Search arXiv⌕ Search
Home/Archive/arXiv

arXiv · 2006.05519

Large-volume intrathecal administrations: impact on CSF pressure and safety implications

Vasily Belov·Janine Appleton·Stephan Levin·Pilar Giffenig·Beata Durcanova·Mikhail Papisov
View original source ↗Read source document ↗Export metadata ↓

Abstract

The increasing number of studies demonstrates the high potency of the intrathecal (IT) route for the delivery of biopharmaceuticals to the central nervous system (CNS). Our earlier data exhibited that both the infused volume and the infusion rate can regulate the initial disposition of the administered solute within the cerebrospinal fluid (CSF). On the other hand, fast additions of large volumes of liquid to the CSF inevitably raise the intracranial pressure (ICP), which may in turn lead to adverse reactions if the physiologically delimited threshold is exceeded. While long-term biological effects of elevated ICP (hydrocephalus) are known, the safety thresholds pertaining to short-term ICP elevations caused by IT infusions have not yet been characterized. This study aimed to investigate the dynamics of ICP in rats and non-human primates (NHPs) with respect to IT infusion rates and volumes. The data revealed that the addition of a liquid to the CSF raised the ICP in a rate and volume-dependent manner. At low infusion rates (<0.12 ml/min in rats and <2 ml/min in NHPs), NHPs and rats displayed similar tolerance patterns for extended durations. Specifically, safe accommodations of such added volumes were mainly facilitated by the accelerated pressure-dependent CSF drainage into the blood, with ICPs stabilizing at different levels below the safety threshold of 28+/-4 mm Hg in rats and 50+/-5 mm Hg in NHPs. High infusion rates caused uncompensated ICP elevations rapidly exceeding the safety thresholds. Their tolerance was species-dependent and was facilitated by the compensatory role of the varied components of craniospinal compliance while not excluding the possibility of other contributing factors. In conclusion, large volumes of liquids can safely be delivered via IT routes provided that ICP is monitored as a safety factor and cross-species physiological differences are accounted for.

Explore related subjects

q-bio.TO

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Vasily Belov, Janine Appleton, Stephan Levin, Pilar Giffenig, Beata Durcanova, Mikhail Papisov. 2020-06-09. Large-volume intrathecal administrations: impact on CSF pressure and safety implications. https://arxiv.org/abs/2006.05519

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related papers

arXiv2026

A Combined ODE Model of Carbohydrate Fermentation and Colorectal Cancer

We formulate and analyze a system of non-linear ordinary differential equations that describe key metabolic and immunological interactions between butyrate produced by fiber-fermenting gut microbiota, colorectal cancer cells and host cell populations. The model is studied both independently and in conjunction with a pre-existing carbohydrate fermentation model. The parameter space is explored through sensitivity analyses. Simulation experiments are conducted to illustrate the emergence of varying dynamical behaviour driven by butyrate availability. Our model predicts that butyrate production is driven by fiber consumption and further supported by probiotics in the case of microbial dysbiosis. It also suggests that butyrate may help in suppressing tumour growth. We also show that by adding noise with sufficiently high intensity, cancer elimination occurs almost surely in infinite time and that this threshold level of noise intensity decreases with increasing butyrate concentrations.

q-bio.TO↗
arXiv2026

Intestinal villi and crypt density robustly maximizes nutrient absorption

The villi and crypts of the gastrointestinal tract increase the effective surface area of the intestinal mucosa, potentially enhancing nutrient absorption. It is commonly assumed that this is their primary function, and that a higher villi density necessarily leads to improved absorption. However, when villi are packed too closely together, diffusion can be hindered, potentially offsetting this benefit. In this work, we investigate quantitatively the relationship between the density of these structures and the overall efficiency of absorption. In three different simplified geometries, approximating leaf-like villi, finger-like villi, and colonic crypts, we calculate analytically the concentration profile and the absorption flux, assuming that there is only diffusion between these structures while the lumen is well mixed. When plotting the absorption flux per unit of gut length as a function of the structures' density, we observe that there is a density maximizing absorption. We study numerically this optimum. We find that it is robust to the nutrient absorption properties: a geometry optimal for one nutrient is close to optimum for another nutrient. Physiological data from various animal species fall within this predicted optimal range, consistent with the hypothesis that structure density is shaped by selection for efficient nutrient uptake.

q-bio.TO↗
arXiv2026

Interstitial flow in the chick yolk sac exhibits organ-scale patterns driven by segregated leakage and drainage

Interstitial flow plays a key role in drug delivery, angiogenesis, cancer, and edema. Recent studies have identified connected interstitial pathways that can transport material over long distances. However, the spatial scale of physiological interstitial flow remains unclear: despite the existence of connected pathways, flow may be dominated by nearby vascular filtration or extend over longer distances. Here, we identify organ-scale interstitial flow patterns in the chick yolk sac and elucidate the mechanisms that determine their spatial scale. The yolk sac contains an organ-scale interstitial region that enables large-scale flow patterns to be identified without truncation. Our approach combines experimental imaging with computational modeling of coupled blood and interstitial flow in the whole yolk sac. Scaling analysis identifies a hydraulic conductivity ratio that controls the transition from small-scale to organ-scale flow. In organ-scale patterns, we find interstitial flow speed to be substantially greater than the transvascular flow speed. Mechanistically, the organ-scale patterns arise from the spatial segregation of the leakage and drainage of interstitial fluid from the vessels. These findings have important implications for biological transport by interstitial flow, suggesting that flow-mediated cues may be sensed locally but generated nonlocally.

q-bio.TO↗