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Effects of Intranasal Epinephrine on Cerebrospinal Fluid Epinephrine Pharmacokinetics, Nasal Mucosa, Plasma Epinephrine Pharmacokinetics, and Cardiovascular Changes

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Abstract

Purpose

We aimed to assess intranasal (IN) epinephrine effects on cerebrospinal fluid (CSF) absorption, nasal mucosa quality, plasma epinephrine pharmacokinetics (PK), and cardiovascular changes in dogs.

Methods

CSF epinephrine concentration was measured and nasal mucosa quality was evaluated after IN epinephrine 4 mg and one or two 4 mg doses (21 min apart), respectively. Maximum plasma concentration [Cmax], time to Cmax [Tmax], area under the curve from 0 to 120 min [AUC0–120], and cardiovascular effects were evaluated after epinephrine IN (4 and 5 mg) and intramuscular (IM; 0.3 mg). Clinical observations were assessed.

Results

After epinephrine IN, there were no changes in CSF epinephrine or nasal mucosa. Cmax, Tmax, and AUC1–120 were similar following epinephrine IN and IM. Epinephrine IN versus IM increased plasma epinephrine at 1 min (mean ± SEM, 1.15 ± 0.48 for 4 mg IN and 1.7 ± 0.72 for 5 mg IN versus 0.47 ± 0.11 ng/mL for 0.3 mg IM). Epinephrine IN and IM produced similar heart rate and ECG results. Clinical observations included salivation and vomiting.

Conclusions

Epinephrine IN did not alter CSF epinephrine or nasal tissue and had similar cardiovascular effects as epinephrine IM. Epinephrine IN rapidly increased plasma epinephrine concentration versus epinephrine IM.

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Abbreviations

AUC0–120 :

area under the curve from 0 to 120 min

AUC0–24 :

area under the curve from 0 to 24 h; bpm, beats per minute

Cmax :

maximum plasma concentration

CNS:

central nervous system

CSF:

cerebrospinal fluid

GLP:

good laboratory practice

IM:

intramuscular

IN:

intranasal

LC-MS/MS:

liquid chromatography tandem-mass spectrometry

MRTlast :

mean residence time

PK:

pharmacokinetics

SEM:

standard error of the mean

SMBS:

sodium metabisulfite

Tmax :

time to reach maximum plasma concentration

USDA:

United States Department of Agriculture

USP:

United States Pharmacopeia

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Authors and Affiliations

  1. Mesa Science Associates, Inc., 4539 Metropolitan Ct, Frederick, MD, 21701, USA

    Kenneth L. Dretchen, Zack Mesa & Michael Mesa

  2. Robben Consulting LLC, Rochester, NY, USA

    Matthew Robben

  3. MRIGlobal, Kansas City, MO, USA

    Desmond Slade, Scott Hill, Kara Forsee & Claire Croutch

Authors
  1. Kenneth L. Dretchen
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  2. Zack Mesa
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  3. Matthew Robben
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  8. Michael Mesa
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Correspondence to Kenneth L. Dretchen.

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Dretchen, K.L., Mesa, Z., Robben, M. et al. Effects of Intranasal Epinephrine on Cerebrospinal Fluid Epinephrine Pharmacokinetics, Nasal Mucosa, Plasma Epinephrine Pharmacokinetics, and Cardiovascular Changes. Pharm Res 37, 103 (2020). https://doi.org/10.1007/s11095-020-02829-5

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