Biomedical subjects

S Eksborg

Publications and source records attributed to S Eksborg.

At least 73 records · Page 4Linked to original sources

PubMed1990

Effects on cyclo-oxygenase of low and high dose aspirin.

The study was undertaken to develop clinically applicable methods to detect the influence of low dose treatment with acetylsalicylic acid (ASA) on the platelet function. The cyclooxygenase activity of the platelets was measured by determination of the metabolite 12-HHT after challenge with arachidonic acid. Two healthy subjects received 600 mg ASA in a single dose. Two hours after intake the salicylate concentration level in plasma was 600 nmol/ml, with a 90 per cent reduction after 24 hours. The platelet cyclooxygenase activity (12-HHT) was completely and irreversibly inhibited within two hours after ASA intake. Five subjects received 75 mg ASA for eight consecutive days. The salicylate concentrations two hours after the intake of the first and last tablet were within 65 and 71 nmol/ml plasma, indicating that no accumulation of salicylate occurred during the treatment period. The decrease in cyclooxygenase activity during low dose treatment varied in the different subjects between 60 and 90 per cent. The rate of recovery of cyclooxygenase activity after termination of the low dose ASA treatment was faster than after the large single dose.

Adult↗

PubMed1990

Oral melphalan pharmacokinetics: influence of interferon-induced fever.

The influence of interferon-induced fever on oral melphalan pharmacokinetics has been studied in 10 myeloma patients in a randomized crossover design. The melphalan dose (0.25 mg/kg) was given alone and 5 hours after the administration of human interferon alpha (7 x 10(6) IU/m2), respectively. The plasma concentration of melphalan was determined by liquid chromatography with fluorometric detection after derivatization of melphalan with N-acetylcysteine. The area under the plasma concentration-time curve (AUC) was significantly lower (p = 0.02) when melphalan was given with interferon. There was a significant negative correlation (p = 0.008) between body temperature and dose normalized AUC, whereas no effect was noticed on the maximum plasma concentration (Cmax) and on the time to obtain Cmax. The rate of elimination showed a tendency (p = 0.06) to increase with increasing body temperature. It is suggested that the cytotoxicity of the drug is most probably enhanced because of the higher alkylating activity of the compound at elevated body temperatures.

Aged↗

PubMed1990

Electrochemical treatment of cancer. II: Effect of electrophoretic influence on adriamycin.

Electrochemical treatment of cancer with DC electrodes changes the microenvironment of the cancer cells by electrophoresis. They may deteriorate and resorb. In larger neoplasms, the effects can be enhanced by electrophoresis of a chemotherapeutic agent. Adriamycin delivered into an electropositive neoplasm electrode will move outwards in the neoplastic area in a high concentration. When given intravenously and the neoplasm electrode is electronegative, the systemic effects may be diminished. The agent is instead accumulated in the neoplastic region in a high concentration. This principle may be used to reduce systemic effects of charged chemotherapeutic compounds. In this preliminary study of cancer in 14 patients, incurable with surgery, radiation treatment, or chemotherapy, beneficial effects were obtained after combined electrochemical treatment and the use of Adriamycin.

Adult↗

PubMed1990

Electrochemical treatment of cancer. III: Plasma pharmacokinetics of adriamycin after intraneoplastic administration.

Plasma pharmacokinetics of Adriamycin (doxorubicin) has been studied after intraneoplastic administration during electrochemical treatment to patients with lung cancer that is noncurable with radiotherapy, surgery, or chemotherapy. Intraneoplastic administration of Adriamycin via the anode resulted in a dramatic change of the pharmacokinetic pattern in plasma as compared with what has been previously observed after intravenous administration. A fivefold reduction of the area under the plasma concentration time curve and a 25-fold reduction of the maximum plasma concentration was observed.

Adult↗

PubMed1990

Current status of epirubicin (Farmorubicin) in the treatment of solid tumours.

Epirubicin (Farmorubicin) is a drug of significant interest in the treatment of a variety of solid tumours and a comprehensive review of reported investigations is given. From experimental and clinical studies it appears that in general doxorubicin and epirubicin exhibit no qualitative, but only some quantitative, differences. Thus, the pharmacokinetic and pharmacodynamic characteristics of the two drugs are essentially similar, as are the tumour spectrum and the level of their clinical efficacies. To achieve haematological equitoxicity of the two drugs the dose of epirubicin should be approximately 20% higher than that of doxorubicin, giving rise to a higher cumulative dose of epirubicin. On the other hand, epirubicin is significantly less cardiotoxic than doxorubicin. Thus, the recommended cumulative dose of doxorubicin is 500 mg/m2 and the corresponding figure for epirubicin is 1,000 mg/m2. For either drug a number of questions are still left open, the most important of which include the questions about optimal treatment schedules and the existence of a clinical relevant dose/efficacy relationship.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1990

Anthracycline pharmacokinetics. Limited sampling model for plasma level monitoring with special reference to epirubicin (Farmorubicin).

