fallers coordinate acceleration variability between the trunk and feet differently compared to elderly non-fallers and young adults. Discussion: The current results indicate that during gait, elderly fallers demonstrate more constrained, less adaptable trunk movement relative to their foot movement and this pattern is different compared to elderly non-fallers and healthy young. Conclusions: Coordination between trunk and foot acceleration variability plays an important role in maintaining stability during gait.NIH T32 HD057850Frontiers Pilot and Collaborative Studies Funding Program (UL1TR000001)School of Health Professions Pilot Research Gran

Multiple Sclerosis Alters the Mechanical Work Performed on the Body\u27s Center of Mass During Gait

Patients with multiple sclerosis (MS) have less-coordinated movements of the center of mass resulting in greater mechanical work. The purpose of this study was to quantify the work performed on the body’s center of mass by patients with MS. It was hypothesized that patients with MS would perform greater negative work during initial double support and less positive work in terminal double support. Results revealed that patients with MS perform less negative work in single support and early terminal double support and less positive work in the terminal double support period. However, summed over the entire stance phase, patients with MS and healthy controls performed similar amounts of positive and negative work on the body’s center of mass. The altered work throughout different periods in the stance phase may be indicative of a failure to capitalize on passive elastic energy mechanisms and increased reliance upon more active work generation to sustain gait

The effect of pharmacological treatment on gait biomechanics in peripheral arterial disease patients

<p>Abstract</p> <p>Background</p> <p>Pharmacological treatment has been advocated as a first line therapy for Peripheral Arterial Disease (PAD) patients suffering from intermittent claudication. Previous studies document the ability of pharmacological treatment to increase walking distances. However, the effect of pharmacological treatment on gait biomechanics in PAD patients has not been objectively evaluated as is common with other gait abnormalities.</p> <p>Methods</p> <p>Sixteen patients were prescribed an FDA approved drug (Pentoxifylline or Cilostazol) for the treatment of symptomatic PAD. Patients underwent baseline gait testing prior to medication use which consisted of acquisition of ground reaction forces and kinematics while walking in a pain free state. After three months of treatment, patients underwent repeat gait testing.</p> <p>Results</p> <p>Patients with symptomatic PAD had significant gait abnormalities at baseline during pain free walking as compared to healthy controls. However, pharmacological treatment did not produce any identifiable alterations on the biomechanics of gait of the PAD patients as revealed by the statistical comparisons performed between pre and post-treatment and between post-treatment and the healthy controls.</p> <p>Conclusions</p> <p>Pharmacological treatment did not result in statistically significant improvements in the gait biomechanics of patients with symptomatic PAD. Future studies will need to further explore different cohorts of patients that have shown to improve significantly their claudication distances and/or their muscle fiber morphology with the use of pharmacological treatment and determine if this is associated with an improvement in gait biomechanics. Using these methods we may distinguish the patients who benefit from pharmacotherapy and those who do not.</p

Gait Variability Measures Reveal Differences between Multiple Sclerosis Patients and Healthy Controls

The purpose of this study was to determine the differences in gait variability between patients with multiple sclerosis (MS) and healthy controls during walking at a self-selected pace. Methods: Kinematics were collected during three minutes of treadmill walking for 10 patients with MS and 10 healthy controls. The Coefficient of Variation (CoV), the Approximate Entropy (ApEn) and the Detrended Fluctuation Analysis (DFA) were used to investigate the fluctuations present in stride length and step width from continuous strides. Results: ApEn revealed that patients with MS had significantly lower values than healthy controls for stride length (p \u3c .001) and step width (p \u3c .001). Conclusions: ApEn results revealed that the natural fluctuations present during gait in the stride length and step width time series are more regular and repeatable in patients with MS. These changes implied that patients with MS may exhibit reduced capacity to adapt and respond to perturbations during gait

Gait Mechanics are Different between Healthy Controls and Patients with Multiple Sclerosis

Multiple sclerosis (MS) causes severe gait problems in relatively young individuals, yet there have been limited studies to quantitatively identify the specific gait parameters that are affected. The purpose of this study was to define any differences in biomechanical gait parameters between patients with MS and healthy controls. A total of 31 MS patients and 31 healthy controls were evaluated: joint torques and joint powers were calculated at the ankle, knee, and hip during the stance phase of gait. The self-selected walking velocity was used as a covariate in the analysis to ensure that group differences were not due to differences in walking velocity between the MS and healthy control groups. Reduced angular range, less joint torque, and reduced joint power were seen in patients with MS. We also found significant correlations between biomechanical gait parameters and EDSS score, which provides a clinical rating of disease severity. Our findings provide a quantitative assessment of the gait mechanics employed in patients with MS. The altered lower extremity mechanics observed in patients with MS reflect both a neurological and strength deficit compared with healthy controls during walking