PubMed Health⌕ Search

Biomedical subjects

H E Rugstad

Publications and source records attributed to H E Rugstad.

At least 19 recordsLinked to original sources
PubMed1996

Human hepatoma cells rich in P-glycoprotein are sensitive to aclarubicin and resistant to three other anthracyclines.

Drug resistance is a major obstacle to successful chemotherapy of primary liver cancer, which is associated with high expression of the multidrug resistance (MDR) gene product P-glycoprotein (Pgp), a multidrug efflux transporter. The most effective single agents in treatment of primary liver carcinoma belong to the anthracycline family, yet several anthracyclines are known to be substrates for Pgp. In the present study, we compared four anthracyclines with respect to cell growth inhibition, intracellular accumulation and cellular efflux using the HB8065/R human hepatoma cell line which is rich in Pgp, and the Pgp-poor parental line HB8065/S. The anthracyclines were also administered in conjunction with the Pgp-modifying agents verapamil and SDZ PSC 833 to assess modulation of resistance. The HB8065/R cells were sensitive to aclarubicin (ACL) and highly resistant to epirubicin (EPI), doxorubicin (DOX) and daunorubicin (DNR). SDZ PSC 833 enhanced accumulation, decreased efflux and increased cytotoxicity of EPI, DOX and DNR in the HB8065/R cells, but none of these effects was seen with ACL. In conclusion, ACL is apparently not transported by Pgp and retains its activity in a multidrug-resistant human hepatoma cell line; such properties can be exploited for clinical purposes.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Binding diversity of antibodies against external and internal epitopes of the multidrug resistance gene product P-glycoprotein.

P-glycoprotein (Pgp) is a trans-membraneous protein that is associated with multidrug resistance (MDR) in human cancer, including hepatocellular carcinomas and leukemias. There is no consensus regarding methods of choice for analysis of Pgp expression, and development of reliable analytical methods is now essential. We have studied the the Pgp expression in human hepatoma and leukemia cell lines using flow cytometry. The aim of the study was to compare binding properties of anti-Pgp antibodies reacting with surface (MRK16, UIC2) and cytoplasmic (C219, JSB-1) epitopes to assess which antibody performed best with respect to fluorescence discrimination. By histogram subtraction the fractions of resistant human hepatoma cells positive for Pgp were 99% (MRK16), 97% (UIC2), 77% (JSB-1), and 51% (C219), demonstrating variations in antibody reactivity. The resolution in detecting decreasing levels of Pgp in hepatoma cells was superior for the externally binding antibodies, showing that there is a correlation between antibody reactivity and fluorescence discrimination. Similar results were obtained for parental and resistant KG1a human leukemia cell lines. The Pgp epitopes remained reactive to the anti-Pgp MAbs after methanol fixation and cryopreservation. By dual parameter flow cytometry it was shown that Pgp expression in viable cells may be assessed together with uptake of epirubicin, which was low in cells expressing high levels of Pgp and vice versa. In conclusion, all tested antibodies proved useful for flow cytometric detection of high levels of Pgp, but the externally binding ones were superior in detection of low and variable levels of Pgp.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Monitoring of azathioprine treatment by determination of 6-thioguanine nucleotide concentrations in erythrocytes.

Thioguanine nucleotides (6-TGN) are intracellular metabolites that may contribute to the antiproliferative effects of AZA. The objectives of our study were to describe the variability of 6-TGN concentrations during AZA therapy and to investigate possible correlations between 6-TGN levels and subsequent myelosuppression. We measured 6-TGN concentrations in RBC of 65 renal transplant recipients from day 0 until 11-64 days after transplantation. High 6-TGN concentrations were observed in relation to elevated S-creatinine. In 15 patients, 6-TGN concentrations above 200 pmol/8 x 10(8) RBCs were measured (high 6-TGN group: mean maximal 6-TGN = 552 pmol/8 x 10(8) RBCs, SE = 91). In the remaining 50 patients, mean maximal 6-TGN was 82 pmol/8 x 10(8) RBCs, SE = 6.1 (low t-TGN group). In the former group, mean S-creatinine measured on the day of maximal 6-TGN was 466 mumol/L (SE = 62.3), while in the latter it was 190 (SE = 14.7). In the high 6-TGN group, we observed a lower mean nadir neutrophil count than in the low 6-TGN group (3.4 vs. 5.1 x 10(9) neutrophils/L). The nadir neutrophil count occurred, on the average, 12.7 days after maximal 6-TGN in the high 6-TGN group, with no such delay in the low 6-TGN group. This study demonstrates for the first time that 6-TGN in RBCs may rise to very high levels during impaired renal function. Furthermore, the results support the hypothesis that myelosuppressive side effects of AZA therapy correlate with 6-TGN concentrations. Renal transplant recipients may benefit from the monitoring of AZA through RBC 6-TGN measurements.

