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Potential for intranasal drug delivery to alter cerebrospinal fluid outflow via the nasal turbinate lymphatics.

Kim H, Moore SA, Johnston MG - Fluids Barriers CNS (2014)

Bottom Line: Specifically, the delivery of NG-monomethyl L-arginine (L-NMMA) significantly increased CSF absorption by 2.29 fold over no treatment (2.29 ± 0.34 mL/min), while the thromboxane A2 analogue U46619 resulted in a 2.44 fold increase in CSF absorption over no treatment (2.44 ± 0.55 mL/min).Saline delivery did not significantly increase CSF absorption (0.88 ± 0.097 mL/min).A trend of increased CSF absorption upon noradrenaline delivery was observed: however, this did not reach statistical significance.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto and Sunnybrook Research Institute, Toronto, Canada. hkim@sri.utoronto.ca.

ABSTRACT

Background: Cerebrospinal fluid absorption (CSF) at the cribriform plate is mediated by direct extracranial connections to the lymphatic system. Given the accessibility of these pharmacologically responsive vessels we hypothesized that the rate of CSF outflow can be modulated via the intranasal delivery of drugs known to affect lymphatic contractile activity.

Findings: Fluid was infused into the lateral ventricle of anesthetized sheep and inflow rate and CSF pressure measured during intranasal administration of pharmacological agents. CSF absorption was calculated at steady-state CSF pressures. The ability of a pharmacological agent to alter CSF absorption was related to the steady-state intracranial pressure (ICP), the concentration and the class of pharmacological agent delivered. An increase in drug concentration correlated with an increase in CSF absorption at high ICP (45 cm H2O, r = 0.42, p = 0.0058). Specifically, the delivery of NG-monomethyl L-arginine (L-NMMA) significantly increased CSF absorption by 2.29 fold over no treatment (2.29 ± 0.34 mL/min), while the thromboxane A2 analogue U46619 resulted in a 2.44 fold increase in CSF absorption over no treatment (2.44 ± 0.55 mL/min). Saline delivery did not significantly increase CSF absorption (0.88 ± 0.097 mL/min). A trend of increased CSF absorption upon noradrenaline delivery was observed: however, this did not reach statistical significance. Increasing drug concentrations inversely correlated with CSF outflow resistance across all drug classes (r = -0.26, p = 0.046).

Conclusions: The administration of nebulized pharmacological agents intranasally has the potential to provide an alternate method to non-invasively modulate CSF absorption and outflow resistance.

No MeSH data available.


Related in: MedlinePlus

Delivery of pharmacological agents alters CSF outflow resistance. To address whether a correlation existed between an overall drug effect and resistance, data points from all agents under no drug treatment (NT), the delivery of the first set of agents (drug conc.#1; 50 μM NA, 10 μM L-NMMA, 0.1 μM U46619) and the delivery of the second set of agents (drug conc.#2; 500 μM NA, 100 μM L-NMMA, 1 μM U46619) were plotted against resistance to outflow, which was derived from the linear regression analysis of the raw data. The straight line linking the averages within each treatment group was calculated with the Pearson correlation test.
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Figure 5: Delivery of pharmacological agents alters CSF outflow resistance. To address whether a correlation existed between an overall drug effect and resistance, data points from all agents under no drug treatment (NT), the delivery of the first set of agents (drug conc.#1; 50 μM NA, 10 μM L-NMMA, 0.1 μM U46619) and the delivery of the second set of agents (drug conc.#2; 500 μM NA, 100 μM L-NMMA, 1 μM U46619) were plotted against resistance to outflow, which was derived from the linear regression analysis of the raw data. The straight line linking the averages within each treatment group was calculated with the Pearson correlation test.

Mentions: Given that the observed total drug effect increased overall CSF absorption (Figure 3B) we hypothesized that this would correlate with a decrease in CSF outflow resistance under steady-state pressure. Indeed, we observed that increasing drug concentrations correlated inversely with outflow resistance across all drug classes (r = -0.26, p = 0.046 one-way probability) (Figure 5).