A new principle for plasma level monitoring of the anthracyclines doxorubicin and epirubicin is presented. The area under the plasma concentration time curve (AUC) is linearly correlated with the maximum plasma concentration of the drugs at the end of 2 and 4 hours' constant rate infusions. From this relationship it is possible to obtain accurate estimates of the AUC values of the drugs in the individual patients from plasma samples, withdrawn during the last 15 minutes prior to the completion of the infusions. The limited sampling model for drug monitoring of doxorubicin and epirubicin described here is robust and simple to use. It does not require a strict time control for the withdrawing of samples. Measured maximum plasma concentrations of epirubicin during 2 hours' constant rate infusions of 70 mg m-2 to patients with lymphoma (median age: 46.5 years) were within the range 171-404 ng ml-1 (median value: 265 ng ml-1).

Adult↗

PubMed1990

Plasma pharmacokinetics of Idarubicin and its 13-hydroxymetabolite after intravenous and oral administration under fasting and non-fasting conditions.

The plasma pharmacokinetics of Idarubicin and its 13-hydroxy-metabolite have been studied in 10 patients with solid tumours after intravenous and oral administration under fasting and non-fasting conditions in a randomized cross-over design. The plasma concentration time curves of Idarubicin after intravenous administration could be described by the open two or three compartment models. No pharmacokinetic modelling of Idarubicin was possible after oral administration. After oral administration of Idarubicin, the amount of intact drug was higher under non-fasting conditions. The extensive and long-lasting appearance of Idarubicinol suggests that this cytotoxic metabolite is of major clinical importance in i.v. and oral therapy with Idarubicin. The pharmacokinetics of Idarubicinol was not affected by food intake.

Administration, Oral↗

PubMed1990

Electrochemical treatment of cancer. IV: Leukocyte and platelet counts in peripheral blood after electrochemical treatment of solitary lung neoplasms.

The effects on hematological parameters in peripheral blood was measured by electronic cell counting after electrochemical treatment (n = 11), after electrochemical treatment with concomitant intraneoplastic injection of the chemotherapeutic agent doxorubicin (Adriamycin) (n = 13), and after electrochemical treatment with concomitant intravenous infusion of Adriamycin (n = 2). After treatment, a reduction in lymphocyte count (p less than 0.01) and an increase in total leukocyte count (p less than 0.01) was observed. There was a trend that during treatment the platelet count was reduced.

Adult↗

PubMed1989

Reversed-phase liquid chromatographic determination of idarubicin and its 13-hydroxy metabolite in human plasma.

A method is given for the determination of idarubicin and its main metabolite, idarubicinol, in plasma from cancer patients. Idarubicin and idarubicinol are extracted from 2-ml samples of buffered plasma (pH 8.1) using chloroform-1-heptanol (9:1). After reextraction into phosphoric acid (0.1 M), separation is performed by reversed-phase liquid chromatography on a LiChrosorb RP-2 column (5 microns) with a mobile phase of acetonitrile-water, acidified with phosphoric acid. The absolute recovery in the range 5-100 ng/ml was greater than 83% with a precision better than 8% (relative standard deviation), using photometric detection at 484 nm. Proper handling of whole blood samples containing idarubidin is essential to avoid metabolic conversion into idarubicinol. Prolonged storage of the drug and its main metabolite under alkaline conditions should be avoided to prevent chemical degradation.

Chemical Phenomena↗

PubMed1989

Pharmacokinetic and metabolic studies of high-dose busulphan in adults.

The pharmacokinetics of high-dose busulphan was studied in adult patients with acute myeloblastic leukaemia after oral doses of 1 mg.kg-1 every 6 h for 4 days. The mean steady-state plasma concentration was 1080 ng/ml-1 during the treatment. Individual steady-state concentrations after the last dose on average were 32% lower than those predicted from total AUC measurements following the first dose. Mean elimination half-life in plasma was 2.3 h after the last dose and 3.4 h after the first dose which suggests that busulfan may increase its own metabolic rate on repeated treatment. The cerebrospinal fluid/plasma concentration ratio of busulphan was 1.3. Busulphan showed insignificant protein binding in plasma (7.4%). About 2% of the dose was excreted unchanged in the urine. For the first time sulpholane, 3-hydroxysulpholane and tetrahydrothiophene 1-oxide were identified as urinary metabolites of busulphan in man.

