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Biomedical subjects

M Kurowski

Publications and source records attributed to M Kurowski.

At least 37 records · Page 2Linked to original sources
PubMed1996

A phase I and pharmacokinetic study of oral uracil, ftorafur, and leucovorin in patients with advanced cancer.

A phase I and pharmacokinetics study of oral uracil, ftorafur, and leucovorin was performed in patients with advanced cancer. Uracil plus ftorafur (UFT) was given in a 4:1 molar ratio in three divided doses for 28 consecutive days. Patient cohorts were treated at 200, 250, 300, and 350 mg/m2 of UFT daily. For all patients, 150 mg of leucovorin was given daily in three oral doses. A 1-week rest period followed each 28-day treatment course. Gastrointestinal toxicity, characterized by diarrhea, nausea, and vomiting, was dose-limiting at 350 mg/m2 UFT in patients who had received prior chemotherapy. Mild fatigue and transient hyperbilirubinemia were also common. In previously untreated patients, UFT at 350 mg/m2 was well-tolerated, suggesting this as an acceptable phase II dose in this schedule with leucovorin. Two of eight previously untreated patients with advanced colorectal cancer had partial responses with UFT (350 mg/m2) plus leucovorin. Pharmacokinetic parameters [ftorafur, uracil, 5-fluorouracil (5-FU), 5-methyltetrahydrofolate] showed wide interpatient variations. Plasma levels of 5-FU (Cmax 1.4 +/- 1.9 microM) were comparable to those achieved with protracted venous infusions, and folate levels (Cmax 6.1 +/- 3.6 microM) were sufficient for biochemical modulation. Ongoing study will determine if this convenient oral regimen will compare favorably in terms of efficacy, toxicity, and cost with intravenous fluoropyrimidine programs.

Aged↗
PubMed1994

The efficacy and relative bioavailability of diclofenac resinate in rheumatoid arthritis patients.

The pharmacodynamics and pharmacokinetics of 75 mg resin-bound diclofenac (resinate) were compared with enteric-coated tablets containing 75 mg of diclofenac in a double-blind randomized crossover trial in 16 patients suffering from rheumatoid arthritis. Diclofenac was significantly faster absorbed from the resinate than from the enteric coated formulation (tlag = 0.454 h vs. 0.998 h, tmax = 1.41 h vs. 2.56 h) and reached lower peak concentrations (Cmax = 1.64 micrograms/ml vs. 2.59 micrograms/ml). No significant differences were found concerning the area under the plasma level-time curves and the mean residence times. Smaller variances were found for the tmax and the mean residence times in the group treated with diclofenac resinate. Onset and duration of analgesia, as assessed by visual analogue scales were similar in both treatment groups, but did not correlate with the plasma concentrations. Four patients experienced adverse effects including gastric pain, transaminase increases, proteinuria and plasma creatinin increase. No uncommon adverse effects were observed with the new preparation.

Absorption↗
PubMed1989

The transsynovial distribution of oxaprozin.

Oxaprozin (Wy-21743) is a novel and unique compound among NSAIDs: it bears an aliphatic propionic acid function as a side chain in contrast to the large group of acetic acids and profens. The transsynovial distribution was studied in 18 RA-patients, who required articular surgery. Following a wash-out period of 7 days they were treated with 2 x 600 mg of oxaprozin. The patients were assigned to four different groups representing different treatment duration (2, 3, 4 and 5 days). 12 hours after the last dose during surgery synovial fluid and synovial tissue specimen were removed. Blood samples were taken simultaneously and analysed for oxaprozin employing HPLC. In the synovial tissue samples concentrations of 27 micrograms/g were detected. The concentrations were considerably higher than blood (10-17 micrograms/ml) or synovial fluid (4.9-7.6 micrograms/ml) levels. Oxaprozin shows a different pattern of transsynovial distribution and tissue affinity as compared to other NSAIDs.

Adult↗
PubMed1988

Transsynovial kinetics of piroxicam in patients with rheumatoid arthritis.

Twenty-four patients suffering from rheumatoid arthritis, who required articular puncture, participated in this open label study. Following a washout period of 7 days piroxicam 20 mg was administered once daily for 7 days. The average drug concentration in a dose interval in plasma fluctuated between 4.45 micrograms/ml and 8.02 micrograms/ml, and in synovial fluid it ranged between 4.16 micrograms/ml and 5.55 micrograms/ml. Piroxicam was eliminated from plasma with a half-life of 41.7 h and 43.2 h from synovial fluid as calculated from measured and interpolated data from all patients. Despite the short treatment period, clinical improvement could clearly be demonstrated.

Adult↗
PubMed1988

Transsynovial kinetics of indoprofen in patients with rheumatoid arthritis and cyclooxygenase-inhibition in vitro.

