ABSTRACT
BACKGROUND: Cyclopropyl-methoxycarbonyl metomidate, or ABP-700, is a second generation analogue of etomidate, developed to retain etomidate's beneficial haemodynamic and respiratory profile but diminishing its suppression of the adrenocortical axis. The objective of this study was to characterise the safety and efficacy of 30-min continuous infusions of ABP-700, and to assess its effect on haemodynamics and the adrenocortical response in healthy human volunteers. METHODS: Five cohorts involving 40 subjects received increasing infusion doses of ABP-700, propofol 60 µg kg-1 min-1 or placebo. Safety was evaluated through adverse event (AE) monitoring, safety laboratory tests, and arterial blood gasses. Haemodynamic and respiratory stability were assessed by continuous monitoring. Adrenocortical function was analysed by adrenocorticotropic hormone (ACTH) stimulation tests. Clinical effect was measured using the modified observer's assessment of alertness/sedation (MOAA/S) and continuous bispectral index monitoring. RESULTS: No serious AEs were reported. Haemodynamic and respiratory effects included mild dose-dependent tachycardia, slightly elevated blood pressure, and no centrally mediated apnoea. Upon stimulation with ACTH, no adrenocortical depression was observed in any subject. Involuntary muscle movements (IMM) were reported, which were more extensive with higher dosing regimens. Higher dosages of ABP-700 were associated with deeper sedation and increased likelihood of sedation. Time to onset of clinical effect was variable throughout the cohorts and recovery was swift. CONCLUSIONS: Infusions of ABP-700 showed a dose-dependent hypnotic effect, and did not cause severe hypotension, severe respiratory depression, or adrenocortical suppression. The presentation and nature of IMM is a matter of concern. CLINICAL TRIAL REGISTRATION: NTR4735.
Subject(s)
Anesthetics, Intravenous/adverse effects , Etomidate/analogs & derivatives , Adolescent , Adrenal Cortex/drug effects , Adrenal Cortex/metabolism , Adult , Anesthetics, Intravenous/administration & dosage , Anesthetics, Intravenous/pharmacology , Blood Pressure/drug effects , Dose-Response Relationship, Drug , Etomidate/administration & dosage , Etomidate/adverse effects , Etomidate/pharmacology , Female , Healthy Volunteers , Heart Rate/drug effects , Humans , Infusions, Intravenous , Male , Middle Aged , Propofol/adverse effects , Propofol/pharmacology , Respiratory Mechanics/drug effects , Single-Blind Method , Young AdultABSTRACT
We have devised a purification scheme for human complement proteins C3, C3u, and C5. Affinity chromatography is employed to isolate each of these three proteins in a highly purified form. Typical yields were 910, 30, and 53 mg for C3, C3u, and C5, respectively, from 3 liters of human plasma. These yields reflect 31 and 32% recoveries for C3 and C5, respectively. The major advantages of this protocol over other published procedures are the application of affinity chromatography to yield high quality purified complement components, and the fact that the purification of C3, C3u, and C5 is part of a broader scheme designed for the isolation of over 20 plasma proteins from a single batch of plasma.