Adult↗

PubMed1989

Pharmacokinetics of 4' epi-adriamycin after morning and afternoon intravenous administration.

The chronopharmacokinetics of 4' epi-adriamycin (Epi) have been studied in ten patients with gynecological malignancies. The drug (45 mg m-2) was administered as a short time (5.0 min) intravenous infusion at 7 a.m. and 7 p.m., in a randomized cross-over design. The pharmacokinetics of Epi were evaluated according to the statistical moment theory. Morning and afternoon dosing of Epi was not bioequivalent. The area under the plasma concentration-time curve (AUC), the maximum plasma concentration (Cmax), mean residence time (MRT) and the terminal half-life time (t1/2) could differ by more than 35% after morning and afternoon dosing. The inter-individual variation of AUC and Cp,max were larger after morning dosing than after afternoon dosing (P less than 0.04). The morning dose of Epi resulted in higher values of AUC in seven of the ten treated patients as compared to the afternoon dose. The terminal half-life times were shorter in eight of the patients after the morning dose.

Aged↗

PubMed1989

Oral melphalan pharmacokinetics--relation to dose in patients with multiple myeloma.

The pharmacokinetics of melphalan have been studied after oral doses of 5, 10 and 20 mg, and 10 mg i.v. Seven patients with multiple myeloma received the drug on 4 consecutive days and the concentration of melphalan was determined by liquid chromatography. Melphalan was rapidly absorbed after p.o. administration. Absorption lag-time was less than 1 h. The median time for attaining the peak concentration was 1.12 h (97% confidence interval: 0.68-1.55), 1.21 h (0.85-1.43) and 1.08 h (0.84-1.29) after doses of 5, 10 and 20 mg. The bioavailability showed large interindividual variations, and was not significantly affected by the dose given. There was a significant decrease in bioavailability during the treatment course (P less than 0.05). Absorption of melphalan obeys first-order kinetics in the dose interval studied. The results indicate that it might be of benefit to administrate oral melphalan for fewer days than the usually used 4 day regimen, in an attempt to achieve a higher bioavailability.

Administration, Oral↗

PubMed1989

Pharmacokinetics of oral melphalan in relation to renal function in multiple myeloma patients.

The impact of renal function on oral melphalan pharmacokinetics was studied in 15 patients with multiple myeloma. A two-fold interindividual variation in the plasma concentration-time curve (AUC) was found. An increase in AUC and melphalan mean residence time (MRT) was noted in patients with renal dysfunction. No correlation was found between GFR and the terminal plasma half-life time. We conclude from these results that renal dysfunction is associated with an increase in AUC and MRT of oral melphalan. A careful follow-up of hematological toxicity and possibly a dose reduction of melphalan are proposed for myeloma patients with renal impairment.

Aged↗

PubMed1989

Pharmacokinetics and central haemodynamic effects of doxorubicin and 4'epi-doxorubicin in the pig.

The relationship between the cardiotoxicity and the haemodynamics/pharmacokinetics of clinical concentrations of doxorubicin and 4'epi-doxorubicin was studied. Twelve pigs were randomized to receive i.v. infusions of either drug of 50 mg/m2 over 3.0 min. Aortic, pulmonary arterial, coronary sinus and central venous plasma concentrations of the agents were determined until 180 min after the infusion. The V5 ECG, left ventricular dP/dT, aortic, pulmonary arterial and right atrial pressures were recorded continuously, cardiac output and coronary sinus blood flow were recorded intermittently. No haemodynamic changes were recorded after administration of either drug. Pharmacokinetic data indicated myocardial extraction, followed by myocardial release of both drugs. This release was higher after administration of 4'epi-doxorubicin than after doxorubicin, within the range 2-4 min and 20-40 min after the infusion. The tendency of greater myocardial release of 4'epi-doxorubicin may explain its lower cardiotoxicity.

Animals↗

PubMed1989

Pharmacokinetics of anthracyclines.