Adolescent↗
PubMed1994

Kinetics of mercaptopurine and thioguanine nucleotides in renal transplant recipients during azathioprine treatment.

The purpose of this study was to examine the pharmacokinetics of mercaptopurine (6-MP) and thioguanine nucleotides (6-TGN) during azathioprine treatment. Plasma profiles and urinary excretion of 6-MP and 6-TGN concentrations in red blood cells (RBCs) were measured repeatedly during the first 3 weeks following transplantation in 10 adults, who had received kidney grafts from living related donors. Mean maximal 6-MP plasma concentration (Cmax) was 340 nmol/L (SD = 290), mean time to Cmax (Tmax) was 2 h (SD = 1.8), and mean area under the plasma concentration-time curve (AUC) was 930 nmol/L/h (SD = 770). The mean fraction of azathioprine dose excreted as 6-MP in urine was 1.32% (SD = 1.11). Up to eightfold variability of Cmax and AUC was observed from day to day within each patient. The correlation between 6-MP AUC and amount excreted in the urine was weak (r = 0.37, 95% CI from 0.02 to 0.64). In this group of patients the observed 6-TGN levels in RBCs were low; maxima during the observation period ranged from undetectable to 250 pmol/8 x 10(8) RBCs. In individual patients, 6-TGN levels were relatively stable throughout the dosing interval ("within-dose-interval-CV" < 19%), even when sharp and high 6-MP peaks in plasma were observed.

Adult↗
PubMed1994

Effect of cimetidine on gastrointestinal symptoms in patients taking nonsteroidal anti-inflammatory drugs. A large double-blind placebo controlled study.

The effect of cimetidine on gastrointestinal (GI) symptoms in patients taking non-steroidal anti-inflammatory drugs was studied in a multicentre, double-blind, placebo-controlled 4 week trial. Five hundred and seventy osteoarthritis patients received cimetidine 400 mg bid or placebo. Seventy-nine % in the cimetidine group had no GI symptoms at week 4 compared to 72% in the placebo group (p = 0.07). Only 5.6% in the cimetidine group reported heartburn compared to 19.2% in the placebo group. Diarrhoea was more pronounced in cimetidine treated patients; 18.5% compared to 2.7%. In a subgroup of patients with previous GI discomfort on NSAID therapy (N = 123), 63% reported disappearance of symptoms in the cimetidine group compared to 45% in the placebo group (p = 0.05). In patients with GI symptoms starting NSAID therapy and in patients on NSAID with a heartburn problem, cimetidine seems to be of value.

Adult↗
PubMed1993

Automated determination of free phenytoin in human plasma with on-line equilibrium dialysis and column-switching high-performance liquid chromatography.

Free phenytoin in human plasma was automatically determined by on-line equilibrium dialysis using the automated sequential trace enrichment of dialysate (ASTED) sample preparation system and HPLC. The dialysis cell was a modification of the cell supplied with the ASTED. Total phenytoin was analysed with the same analytical set-up and plasma protein binding was determined. Free phenytoin was determined in plasma from epileptic patients and the results were compared to those obtained by ultrafiltration. Automated determination of free and total phenytoin in plasma by the ASTED-HPLC combination was shown to be an accurate and reproducible method and the results in free phenytoin analyses were in agreement with those found with ultrafiltration. The sample throughput with the automated on-line combination of dialysis and column-switching HPLC was 75 samples in 24 h when the sample was dialysed at 37 degrees C.

Autoanalysis↗
PubMed1993

Metallothionein: a protein conferring resistance in vitro to tumor necrosis factor.

The role of metallothionein (MT) in the cytotoxicity of tumor necrosis factor (TNF) was investigated in vitro. A human epithelial cell line (HE100) and a mouse fibroblast line (CI 1D100) had previously been cultured to become resistant to 100 microns CdCl2 and were cultured routinely in cadmium-containing medium. The MT content of these cells and the nonresistant parent cell lines (HE and CI 1D) was determined both qualitatively and quantitatively by immunochemical techniques. Immunofluorescence microscopy revealed the cadmium-resistant cell lines to be intensely rich in MT in both the nuclear and cytoplasmic compartments. This finding was confirmed by immuno-electron microscopy which also showed the labeling to be freely distributed and not membrane-bound. In comparison, a very weak labeling of the parent cell lines was observed. MT concentration, as determined by enzyme-linked immunosorbant assay, was found to be 4.05 +/- 1.13% and 3.91 +/- 0.7% of the total protein for HE100 and CI 1D100 cells, respectively. We were unable to detect MT in the parent cell lines by this technique. Dose-survival curves obtained after 3 days treatment of the cells with TNF (0.125-500 ng/ml) revealed that the MT-rich substrains were significantly resistant compared to the parent strains (P < 0.001; t tests). In growth rate studies, where cells were exposed to TNF over a dose range of 0.25-250 ng/ml for 6 days, the resistance of the MT-rich cell lines was confirmed (P < 0.002). These data indicate that MT confers resistance to the cytotoxic effects of TNF in vitro and that sensitivity to TNF may be related to the MT content of the cell.

