A Dose-Finding Study of Dexketoprofen in Patients Undergoing Laparoscopic Cholecystectomy: A Randomized Clinical Trial on Effects on the Analgesic Concentration of Oxycodone.

BACKGROUND: Dexketoprofen has been shown to provide efficient analgesia and an opioid-sparing effect after orthopedic surgery. In this dose-finding study, we evaluated the analgesic efficacy and opioid-sparing effect of dexketoprofen administered intravenously (i.v.) after laparoscopic cholecystectomy (LCC). METHODS: Twenty-four patients undergoing LCC were randomized to receive dexketoprofen 10 or 50 mg i.v. 15 min before the end of the surgery. Subjects were provided with 0.2 mg/kg of oxycodone at anesthesia induction. In the recovery room, pain was assessed with an 11-point numerical rating scale (NRS; score of 0 = no pain, score of 10 = most severe pain) every 10 min. When the NRS score was ≥3/10 at rest or ≥5/10 at wound compression, a plasma sample was taken for analysis of oxycodone [to determine the minimum effective concentration (MEC)], its metabolites, and dexketoprofen. After that, subjects were titrated with oxycodone 2 or 3 mg i.v. every 10 min until the NRS score was <3/10 at rest and <5/10 at wound compression. At this point, a second plasma sample was taken for analysis of oxycodone [minimum effective analgesic concentration (MEAC)], its metabolites, and dexketoprofen. RESULTS: At the onset of pain, the plasma oxycodone concentrations (MEC) were similar in the two groups: median 60 ng/mL (range 37-73) in the 10 mg group and median 52 ng/mL (range 24-79) in the 50 mg group. At the time of pain relief, the MEACs were 98 ng/mL (range 59-150) in the 10 mg group and 80 ng/mL (range 45-128) in the 50 mg group. The total doses of oxycodone needed to achieve pain relief were similar: 0.11 mg/kg (range 0-0.33) in the 10 mg group and 0.08 mg/kg (range 0-0.24) in the 50 mg group. Eleven subjects developed mild desaturation or a decreased respiratory rate after oxycodone titration. CONCLUSION: In the present double-blinded, randomized clinical trial, the need for a rescue opioid analgesic, oxycodone, was similar with the two dose levels of dexketoprofen-10 and 50 mg i.v.-after LCC.

The transfer of ketorolac tromethamine from maternal to foetal blood.

Thirty two women who were participating in an efficacy study comparing 10 mg ketorolac with 50 mg or 100 mg of pethidine in the relief of labour pain, underwent sampling of vein blood, for determination of plasma ketorolac concentrations. The sample was withdrawn at delivery and a sample of umbilical cord blood was withdrawn at the same time. The ratio of ketorolac concentrations in the cord blood sample: the maternal venous sample were calculated and plotted against the time elapsed between drug administration and sampling. Samples for one patient, withdrawn 24 min after dosing, had ketorolac concentrations below the quantification limit. The ratios in the remaining patients were all low and showed a tendency to increase with time. The mean ratio was 0.116 with a range of 0.04 in 2 patients, at 43 min and 1 h 6 min, to 0.25 at 6 h 34 min.

Pharmacokinetics of ketorolac tromethamine in humans after intravenous, intramuscular and oral administration.

The pharmacokinetics of ketorolac tromethamine, a potent non-narcotic analgesic agent used for relief of moderate to severe pain, has been studied in 15 healthy volunteers who received single 10 mg doses intravenously (i.v.), intramuscularly (i.m.) and orally (p.o.) in a three-way cross-over design. The kinetics of i.v. ketorolac were characterized by a terminal half-life of 5.09 h, a small plasma clearance (CL = 0.35 ml.min-1.kg-1) and a small tissue distribution (Vss = 0.11 l.kg-1, V beta = 0.17 l.kg-1; mean (SD). Following i.m. and p.o. administration, peak levels of approximately 0.8 microgram/ml were rapidly attained (tmax = 0.8 and 0.9 h, respectively) and the systemic bioavailability was essentially complete.

Ocular bioavailability and tissue distribution of [14C]ketorolac tromethamine in rabbits.

The ocular bioavailability of 0.5% [14C]ketorolac tromethamine administered topically (50 microL) to the eye was determined. The ocular bioavailability of ketorolac was 4% in anesthetized rabbits and was determined by comparing drug concentrations in the aqueous humor after topical application with those obtained after intracameral injection of an equivalent dose of 0.25 mg of ketorolac tromethamine per eye. Although ketorolac administered to the eye was completely absorbed systemically, concentrations of ketorolac (AUC) were, on the average, 13 times higher in the aqueous humor than in plasma after topical administration. In a separate ocular distribution study, peak concentrations of radioactivity were achieved in the ocular tissues and in plasma within 1 h post instillation. Concentrations of total radioactivity were highest in the cornea and sclera and lowest in the lens.

Pharmacokinetics of TRIS (hydroxymethyl-)aminomethane in healthy subjects and in patients with metabolic acidosis.

To investigate the pharmacokinetics of TRIS, an infusion of the buffer was given to 6 healthy volunteers (121 mg/kg = 1 mmol/kg;pH 7.4) and to 20 patients suffering from metabolic acidosis (109--376 mg/kg; pH 10.9). The drug exhibited two-compartment characteristics in volunteers (t0.5,beta = 5.6 h) and patients with intact renal function (t0.5,beta = 16.3--45.6 h). The final volume of distribution (V beta) indicated uptake into tissues, but equilibration between body compartments was slow. Mainly unchanged TRIS was eliminated by the kidney; 82% of the administered dose was recovered from 24 h-urine of healthy subjects. In the patients a linear correlation between creatinine-clearance and TRIS-clearance was observed, the latter always being somewhat greater than the former. Only insignificant amounts of the drug were found in bile and gastric juice. In anuric patients the plasma concentration of TRIS declined monoexponentially, with a half-life between 10 and 58 h. Haemodialysis or haemofiltration did not influence this process. From the data it seems questionable whether cellular uptake of TRIS is an important factor in the therapy of intracellular acidosis, but the possibility of drug accumulation must be borne in mind if repeated doses are given to the same patient.

Nonequilibrium steady-state differences in partial pressure of CO 2 and in concentration of weak acids and bases between blood and tissue.

Several investigators have demonstrated that under conditions where little or no gas exchange occurs across the alveolar capillary membrane the PCO(2) is higher in the alveolus than in the mixed venous blood, whereas there are no PO(2) differences. Gurtner et al. have explained the DeltaPCO(2) by a model in which H(+) dissociation of proteins due to an electrical field caused by a negatively charged capillary wall (Wien effect) sets up an intracapillary PCO(2) difference between wall and bulk phase which is maintained by blood flow. The model is not specific for CO(2) and predicts that weak acids should be concentrated in a manner similar to CO(2) whereas weak bases should be relatively excluded from the alveolar space. Measurements of the steady-state distribution of the uncharged forms of the weak acids 5,5-dimethyloxyazoladinedione (DMO) and barbital and of the weak base tris(hydroxymethyl)aminomethane (THAM) between mixed venous blood and a fluid-filled lobe of lung were made in living dogs. The results agree fairly well with the predicted values.