fospropofol and Pain

The development of new propofol formulations has advanced rapidly in the last ten years with the achievement of the marketing a new prodrug of propofol: fospropofol, pharmacologically different from the original compound. It is a water soluble compound that requires metabolism of the prodrug to propofol, which leads to a time delay between its administration and the appearance of its pharmacological effect. Its pharmacokinetic and pharmacodynamic characteristics are different to the original formula. Due to its formulation it does not cause pain on intravenous injection, does not lead to hyperlipidaemia or excess bacterial growth. Although it is currently unavailable in Spain, it has been approved by the FDA (American Food and Drug Administration) for sedation in controlled care in diagnostic and therapeutic procedures in adults. It must only be administered by personnel qualified to administer anaesthesia, and the patients must be monitored throughout the whole procedure.

Topics: Adult; Anesthetics; Biological Availability; Biotransformation; Clinical Trials, Phase III as Topic; Humans; Hypertriglyceridemia; Hypnotics and Sedatives; Infusions, Intravenous; Injections, Intravenous; Pain; Paresthesia; Prodrugs; Propofol; Solubility; Solvents; Spain; Tissue Distribution; United States; United States Food and Drug Administration; Water

The pharmacokinetics and pharmacodynamics of fospropofol (FP) disodium injection, propofol emulsion (PE), and cyclodextrin-enabled propofol (CDP) solution following bolus parenteral administration in dogs was evaluated. Three healthy male beagle dogs were treated in a three-way cross-over study (14 day washout period) with 6 mg/kg propofol equivalents. Blood samples were collected predose and at 16 points postdose through 1440 min and analyzed for propofol and FP, when appropriate. From 5 min predose to 30 min postdose, brain electrical activity [electroencephalography (EEG)] was recorded and analyzed by power spectrum analysis techniques. Each formulation appeared to be well tolerated with transient discomfort observed in the PE and CDP animals and minor excitability in the FP animals prior to loss of consciousness. Blood propofol followed three-compartment pharmacokinetic behavior and derived parameters were not statistically different except for elimination half-life from the CDP formulation and onset, and duration of anesthesia from the FP formulation. The effect site concentrations at 50% the maximum EEG effect for the FP and CDP formulations were approximately one-half that of the PE formulation. Onset and duration of anesthesia are correlated with modeled effect site propofol concentrations. The implications of formulation on pain on injection and propofol activity are discussed.

Topics: Anesthetics, Intravenous; Animals; beta-Cyclodextrins; Brain Waves; Chemistry, Pharmaceutical; Consciousness; Cross-Over Studies; Dogs; Electroencephalography; Emulsions; Half-Life; Injections, Intravenous; Male; Models, Biological; Pain; Propofol

Propofol-evoked injection site pain is not observed with fospropofol. We hypothesized that unlike propofol, fospropofol does not activate the irritant receptor, transient receptor potential 1 (TRPA1).. We tested the hypothesis using electrophysiology and behavioral studies.. Our data demonstrate that propofol (100 μM) evokes an inward current only in TRPA1-expressing neurons. However, fospropofol (100 μM and 1 mM) is unable to evoke depolarizing currents in either TRPA1-positive or TRPA1-negative neurons. Both propofol and fospropofol produced general anesthesia.. The lack of algogenic activity in fospropofol is most likely the result of its inability to activate TRPA1 on nociceptors.

Topics: Animals; Cells, Cultured; Hypnotics and Sedatives; Injections, Intravenous; Male; Pain; Prodrugs; Propofol; Rats; Rats, Sprague-Dawley; TRPA1 Cation Channel; TRPC Cation Channels