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Epilepsy Research, 2009
Intranasal therapy has been proposed as an alternative for the management of seizure emergencies.... more Intranasal therapy has been proposed as an alternative for the management of seizure emergencies. The bioavailability, dose proportionality and tolerability of a supersaturated intranasal formulation of diazepam (DZP) solubilized in a glycofurol-water cosolvent system was investigated. Eight healthy volunteers were randomized into a single-blind, three-way crossover study to compare 5 and 10mg intranasal DZP doses of the investigational formulation with a 5mg dose of a DZP solution (DZP injectable, 5mg/mL) administered intravenously. Treatments were separated by a two-week washout period. Plasma samples for DZP analysis were collected pre-dose and at regular intervals up to 48h post-dose and assayed by HPLC. Visual analog scales (VAS) were used to assess tolerability (1-tolerable; 10-extremely intolerable) and pain (1-no pain; 4-extreme pain) at predefined time points. Following the 5 and 10mg doses, the median t(max) were 20 and 30min and the mean C(max) were 134.3+/-62 and 247.6+/-61ng/mL. Estimated bioavailability was 75% for both doses. Pain scores of 2 and 2.3 were observed following the 5 and 10mg doses; tolerability scores were 4.4 and 4.7. Pain and tolerability scores returned to baseline within 10h. Our formulation provided reasonable bioavailability, but was not well tolerated.
Pediatric Neurology, 2002
Acta Neurologica Scandinavica, 2009
Acta Neurologica Scandinavica, 2008
Acta Neurologica Scandinavica, 2009
Objective -The purpose of this pilot study was to determine the pharmacokinetics and tolerability... more Objective -The purpose of this pilot study was to determine the pharmacokinetics and tolerability of an investigational diazepam (DZP) formulation and a parenteral midazolam (MDZ) formulation following intranasal (i.n.) administration for the efficient treatment of seizure emergencies. Methods -Each subject received 5 mg of DZP and MDZ via both i.n. and intravenous routes in a four-way, randomized crossover trial. Blood samples were collected over 48 h. DZP and MDZ concentrations were measured using HPLC. Using analog scales, subjects rated tolerability (0 = no change from normal; 10 = maximum intolerability) and pain (0 = no pain; 4 = extreme pain) prior to and 0, 5, 15, 60 min, and 8 h after administration. Results -The C max and T max values for i.n. DZP and MDZ were 179.2 ng ⁄ ml and 28.8 min vs 62.8 ng ⁄ ml and 21.6 min, respectively. Immediately following i.n. administration, subjects reported tolerability scores of 6.75 and 6.0, and identical pain scores, 3.2, for DZP and MDZ, respectively. Conclusion -Both formulations were rapidly absorbed following i.n. administration with transient discomfort. DZP had a longer half-life, which may result in an extended duration of action. Further studies in large patient populations to evaluate the safety after long term use, efficacy and pharmacokinetics of i.n. DZP are warranted.
Epilepsy Research, 2009
Intranasal therapy has been proposed as an alternative for the management of seizure emergencies.... more Intranasal therapy has been proposed as an alternative for the management of seizure emergencies. The bioavailability, dose proportionality and tolerability of a supersaturated intranasal formulation of diazepam (DZP) solubilized in a glycofurol-water cosolvent system was investigated. Eight healthy volunteers were randomized into a single-blind, three-way crossover study to compare 5 and 10mg intranasal DZP doses of the investigational formulation with a 5mg dose of a DZP solution (DZP injectable, 5mg/mL) administered intravenously. Treatments were separated by a two-week washout period. Plasma samples for DZP analysis were collected pre-dose and at regular intervals up to 48h post-dose and assayed by HPLC. Visual analog scales (VAS) were used to assess tolerability (1-tolerable; 10-extremely intolerable) and pain (1-no pain; 4-extreme pain) at predefined time points. Following the 5 and 10mg doses, the median t(max) were 20 and 30min and the mean C(max) were 134.3+/-62 and 247.6+/-61ng/mL. Estimated bioavailability was 75% for both doses. Pain scores of 2 and 2.3 were observed following the 5 and 10mg doses; tolerability scores were 4.4 and 4.7. Pain and tolerability scores returned to baseline within 10h. Our formulation provided reasonable bioavailability, but was not well tolerated.
Pediatric Neurology, 2002
Acta Neurologica Scandinavica, 2009
Acta Neurologica Scandinavica, 2008
Acta Neurologica Scandinavica, 2009
Objective -The purpose of this pilot study was to determine the pharmacokinetics and tolerability... more Objective -The purpose of this pilot study was to determine the pharmacokinetics and tolerability of an investigational diazepam (DZP) formulation and a parenteral midazolam (MDZ) formulation following intranasal (i.n.) administration for the efficient treatment of seizure emergencies. Methods -Each subject received 5 mg of DZP and MDZ via both i.n. and intravenous routes in a four-way, randomized crossover trial. Blood samples were collected over 48 h. DZP and MDZ concentrations were measured using HPLC. Using analog scales, subjects rated tolerability (0 = no change from normal; 10 = maximum intolerability) and pain (0 = no pain; 4 = extreme pain) prior to and 0, 5, 15, 60 min, and 8 h after administration. Results -The C max and T max values for i.n. DZP and MDZ were 179.2 ng ⁄ ml and 28.8 min vs 62.8 ng ⁄ ml and 21.6 min, respectively. Immediately following i.n. administration, subjects reported tolerability scores of 6.75 and 6.0, and identical pain scores, 3.2, for DZP and MDZ, respectively. Conclusion -Both formulations were rapidly absorbed following i.n. administration with transient discomfort. DZP had a longer half-life, which may result in an extended duration of action. Further studies in large patient populations to evaluate the safety after long term use, efficacy and pharmacokinetics of i.n. DZP are warranted.