title: Pharmacokinetics and pharmacodynamics of a new highly concentrated intranasal midazolam formulation for conscious sedation.
abstract: To evaluate the pharmacokinetics, pharmacodynamics, nasal tolerance and effects on sedation of a highly concentrated aqueous intranasal midazolam formulation (Nazolam) and to compare these to intravenous midazolam.
  
  
  
  In this four-way crossover, double-blind, double-dummy, randomized, placebo-controlled study, 16 subjects received 2.5 mg Nazolam, 5.0 mg Nazolam, 2.5 mg intravenous midazolam or placebo on different occasions. Pharmacokinetics of midazolam and α-hydroxy-midazolam were characterized and related to outcome variables for sedation (saccadic peak velocity, the Bond and Lader visual analogue scale for sedation, the simple reaction time task and the observer's assessment of alertness/sedation). Nasal tolerance was evaluated through subject reporting, and ear, nose and throat examination.
  
  
  
  Nazolam bioavailability was 75%. Maximal plasma concentrations of 31 ng ml-1(CV, 42.3%) were reached after 11 min (2.5 mg Nazolam), and of 66 ng ml-1(coefficient of variability, 31.5%) after 14 min (5.0 mg Nazolam). Nazolam displayed a significant effect on OAA/S scores. Sedation onset (based on SPV change) occurred 1 ± 0.7 min after administration of 2.5 mg intravenous midazolam, 7 ± 4.4 min after 2.5 mg Nazolam, and 4 ± 1.8 min after 5 mg Nazolam. Sedation duration was 118 ± 95.6 min for 2.5 mg intravenous midazolam, 76 ± 80.4 min for 2.5 mg Nazolam, and 145 ± 104.9 min for 5.0 mg Nazolam. Nazolam did not lead to nasal mucosa damage.
  
  
  
  This study demonstrates the nasal tolerance, safety and efficacy of Nazolam. When considering the preparation time needed for obtaining venous access, conscious sedation can be achieved in the same time span as needed for intravenous midazolam. Nazolam may offer important advantages in conscious sedation.
authors: Centre for Human Drug Research (CHDR), Leiden, The Netherlands.
authors: Lenneke
authors: L
authors: Schrier
authors: Centre for Human Drug Research (CHDR), Leiden, The Netherlands.
authors: Rob
authors: R
authors: Zuiker
authors: MEDIR B.V., Doorn, The Netherlands.
authors: Frans W H M
authors: FW
authors: Merkus
authors: Centre for Human Drug Research (CHDR), Leiden, The Netherlands.
authors: Erica S
authors: ES
authors: Klaassen
authors: Centre for Human Drug Research (CHDR), Leiden, The Netherlands.
authors: Zheng
authors: Z
authors: Guan
authors: TCIM B.V., Willemstad, The Netherlands.
authors: Bert
authors: B
authors: Tuk
authors: Centre for Human Drug Research (CHDR), Leiden, The Netherlands.
authors: Joop M A
authors: JM
authors: van Gerven
authors: 3D-PharmXchange B.V., Tilburg, The Netherlands.
authors: Ronald
authors: R
authors: van der Geest
authors: Centre for Human Drug Research (CHDR), Leiden, The Netherlands.
authors: Geert Jan
authors: GJ
authors: Groeneveld
mesh_terms: D000281:Administration, Intranasal; D061605:Administration, Intravenous; D000328:Adult; D001682:Biological Availability; D016292:Procedural Sedation / Q000379:methods*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D008874:Midazolam / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D008875:Middle Aged; D009297:Nasal Mucosa / Q000187:drug effects / Q000378:metabolism; D011930:Reaction Time / Q000187:drug effects; D055815:Young Adult
chemical_list: D006993:Hypnotics and Sedatives; C040081:1-hydroxymethylmidazolam; D008874:Midazolam
keywords: conscious sedation; intranasal; midazolam; pharmacodynamics; pharmacokinetics