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Pharmacokinetics and anti-inflammatory effect of naproxen in rats with acute and subacute spinal cord injury

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Abstract

Previous reports have warned about the influence of spinal cord injury (SCI) on the pharmacokinetics of various drugs. However, the role of SCI in the efficacy and safety of pharmacotherapy remains unknown. Thereby, our aim was to explore the role of SCI on pharmacokinetics and anti-inflammatory effect of naproxen in response to a local inflammatory challenge. Rats received a severe contusive SCI at T9 or sham injury. Pharmacokinetics of a single intravenous dose of naproxen (10 mg kg−1) was studied at days 1 and 15 post-surgery. For the anti-inflammatory assessment, carrageenan was subcutaneously injected in forelimb and hindlimb paws at the same post-surgery periods, and naproxen efficacy was evaluated measuring paw swelling. Plasma protein concentrations and body weight changes were also determined. Plasma naproxen levels and pharmacokinetic parameters were unchanged by acute injury, but subacute injury generated alterations in volume of distribution, clearance, and bioavailability, resulting in significantly reduced plasma naproxen concentrations, in the absence of changes in plasma proteins. Assessment of naproxen anti-inflammatory activity during the acute stage of injury could not be determined because of carrageenan failure to elicit swelling. During the subacute stage, naproxen anti-inflammatory effect on forelimbs (above injury) was similar to that observed in sham-injured animals, while it was almost absent in paralyzed hindlimbs. Under conditions of SCI and peripheral inflammation, pharmacokinetics and anti-inflammatory activity of naproxen vary according to post-injury timing and neurological status of the assessed region.

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Funding

AR-C received a fellowship grant (number 378379) from the National Council for Science and Technology (CONACYT, http://www.conacyt.mx/pci/index.php) to support her doctoral studies.

Author information

AR-C was responsible for design of methodology, writing the protocol, performing the experimental procedures, collecting and analyzing data, interpreting results, and writing the original draft.

GC-H was responsible for conception and design of the study, providing study materials, animals, and analysis tools, analysis and interpretation of data, writing the original draft, and presentation of the critically revised work.

LF was responsible for oversight and leadership of the research activity planning and execution, including mentorship external to the core team, and analysis and interpretation of data.

AM-C was responsible for surgical experimental procedures and provided support in collecting and analyzing data.

GG-S was responsible for conception and design of the study, review of the protocol, analysis and interpretation of data, writing the original draft, and presentation of the critically revised work.

LC-A was responsible for design of methodology, management and coordination of research activity, planning, and execution. She also provided support for analysis and interpretation of data, as well as for draft writing.

All authors revised and approved the final version of the manuscript.

Correspondence to Gabriel Guízar-Sahagún.

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Ethical approval

All applicable international, national, and institutional guidelines for the care and use of animals were followed. The Ethics Committee in Research of the Instituto Mexicano del Seguro Social approved this study (file number: R-2015-3601-203). All efforts were made to minimize animal suffering and to reduce the number of animals used.

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The authors declare that they have no conflict of interest.

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Rodríguez-Cal y Mayor, A., Castañeda-Hernández, G., Favari, L. et al. Pharmacokinetics and anti-inflammatory effect of naproxen in rats with acute and subacute spinal cord injury. Naunyn-Schmiedeberg's Arch Pharmacol 393, 395–404 (2020). https://doi.org/10.1007/s00210-019-01745-9

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Keywords

  • Bioavailability
  • Carrageenan
  • Neurological status
  • Peripheral inflammation
  • Pharmacodynamics