The plasma pharmacokinetics of the two commonly used anthracyclines doxorubicin and 4'epi-doxorubicin have been studied by reversed phase liquid chromatography with photometric detection. After intravenous administration the plasma pharmacokinetics of doxorubicin and 4'epi-doxorubicin are characterized by the three compartment open model. Typically, the half-life time of the alpha-phase is 3-5 min and the terminal half-life time in the order 20-30 h. An almost 10-fold inter-individual variation of the dose normalized area under the plasma concentration time curve (AUC/mg/m2) has been observed, underlining the need for an individualization of the dose. The chemical structures of doxorubicin and 4'epi-doxorubicin are very similar. Comparative pharmacokinetic studies were carried out by simultaneous administration of the drugs using a highly selective analytical technique. By this approach it was possible to reduce the influence by the large intra- and inter-individual pharmacokinetic variations. The values of AUC and Cmax were on the average 1.6 and 1.2 times larger for doxorubicin than for 4'epi-doxorubicin. Side effects, reported to be related to the maximum plasma concentration (Cmax), include cardiac toxicity, nausea and vomiting, while the antitumour effect has been associated with the area under the plasma concentration time curve (AUC). A 10-fold decrease of Cmax without a decrease of AUC was observed when doxorubicin was administered as a 4-h infusion as compared to an intravenous bolus injection. A further increase of the administration time had only a minor effect on Cmax. Intrahepatic administration of doxorubicin reduced the values of AUC and Cmax by 1.5 and 1.7 (mean values) respectively. The combination of doxorubicin and 4'epi-doxorubicin with biodegradable starch microspheres (Spherex) resulted in a further decrease of Cmax, while AUC was unaffected. The observed increase of the mean residence time (MRT) supports the assumption of an increased drug exposure of the tumour caused by Spherex.

Chemical Phenomena↗

PubMed1989

Pharmacokinetics of intra-arterial mitomycin C with or without degradable starch microspheres (DSM) in the treatment of non-resectable liver cancer.

The effects of degradable starch microspheres (DSM) on mitomycin C pharmacokinetics and bone marrow toxicity were studied in a phase II multicenter study. Sixty-three patients with non-resectable primary or secondary liver cancer were randomized to receive either i.a. mitomycin C 15 mg/m2 first, followed 5 weeks later by mitomycin C 15 mg/m2 plus DSM 360 mg administered into the hepatic artery (group I) or the same treatments in the opposite sequence (group II). In 36 out of 47 patients who received at least 2 treatments, peripheral venous blood samples were analyzed for mitomycin C pharmacokinetics on a minimum of 2 paired courses. In all patients, the area under the concentration time curve (AUC) was significantly lower when the drug was co-administrated with DSM, but the terminal half-life (t1/2) of mitomycin C was unchanged. In group I the addition of DSM resulted in a significantly lowered AUC, but not in group II. The discrepancy between the 2 groups is probably due to differences in DSM-induced intra-hepatic shunting. The addition of DSM resulted in significantly higher platelet nadir values, but unchanged white blood cell count nadir value. In conclusion, DSM reduce the systemic exposure of mitomycin C and seem to lessen the haematologic toxicity judged from a less pronounced decrease in platelets.

Adult↗

PubMed1989

Tourniquet infusion chemotherapy of the lower extremities--clinical and pharmacokinetic results.

A prospective analysis of tourniquet infusion chemotherapy is reported. Twelve patients with recurrent malignant melanoma and one patient with Kaposi's sarcoma on the lower extremities were treated. An objective tumor response (CR + PR) was noted in 4/8 patients with DTIC and in 1/5 with Adriamycin. Stable disease was registered in 2/8 and 2/5 when respective drugs were used. No major side effects were observed. Pharmacolkinetical analysis of Adriamycin were performed in five patients after two to three treatments. The plasma concentration time-curves of Adriamycin were in most cases described by an open three-compartment model. The AUC (area under the curve) values for Adriamycin were 3.4 (median value 95% CI 2.9-5.1) times higher than for Adriamycinol. The reproducibility of the intra-arterial techniques was established by the repeated pharmacokinetic analysis. This technique seems to give lower AUC (mg/m2) when compared with earlier published intravenous data. The results indicate that tourniquet infusion chemotherapy produces a reasonable response, and that further evaluation with other drugs and comparison with isolation hyperthermic drug perfusion will be of interest.

Adult↗

PubMed1988

Organ distribution of Adriamycin after intravesical instillation with or without Tween 80 in the rat.

The absorption of Adriamycin (ADM) into the systemic circulation and into different organs including the urinary bladder was investigated in the rat after intravesical instillation of ADM with or without a surface active detergent, Tween 80. The postinstillation plasma concentration of ADM increased significantly with increasing dose of the drug. Even though the leakage of ADM into the systemic circulation and into extravesical organs in general was slight a significant increase was observed after addition of Tween 80. The uptake of ADM into the urinary bladder wall was also significantly enhanced by Tween 80 thus the role of this agent in conjunction with intravesical chemotherapy should be further investigated.

Absorption↗