title: A phase I, dose-escalation trial evaluating the safety and efficacy of emulsified isoflurane in healthy human volunteers.
abstract: BACKGROUND
  This first-in-human volunteer phase I clinical trial aimed to evaluate the safety, tolerability, and anesthesia efficacy of emulsified isoflurane (EI), an intravenously injectable formulation of isoflurane.
  
  
  METHODS
  Seventy-eight healthy volunteers were recruited in this open-label, single-bolus, dose-escalation, phase I trial and were allocated into 16 cohorts. Each volunteer received a single bolus injection of EI. The dose started with 0.3 mg/kg (for isoflurane) and was planned to end with 64.6 mg/kg. Postdose vital signs, physical examination, laboratory tests, chest radiograph, 12-lead electrocardiogram, and development of any adverse event were closely monitored as safety measurements. Effectiveness in producing sedation/anesthesia was assessed by Modified Observer's Assessment of Alertness/Sedation and Bispectral Index.
  
  
  RESULTS
  The dose escalation ended as planned. The most common adverse events associated with EI were injection pain (77 of 78, 98.7%) and transient tachycardia (22 of 78, 25.6%). Only at high doses (≥38.3 mg/kg) did EI cause transient hypotension (5 of 78, 6.4%) or apnea (11 of 78, 14.1%), but all the affected volunteers recovered uneventfully. Fast onset of unconsciousness (typically 40 s after injection) was developed in all volunteers receiving doses of 22.6 mg/kg or greater. Waking-up time and depression in Modified Observer's Assessment of Alertness/Sedation correlated well with EI dose. None of the postdose tests revealed any abnormal result.
  
  
  CONCLUSIONS
  EI is safe for intravenous injection in human volunteers in the dose range of 0.3 to 64.6 mg/kg. At doses of 22.6 mg/kg or higher, EI produced rapid onset of unconsciousness in all volunteers followed by fast, predictable, and complete recovery.
authors.affiliation: From the Department of Anesthesiology (H.H.), Department of Anesthesiology and Translational Neuroscience Center (R.L., J.L., W.Z., X.Y.), and Department of Neurological ICU (T.L.), West China Second Hospital, Sichuan University, Chengdu, Sichuan, P. R. China.
authors.forename: Han
authors.initials: H
authors.lastname: Huang
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.forename: Jin
authors.initials: J
authors.lastname: Liu
authors.forename: Wensheng
authors.initials: W
authors.lastname: Zhang
authors.forename: Tianzhi
authors.initials: T
authors.lastname: Liao
authors.forename: Xiaoqian
authors.initials: X
authors.lastname: Yi
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D000762:Anesthesia Recovery Period; D001049:Apnea / Q000139:chemically induced; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D064368:Healthy Volunteers / Q000706:statistics & numerical data*; D006801:Humans; D007022:Hypotension / Q000139:chemically induced; D007262:Infusions, Intravenous / Q000009:adverse effects / Q000379:methods; D007530:Isoflurane / Q000008:administration & dosage* / Q000009:adverse effects*; D008297:Male; D010146:Pain / Q000139:chemically induced; D012016:Reference Values; D013610:Tachycardia / Q000139:chemically induced; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D007530:Isoflurane