Disposition of propofol administered as constant rate intravenous infusions in humans

The disposition of the intravenous anesthetic propofol was studied when administered as a constant rate infusion at 3, 6, and 9 mg·kg-1·hr-1 for at least 2 hr to three groups of six patients each undergoing surgery under regional anesthesia. Arterial blood samples were collected at selected times during and up to 8 hr after infusion. Whole blood propofol concentrations were determined by high-performance liquid chromatography with fluorescence detection. Using non-linear least-squares regression analysis, the individual data sets were best fitted by a three-compartment open mamillary model with central elimination in 17 patients. In one patient a biexponential equation was more appropriate. Derived pharmacokinetic parameters expressed as mean values ± SD indicated an initial fast distribution (t( 1/2 π); 2.8 ± 1.2 min), with an intermediate phase (t( 1/2 α); 31.4 ± 14.7 min), and a long terminal phase (t( 1/2 β); 355 ± 227 min), a large volume of distribution at steady state (V(ss), 287 ± 213 L), and a high blood clearance (Cl(b), 1.7 ± 0.3 L/min). The fraction of drug in the central compartment in the terminal phase was low (Fc, 0.02). The elimination rate constant (K10, 0.1190 ± 0.0351 min-1) was large compared with the other transfer rate constants and was responsible for the large amount of drug eliminated during distribution. The fraction of drug eliminated during the terminal phase amounted to 0.28. The slow return of drug from remote tissues (K31, 0.0033 ± 0.0013 min-1) was rate limiting in the ultimate elimination. After 120 min of infusion, 85 ± 15% of the predicted concentration at steady state (C(ss)) was obtained; C(ss) was linearly related to the infusion rate. The pharmacokinetic profile of propofol appeared linear over the dosage range studied.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Endocrine profiles during administration of the new non-steroidal anti-androgen Casodex in prostate cancer

OBJECTIVE Casodex (Zeneca) is a new potent, long-acting non-steroidal anti-androgen, which produces androgen deprivation by blocking the androgen receptor. We evaluated the endocrine effects of Casodex 150 mg daily given in monotherapy as primary treatment for patients with prostate cancer. DESIGN As part of a large, multicentre study comparing the therapeutic effects of surgical castration with 150 mg/day Casodex in monotherapy for patients with prostate cancer, a subgroup of 23 patients on Casodex were studied in detail for changes in endocrine parameters. Serum levels of LH, FSH, testosterone, DHT, oestradiol, prolactin, sex hormone binding globulin and free testosterone were measured at the start of therapy and after 1, 4, 8, 12 and 24 weeks. Effects on libido, sexual activity and the appearance of hot flushes, breast pain and gynaecomastia were recorded. RESULTS Administration of Casodex resulted in a rise in LH levels in all patients with a mean increase after 24 weeks of 102% (P < 0.001). Mean FSH levels showed a limited increase (7%) after 24 weeks, which was significant only after 1 week (P < 0.001). As a result of the high LH levels, total testosterone levels increased after 24 weeks by 66% (P < 0.001), free testosterone by 57% (P < 0.001) and dihydrotestosterone by 24% (P = 0.0112). Parallel to testosterone, oestradiol levels rose by a mean of 66% (P < 0.001). Mean sex hormone binding globulin and prolactin levels rose by respectively 8% (P = NS) and 65% (P < 0.01). Despite an increase in testosterone levels, excellent androgen blockade was obtained, as shown by a decrease in prostate specific antigen levels in 22/23 patients. Libido was maintained in 8/11 patients, and sexual activity in 5/6. No patient complained of hot flushes. However, mild gynaecomastia and/or breast tenderness were seen in 48 and 30% of cases respectively. CONCLUSION Casodex 150 mg/day monotherapy resembles surgical castration in achieving androgen deprivation, despite an increase in LH and testosterone levels. In contrast to castration, libido and sexual activity are usually maintained and hot flushes are rare. However, mild gynaecomastia and/or breast tenderness were noted in 48 and 30% of patients

Evaluation and optimisation of a targetcontrolled infusion system for administering propofol to dogs as part of a total intravenous anaesthetic technique during dental surgery

The performance of a modified target-controlled infusion system was investigated in 16 dogs undergoing routine dental work, by comparing the predicted concentrations of propofol in venous blood samples with direct measurements; the optimum targets for the induction and maintenance of anaesthesia were also identified. The performance of a target-controlled infusion system is considered clinically acceptable when the median prediction error, a measure of bias, is not greater than +/-10 to 20 per cent, and the median absolute performance error, a measure of the accuracy, is not greater than 20 to 30 per cent. The results fell within these limits indicating that the system performed adequately. The optimal induction target was 3 microg/ml, and anaesthesia of adequate depth and satisfactory quality was achieved with maintenance targets of between 2.5 and 4.7 microg/ml propofol. The system was easy to use and the quality of anaesthesia was adequate for dental work