Twenty-four patients suffering from rheumatoid arthritis and requiring articular punctures were treated with 200 mg of indoprofen thrice daily for four days. The subjects were divided into four groups each of six patients. Following the last dose, blood and synovial fluid samples were taken simultaneously according to different time schedules. Maximum plasma levels of 17.5 micrograms/ml were observed after 2.5 h. Peak synovial fluid concentrations amounted to 8.1 micrograms/ml 4 h following the last dose. Elimination from synovial fluid occurred at 10.6 h compared to 9.3 h from plasma. Free synovial fluid levels of approximately 50 ng/ml are in the range of concentrations necessary for cyclooxygenase inhibition in mouse peritoneal macrophages.

Arthritis, Rheumatoid↗
PubMed1987

Effects of pirazolac on arachidonic acid metabolism in the human synovial system.

Six patients suffering from rheumatoid arthritis with massive knee joint effusions were treated with single daily doses of 600 mg pirazolac, a novel non-steroidal anti-inflammatory drug, for 3 days. Before the first dose, 3 hours after the second and the third dose, specimens of plasma and synovial fluid were drawn simultaneously. Plasma and synovial fluid concentrations of pirazolac, as determined by HPLC, amounted to 47.9 micrograms/ml and 19.8 micrograms/ml (Day 2) and 55.5 micrograms/ml and 18.7 micrograms/ml (Day 3), respectively. The samples were analyzed for PGE2, LTB4, LTC4 and LTD4 applying various extraction procedures and subsequent radioimmunoassays. PGE2 levels decreased during treatment from 928 pg/ml to 443 pg/ml after the third dose of pirazolac. LTB4 levels were slightly but insignificantly augmented. LTC4 and LTD4 concentrations were below the detection limit prior to and after administration of the drug.

Aged↗
PubMed1986

Transsynovial distribution and protein binding of pirazolac in patients with rheumatoid arthritis.

Following a washout period of 7 days, twenty-one patients suffering from rheumatoid arthritis and 3 from osteo-arthritis, who all required articular puncture were given a non-steroidal anti-inflammatory drug pirazolac 450 mg b.d. for 7 days. After discontinuation of the treatment the subjects were divided into 4 groups each of 6 patients. The non protein bound fraction of pirazolac in synovial fluid (0.86%) was significantly higher than that in plasma (0.53%). The average pirazolac concentration in plasma within the dosing interval fluctuated between 30.9 micrograms/ml and 59 micrograms/ml, and in synovial fluid between 16.6 micrograms/ml and 29.9 micrograms/ml. The half-life of pirazolac calculated from the measured and interpolated data from all patients was 30.9 h in plasma and 66.2 h in synovial fluid. The absolute free concentrations in plasma and synovial fluid (approx. 250 ng/ml) were in the range of the IC50-values for inhibition of cyclooxygenase in mouse peritoneal macrophages.

Adult↗
PubMed1986

[Metabolic interaction between cimetidine, ranitidine and amitriptyline/chlordiazepoxide].

The effects of cimetidine and ranitidine on plasma levels of amitriptyline and chlordiazepoxide were examined in a biphasic study with 12 young male volunteers. During the first phase all subjects received a fixed combination of 2 X amitriptyline (25 mg) and chlordiazepoxide (10 mg) daily for one week. After the last dose blood samples were drawn up to 72 hours in order to detect plasma levels of the drugs and their main metabolites. Following a wash-out-period of 7 days two groups of 6 subjects, each were formed in a randomized order. In addition to the mentioned medication 3 X 200 mg plus 1 X 400 mg of cimetidine daily or 2 X 150 mg of ranitidine daily were administered for one week. After discontinuation of amitriptyline/chlordiazepoxide the medication with H2-blockers was kept and blood samples were collected again for plasma analysis. Plasma level detections were carried out employing HPLC. The change of the area under the plasma level-time curve (AUC), total clearance and terminal half-life served as parameters indicating interaction. Under treatment with cimetidine plasma levels of amitriptyline and chlordiazepoxide were significantly (5%) increased, whereas such effects could not be observed with ranitidine. Due to these interactions under the conditions of coadministration of H2-blockers and amitriptyline and/or chlordiazepoxide the use of ranitidine is recommended.

Adult↗
PubMed1985

Bioavailability and pharmacokinetics of ketanserin in elderly subjects.

The bioavailability of ketanserin has been examined in a cross-over experiment in 21 elderly subjects (aged 59-72 years) by administration of tablets (40 mg), solution (40 mg) and injectable solution (10 mg). After two weeks of treatment with 40 mg ketanserin tablets further 18 blood samples for analysis were collected under steady-state conditions. Plasma levels were measured by HPLC. The absolute bioavailability of ketanserin tablets was 52.7%; their relative bioavailability compared to a solution containing an equal quantity of active compound was 85.5%. Therefore, the low absolute bioavailability of ketanserin cannot be attributed to the formulation. The active compound was rapidly liberated from the tablet, reaching a peak of 103.8 ng/ml after 0.97 h. Individual plasma level-time curves fitted to an open three compartment model and a half-life of 17.7 +/- 7.26 h was calculated for the terminal elimination phase. An average terminal elimination half-life of 15.4 +/- 4.2 ng/ml was found after administration of the ketanserin solution. Multiple dosing with 40 mg tablets b.d.s. resulted in an AUC over one dosing interval at steady-state of 666 +/- 201 ng X h/ml. The AUC extrapolated to infinity was 1200 +/- 405 ng X h/ml for the last tablet. This is 1.8-times the AUC in one dosing interval, and 2.3-times the AUC of a single dose. Under steady-state conditions, the mean peak plasma level was 155.1 ng/ml (1.08 h after dosing) and the terminal half-life was 19.1 +/- 5.1 h. For the metabolite ketanserinol terminal half-lives of 21.4 h after a single tablet and 31.0 h after discontinuation of multiple dosing were calculated. (ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed1985

