Electroencephalographic effects and serum concentrations after intranasal and intravenous administration of diazepam to healthy volunteers.
OBJECTIVE
To evaluate the electroencephalographic (EEG) effects, blood concentrations, vehicle irritation and dose-effect relationships for diazepam administered nasally.


METHODS
The study had a cross-over design with eight healthy volunteers (one drop out). It consisted of four legs with four different administrations: intranasal (i.n.) placebo, 4 mg diazepam i.n., 7 mg diazepam i.n. and 5 mg intravenous (i.v.) diazepam. Polyethylene glycol 300 (PEG300) was used as a vehicle in the nasal formulations to solubilize a clinically relevant dose of diazepam. Changes in N100, P200 and P300 brain event-related potentials (ERP) elicited by auditory stimulation and electroencephalographic beta-activity were used to assess effects on neurological activity.


RESULTS
The mean [95% confidence intervals] differences between before and after drug administration values of P300-N100 amplitude differences were -0.9 [-6.5, 4.7], -6.4 [-10.1, -2,7], -8.6 [-11.4, -5.8] and -9.6 [-12.1, -7.1] for placebo, 4 mg i.n., 7 mg i.n. and 5 mg i.v. diazepam, respectively, indicating statistically significant drug induced effects. The bioavailabilities of 4 and 7 mg i.n. formulations, were found to be similar, 45% [32, 58] and 42% [22, 62], respectively.


CONCLUSIONS
The present study indicates that it is possible to deliver a clinically effective nasal dose of diazepam for the acute treatment of epilepsy, using PEG300 as a solubilizer.
Lindhardt
K
K
The Royal Danish School of Pharmacy, Department of Pharmaceutics, Universitetsparken 2, 2100 Copenhagen, Denmark.
Gizurarson
S
S
Stefánsson
S B
SB
Olafsson
D R
DR
Bechgaard
E
E
D000281:Administration, Intranasal; D000328:Adult; D000927:Anticonvulsants / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D018592:Cross-Over Studies; D003975:Diazepam / Q000097:blood / Q000493:pharmacokinetics*; D004311:Double-Blind Method; D004569:Electroencephalography / Q000187:drug effects; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D011092:Polyethylene Glycols
D000927:Anticonvulsants; D011092:Polyethylene Glycols; D003975:Diazepam