Potential for intranasal drug delivery to alter cerebrospinal fluid outflow via the nasal turbinate lymphatics.

Kim H, Moore SA, Johnston MG - Fluids Barriers CNS (2014)

Delivery of pharmacological agents alters CSF outflow resistance. To address whether a correlation existed between an overall drug effect and resistance, data points from all agents under no drug treatment (NT), the delivery of the first set of agents (drug conc.#1; 50 μM NA, 10 μM L-NMMA, 0.1 μM U46619) and the delivery of the second set of agents (drug conc.#2; 500 μM NA, 100 μM L-NMMA, 1 μM U46619) were plotted against resistance to outflow, which was derived from the linear regression analysis of the raw data. The straight line linking the averages within each treatment group was calculated with the Pearson correlation test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3927830&req=5

Figure 5: Delivery of pharmacological agents alters CSF outflow resistance. To address whether a correlation existed between an overall drug effect and resistance, data points from all agents under no drug treatment (NT), the delivery of the first set of agents (drug conc.#1; 50 μM NA, 10 μM L-NMMA, 0.1 μM U46619) and the delivery of the second set of agents (drug conc.#2; 500 μM NA, 100 μM L-NMMA, 1 μM U46619) were plotted against resistance to outflow, which was derived from the linear regression analysis of the raw data. The straight line linking the averages within each treatment group was calculated with the Pearson correlation test.
Mentions: Given that the observed total drug effect increased overall CSF absorption (Figure 3B) we hypothesized that this would correlate with a decrease in CSF outflow resistance under steady-state pressure. Indeed, we observed that increasing drug concentrations correlated inversely with outflow resistance across all drug classes (r = -0.26, p = 0.046 one-way probability) (Figure 5).

Bottom Line: Specifically, the delivery of NG-monomethyl L-arginine (L-NMMA) significantly increased CSF absorption by 2.29 fold over no treatment (2.29 ± 0.34 mL/min), while the thromboxane A2 analogue U46619 resulted in a 2.44 fold increase in CSF absorption over no treatment (2.44 ± 0.55 mL/min).Saline delivery did not significantly increase CSF absorption (0.88 ± 0.097 mL/min).A trend of increased CSF absorption upon noradrenaline delivery was observed: however, this did not reach statistical significance.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto and Sunnybrook Research Institute, Toronto, Canada. hkim@sri.utoronto.ca.

ABSTRACT

Background: Cerebrospinal fluid absorption (CSF) at the cribriform plate is mediated by direct extracranial connections to the lymphatic system. Given the accessibility of these pharmacologically responsive vessels we hypothesized that the rate of CSF outflow can be modulated via the intranasal delivery of drugs known to affect lymphatic contractile activity.

Findings: Fluid was infused into the lateral ventricle of anesthetized sheep and inflow rate and CSF pressure measured during intranasal administration of pharmacological agents. CSF absorption was calculated at steady-state CSF pressures. The ability of a pharmacological agent to alter CSF absorption was related to the steady-state intracranial pressure (ICP), the concentration and the class of pharmacological agent delivered. An increase in drug concentration correlated with an increase in CSF absorption at high ICP (45 cm H2O, r = 0.42, p = 0.0058). Specifically, the delivery of NG-monomethyl L-arginine (L-NMMA) significantly increased CSF absorption by 2.29 fold over no treatment (2.29 ± 0.34 mL/min), while the thromboxane A2 analogue U46619 resulted in a 2.44 fold increase in CSF absorption over no treatment (2.44 ± 0.55 mL/min). Saline delivery did not significantly increase CSF absorption (0.88 ± 0.097 mL/min). A trend of increased CSF absorption upon noradrenaline delivery was observed: however, this did not reach statistical significance. Increasing drug concentrations inversely correlated with CSF outflow resistance across all drug classes (r = -0.26, p = 0.046).

Conclusions: The administration of nebulized pharmacological agents intranasally has the potential to provide an alternate method to non-invasively modulate CSF absorption and outflow resistance.

No MeSH data available.


Related in: MedlinePlus