Understanding pharmacokinetics using realistic computational models of fluid dynamics biosimulation of drug distribution within the CSF space for intrathecal drugs. We developed a 3. D computational fluid dynamics model of the spinal canal, based on actual geometry reconstructed from MRI data and dynamics controlled by transient NavierStokes equations. The iterative model building process allowed for a detailed investigation of the principal transport mechanisms observable in this system. The results from this approach of using realistic anatomical features coupled with biophysical principles of fluid flow dynamics and physiological characteristics of the cerebrospinal system have offered insights into the primary factors that can influence the intrathecal distribution of drug after lumbar administration. By providing an industry unique framework for appropriate integration of biophysics first principles and clinical data into a dynamic system physiology platform, this technology allows for the simulation of different clinical scenarios to support decision making, bringing model based drug development to a next level. Considering the limited number of CSF modeling examples in the literature and the stringent safety and ethical restrictions on experiments and clinical trials related to spinal cord injury, we were motivated to introduce a new quantitative assessment method of drug distribution in the CSF to help assess results from preclinical experiments and ongoing clinical trials, and combine them with physiological observations at the level of tissue organ system interactions and selected physiochemical properties. The goal was to understand factors that could affect the pharmacokinetics of a therapeutic antibody administered in the CSF, contributing to a greater understanding of therapeutic delivery for spinal cord injury. One clinically relevant question that we could approach with the biophysical model described here was whether there is a practical distribution difference if the same dose and volume is administered by slow more than 6. Search metadata Search full text of books Search TV captions Search archived web sites Advanced Search. Ver Silencio Online 2016 Informacin completa sobre la pelcula Silencio en espaol latino, subtitulada. Simulating these two administration scenarios revealed that initially the drug would move up the intrathecal space at different velocities, and that the orientation of the drug delivery needle relative to the CSF space would have an influence on axial dispersion of the drug, whereby maximally laminar flows would enhance axial dispersion of the injected drug and more turbulent flow would aid in circumferential dispersion 2. However, when projected in the time scale of hours, those local differences would tend to dissipate, transport being dominated by the main driving forces of pulsation and breathing. These insights guided the clinical team when deciding on the clinical parameters of bolus administration to spinal cord injury patients enrolled in clinical trials, substituting to prior human dosing experimentation which would have been ethically difficult if not impossible to perform. In a meta analysis by Fettes et al., 2. Human clinical error can have a large impact on spinal anesthesia results within a population of clinicians who are commonly performing these types of treatments and assessments. Given that clinicians that have great experience in this procedure still produce variable results, there is need to better understand how drug is distributed throughout the CSF after intrathecal injection and what steps, if any, clinicians can take to use this effective drug delivery route more consistently. The model of spinal CSF dynamics presented here allowed for the approximation of molecular drug concentration levels in the cervical spine following lumbar injection at certain time points post injection as a function of biophysical, as well as injection parameters. We introduce how biophysical modeling in pharmaceutical research and development, combining physiological observations at the tissue, organ and system level with. Wolfgang Amadeus Mozart, Soundtrack The Kings Speech. Wolfgang Amadeus Mozart grew up in Salzburg under the regulation of his strict father Leopold who also was a. A number of significant scientific events occurred in 2013, including the discovery of numerous Earthlike exoplanets, the development of viable labgrown ears, teeth. Cranium Intel Streaming' title='Cranium Intel Streaming' />Thus, differences in distribution over hours following either slow infusion or instantaneous bolus injection could be observed in the simulations 2. These results suggested that bolus injection would not lead to an inferior distribution range compared to slow infusion. Because bolus injection delivers the total amount of drug to the lumbar injection site almost instantaneously, driving forces are likely to exert their effect on all drug molecules over a longer period of time, therefore increasing the chance for the drug to reach distant cervical targets faster and with higher concentration. These results, although more qualitative in nature, provided the clinical team with useful confidence when deciding for bolus as the sole administration mode for later cohorts of ongoing clinical trials. Predicting the amount of drug at a particular level of the spinal column after administration is difficult. Previous attempts to use classical pharmacokinetic approaches for modeling drug delivery in the cerebrospinal fluid have worked reasonably well for describing the doseresponse relationship when the target site of drug effect is directly at the site of injection 2. Movies For Apple Ipod Cars. This has advanced the understanding and utility of spinal anesthesia for instance. However, when drug exposure after spinal administration occurs away from the site of injection, or the anticipated dose concentration effect relationship does not appear to hold, the limitations of the classical pharmacokinetic approach to spinal drug delivery become apparent. The further away the pharmacological target is from the site of administration, the more challenging it becomes to achieve a predictable concentration for attaining clinical effect. Reasons behind these difficulties were recently highlighted in an editorial by Drasner in the British Journal of Anaesthesia where he very colorfully recounts August Biers initial clinical report of spinal anesthesia with cocaine in 1. Consistent in both Biers experiment and current clinical practice is the problem of variability in clinical response that limits our knowledge of cerebrospinal fluid drug delivery. This editorial accompanied an article by Ruppen et al. Their results show that the range of concentrations one can measure from CSF is very large 2. This provides further confirmation that the intrathecal space does not behave as a well mixed volume and that measuring concentration in the CSF after injection to support a classical pharmacokinetic approach may not provide any meaningful data for analysis, or information for clinical decision making. What are the most important factors affecting intrathecal distribution With the challenges to interpreting the clinical data that exists for characterizing the dose concentration effect relationship in spinally administered agents, our approach for understanding the influence of biophysical forces on distribution appears to be well motivated. By approaching the problem from first principles, the contribution of physiologic forces due to breathing and cardiac cycles was predicted as a primary factor that allows a drug to distribute through the spinal canal. While this allows axial spread of the administered agent, our results show that subtle factors such as drug speed of injection, orientation of the injecting needle, and the amount of fluid administered will have a differentiating effect on the pattern of drug distribution in the CSF. Given the variability that can occur in the CSF distribution, it is not surprising that measured values within a population of patients may not have a strong correlation to either the amount of drug given, the patients response to the agent if directly measurable like anesthesia or to a number of other typical covariates that are commonly used to adjust patient dosage. These results provided evidence that allow us to assess the factors, which contribute the most significantly to variation in the overall distribution.