Pharmacokinetics of indoprofen in elderly patients following repeated oral administration.

Twenty patients suffering from osteoarthritis or rheumatoid arthritis, aged between 60 and 85 years, received 200 mg indoprofen tablets thrice daily for 4-7 days. Following the last dose, plasma samples were drawn and analysed for indoprofen. The mean peak plasma concentration of 25.5 +/- 7.06 micrograms/ml indoprofen was reached after 1.25 +/- 0.71 h. The total area under the curve was calculated as 207.2 +/- 108.7 micrograms X h/ml. Indoprofen was eliminated with a mean elimination half-life of t1/2 beta = 8.29 +/- 2.93 h compared with 5.5 +/- 0.64 h in young subjects. In elderly patients receiving indoprofen, terminal plasma half-lives and area under the plasma level time curves corrected for body weight were moderately increased compared with young subjects whereas no significant differences were found for Vd beta. During the dosage interval indoprofen levels were appreciably higher in elderly patients than in healthy volunteers due to higher nadir values and slower elimination half-lives, whereas only minor differences could be detected for peak plasma levels. The differences observed between young healthy volunteers and elderly patients may be explained by the reduction of renal function with increasing age, since creatinine clearance was 30-40% lower than normal values. The dose schedule for elderly patients over 60 years of age should therefore be adjusted to 200 mg indoprofen twice daily. A further reduction of the total daily dose should be considered for patients suffering from renal diseases associated with reduced creatinine clearance.

Administration, Oral↗
PubMed1982

Relationship between EEG dynamics and pharmacokinetics of the benzodiazepine lormetazepam.

Clinical experience with benzodiazepines shows that observable effects like sedation do not persist as long as predicted by pharmacokinetic data. As a pharmacodynamic parameter closely related to effects of tranquillizers we used the quantitative pharmaco-EEG to compare time courses of these parameters with plasma level time courses. The subjects received single oral doses (1, 2 and 3 mg) of the benzodiazepine lormetazepam. Plasma levels were detected by radioimmunoassay. After fast absorption dose-dependent plasma level peaks could be determined 2 hours after administration. Applying an open two-compartment body model the drug was excreted with an elimination half-life of 10.3 hours. EEG power reached maximum changes after 1 hour in the delta, theta, alpha 2 and beta 1 frequency bands, as well as in the dominant alpha-frequency, and declined after that with different speeds to previous levels. Three to five hours after drug administration no significant changes could be detected. Vigilance sensitive EEG changes (delta, alpha 2) diminished earlier than indicated by plasma level half-lives. In contrast the decline of relative beta-power parallels plasma level time courses more closely under the 3 mg dose. In the present investigation, the computerized EEG appears to be a suitable indicator of monitoring time courses of sedative effects after single oral doses of benzodiazepines.

Administration, Oral↗
PubMed1979

The pharmacokinetics and biotransformation of the new benzodiazepine lormetazepam in humans. I. Absorption, distribution, elimination and metabolism of lormetazepam-5-14C.

The pharmacokinetics and metabolism of the new benzodiazepine lormetazepam were investigated in five male volunteers using the 14C-labelled drug (position 5). Lormetazepam was administered intravenously and orally, at a dose of 0.2 and 2 mg respectively, to each of the test subjects. Measurements of total radioactivity showed that the drug was absorbed completely and eliminated almost exclusively by the renal route. Maximum plasma level of active ingredient and total radioactivity were observed about 2 hours and 5 hours following oral administration. As early as 30 min following oral administration, concentration of active ingredient amounted to 80% of the maximum values. After both treatments the terminal half-life of total radioactivity and lormetazepam glucuronide in plasma corresponded to the half-life of elimination in urine of about 13 hours. After enzymatic hydrolysis with beta-glucuronidase/arylsulphatase, an average of 90% of total radioactivity from various urine and plasma samples was extractable with ether. Extracts from plasma contained only unchanged drug, indicating free and conjugated lormetazepam as ingredients of total radioactivity. Extracts from urine could be separated into lormetazepam and its N-demethylation derivative lorazepam. The relative amount of excreted lorazepam conjugate was demonstrated to be time-dependent, probably due to enterohepatic circulation. Since less than 6% of the total dose was demethylated by both routes of administration, it can be assumed that lormetazepam is the active product.

Absorption↗