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.
RCT Entities:
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.
Authors: Jaime Ibáñez; Jesús González de la Aleja; Juan A Gallego; Juan P Romero; Rosana A Saíz-Díaz; Julián Benito-León; Eduardo Rocon Journal: PLoS One Date: 2014-03-25 Impact factor: 3.240