Direct nose-to-brain delivery of diazepam via trigeminal nerve contributes to rapid seizure suppression in pentylenetetrazole-induced status epilepticus model rats

Abstract

The purpose of our present study was to elucidate the involvement of the direct transfer to the brain after intranasal (i.n.) administration of diazepam (DZP), and to provide findings whether i.n. the administration could be used to obtain rapid onset of pharmacological action. We determined the blood and brain kinetics of DZP after administrations of i.n. and other routes, and the relationship between their concentrations and rapid seizure suppression effect; furthermore, and evaluated the distribution process of DZP to the brain. There was a negative connection between the plasma concentration and the amount of DZP delivery to the brain from the systemic circulation during the period that followed intravenous and intrarectal injection before the onset of seizure suppression. I.n. administration resulted in the seizure suppression time below the correlation curve: the seizure suppression effects were observed earlier than estimated despite the low plasma concentrations of DZP, suggesting the involvement of direct nose-to-brain delivery of DZP. The time to maximum concentration (Tmax) in the forebrain, hindbrain, olfactory bulb (OB), trigeminal nerve (TN), and cerebrospinal fluid (CSF) after i.n. the administration was 3 min, which was shorter than the Tmax of the plasma concentration. In fluorescence imaging using Rhodamin-B-base, the TN and the area of the vicinity of the thalamus had stronger fluorescence 1 and 3 min after i.n. administration, compared with the OB and CSF. In summary, direct brain delivery of DZP requires the TN and it was suggested that distribution to the vicinity of the thalamus via the TN may be connected to the quick seizure suppression effect.


Keywords: Status Epilepticus, Diazepam, Intranasal Administration, Nose-to-Brain, Trigeminal Nerve

Keywords: status epilepticus, Diazepam, intranasal administration, nose-to-brain, trigeminal nerve

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Author Biographies

Kazutoshi Watanabe, Laboratory of Hospital Pharmacy, Josai University, 1-1 Keyakidai, Sakado, Saitama 350-0295, Japan

Laboratory of Hospital Pharmacy, Josai University, 1-1 Keyakidai, Sakado, Saitama 350-0295, Japan

Soichiro Kimura, Laboratory of Hospital Pharmacy, Josai University, 1-1 Keyakidai, Sakado, Saitama 350-0295, Japan

Laboratory of Hospital Pharmacy, Josai University, 1-1 Keyakidai, Sakado, Saitama 350-0295, Japan

Yutaro Hazama, Laboratory of Hospital Pharmacy, Josai University, 1-1 Keyakidai, Sakado, Saitama 350-0295, Japan

Laboratory of Hospital Pharmacy, Josai University, 1-1 Keyakidai, Sakado, Saitama 350-0295, Japan

Yasunori Morimoto, Laboratory of Hospital Pharmacy, Josai University, 1-1 Keyakidai, Sakado, Saitama 350-0295, Japan

Laboratory of Hospital Pharmacy, Josai University, 1-1 Keyakidai, Sakado, Saitama 350-0295, Japan

Hideo Ueda, Laboratory of Hospital Pharmacy, Josai University, 1-1 Keyakidai, Sakado, Saitama 350-0295, Japan

Laboratory of Hospital Pharmacy, Josai University, 1-1 Keyakidai, Sakado, Saitama 350-0295, Japan

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Watanabe K, Kimura S, Hazama Y, Morimoto Y, Ueda H. Direct nose-to-brain delivery of diazepam via trigeminal nerve contributes to rapid seizure suppression in pentylenetetrazole-induced status epilepticus model rats. JDDT [Internet]. 15Jan.2023 [cited 27Jan.2023];13(1):44-6. Available from: https://jddtonline.info/index.php/jddt/article/view/5886