Electroencephalographic effects and serum concentrations after intranasal and intravenous administration of diazepam to healthy volunteers

Abstract

Aims: 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.

Conclusion: 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.

Figure 1

Mean (± s.d.) serum concentration-time profiles after intranasal (i.n.) administration of 4 (•) and 7 mg (▪) diazepam and 5 mg (▴) diazepam intravenous (i.v.), respectively, to seven healthy subjects.

Figure 2

Mean values from seven healthy subjects of the ERPs at the vertex electrode elicited by frequent nontarget events (1000 Hz tones, thin line) and rare target events (2000 Hz tones, thick line), respectively. Note the P300 evoked by the rare tones.

Figure 3

Mean values from seven subjects of the ERPs at the vertex electrode after hearing a rare target event (2000 Hz tone) after administration of placebo (thick line), 4 mg diazepam (thin line), 7 mg diazepam (dotted line) intranasally or 5 mg diazepam (dashed line) intravenously. Note the negative peak at 100 ms (N100) and the positive peak at 300 ms (P300).

Figure 4

Mean values from seven subjects of N100-P300 potential differences (obtained by averaging ERPs within each consecutive 2 min period) after administration of placebo intranasally, 4 mg diazepam intranasally (▪), 7 mg diazepam intranasally (diagonal square) or 5 mg diazepam intravenously (dotted square). Values (range 0.6–1.0) are illustrated as ratios of the P300-N100 difference for drug relative to placebo.