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 β‐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.

Is nose-to-brain transport of drugs in man a reality?

“…); Adrenocorticotropin 4±10 (nˆ54) (Derad et al 1998); Insulin (nˆ12) ; Diazepam ((nˆ8) ? (Lindhardt et al 2001).…”

“…It strongly supported the existence of a direct transport route for the drug from nose to brain in man. Lindhardt et al (2001) performed a study in eight volunteers to assess the intranasal administration of diazepam as an alternative to intravenous administration for treatment of acute epileptic seizures. The effect of the drug was evaluated by measuring electroencephalographic (EEG) effects.…”

Intranasal Delivery of Two Benzodiazepines, Midazolam and Diazepam, by a Microemulsion System

“…By the alternative route, diazepam should be easily administered by the surrounding people or caregivers and could dramatically improve the management of out-of-hospital seizures as well as the patient recovery. The intranasal administration of diazepam was evaluated in several studies, in which supersaturated formulations were used with solvents such as a glycofurol/water mixture [7,12], glycofurol/polyethylene glycol 200 [13,14], propylene glycol/ethanol [15], and polyethylene glycol 300 [16]. Human studies [7,12], which were conducted on human volunteers reported that subjects rated nasal diazepam as causing considerable pain immediately following administration.…”

Intranasal Delivery of Antiepileptic Medications for Treatment of Seizures

“…Greenblatt et al 35 established that the degree of impairment on digital-symbol substitution tests was directly correlated with the degree of change in new-onset beta wave activity after triazolam administration. Moreover, Lindhardt et al 32 demonstrated comparable changes in EEG amplitude in the 16 to 35 Hz range comparing 4 mg intranasal to 5 mg intravenous diazepam. Thus, these early studies examining formulation strategy, biopharmaceutics, and local tolerance were suggestive that nasal delivery of benzodiazepines could have a role in treatment of seizures.…”

“…[25][26][27][28][29][30][31][32][33][34] The main considerations from these data might be whether maximum plasma concentrations represented by C max are within ranges known to produce pharmacologic effects, and the second consideration is whether the concentrations are achieved rapidly enough to be appropriate for treating a seizure. Well-designed nasal preparations may demonstrate a pharmacokinetic profile in which the rate and extent of drug exposure is superior to intramuscular injection and approximates IV infusion (FIG.…”