Animals↗
PubMed1993

[Doxazosin (Carduran)--a research survey].

4,260 patients were included in an open surveillance study simultaneously with the introduction of doxazosin for treatment of essential hypertension in Norway. The main aim of the study was to systematically collect information on side effects and events in patients being treated with a new drug. The effect on blood pressure, heart rate and lipids was also recorded. The study lasted for one year. 21 deaths were reported. 53% of the patients reported side effects and/or events. The frequency of side effects was particularly high during the first month of treatment. No new types of side effects were found. The initial higher frequency of reported side effects referred to all organ systems, and was also of the same magnitude in the different systems. A relation was found between certain cardiac side effects and/or events and cessation of previous medication upon starting treatment with doxazosin. The study shows that certain safety precautions should be observed in patients with coronary heart disease and heart failure. In three patients, doxazosin should be used only in combination with more specific treatment. Special caution should be observed when changing the specific basic treatment. Doxazosin had a very favourable antihypertensive effect. A drop in cholesterol and triglycerides was observed, as expected. The HDL-cholesterol value declined, which was unexpected. The results are difficult to interpret, owing to lack of a control group. On the other hand, the study shows how high blood pressure is being treated with drugs in ordinary practice. The authors discuss the methodology of surveillance studies.

Aged↗
PubMed1993

Free plasma concentrations of piroxicam in patients with osteoarthritis: relation to age, sex and efficacy.

Steady state piroxicam plasma samples from 85 patients suffering from osteoarthritis of the hip and/or the knee, and treated with piroxicam 20 mg daily for at least four weeks, were obtained. Twenty-seven of these patients had a newly diagnosed osteoarthritis and had not been treated with a nonsteroidal antiinflammatory drug (NSAID) previously. The plasma samples were subjected to equilibrium dialysis, analyzed by HPLC and total and free drug concentrations measured and unbound fractions were calculated. In the 27 newly diagnosed patients with free piroxicam concentrations ranging from 0.004 to 0.117 micrograms/ml, there was no correlation between free concentration and change in any of the clinical response variables from pretrial to week 4. In the total patient population free concentrations were 0.057 +/- 0.038 micrograms/ml (mean +/- standard deviation). Females had a 79% higher free concentration than males (p < 0.0002) and there was a statistically significant (p < 0.01) increase of free concentration with increasing age in females. The unbound fraction was 0.87% +/- 0.36% (mean +/- SD). There was no difference in unbound fraction between the sexes, nor could we detect any change with increasing age.

Aged↗
PubMed1993

Cyclosporine A monitoring in patients with renal, cardiac, and liver transplants: a comparison between fluorescence polarization immunoassay and two different RIA methods.

In the present study a new method for selectively determining parent cyclosporine (CsA) in whole blood, a fluorescence polarization immunoassay (FPIA; TDx Abbott), was compared with a RIA method (Sandimmun, Sandoz Ltd, Basle, Switzerland). A total of 974 samples were collected during the first 3 post-operative months from 63 renal, cardiac, and liver transplant recipients. The CsA concentrations measured with FPIA ranged from 14% to 19% above RIA (specific) in the middle ranges. Regression equations in renal transplants: FPIA = 1.001 x RIA + 28; in heart transplants: FPIA = 1.08 x RIA + 27 and in liver transplants: FPIA = 1.13 x RIA + 13. Considering the improved precision of the new method (inter-assay CV with FPIA: 3.8-9.5%; with RIA: 18.6%), the slightly lower specificity will usually be of minor importance in the therapeutic range for whole blood CsA concentrations following organ transplantations. The FPIA measurements which deviated most from the regression line compared with RIA-specific CsA values, tended to coincide with high CsA concentrations or rather extreme RIA specific to RIA non-specific ratios. In addition to analytical imprecision with the RIA-specific method, lower specificity of the FPIA vs. some of the metabolites may explain these deviations. The majority of these observations occurred as isolated episodes with normal relationship between RIA specific and FPIA on preceding and following days. Accordingly large dosage adjustments should await verification in repeated samples. Following these precautions the FPIA method may prove useful and safe in the monitoring of cyclosporine treatment.

Cyclosporine↗
PubMed1993

Total and free plasma and total synovial fluid piroxicam concentrations: relationship to antiinflammatory effect in patients with reactive arthritis and other arthritides.

Twenty-five patients (14 males, 11 females), sixteen with reactive arthritis and 9 with other arthritides were treated with piroxicam, 40 mg at day 1 and 20 mg daily the following 9 days. Both local knee joint and general disease activity were assessed at day 0 and day 10. At day 10, plasma and synovial fluid were drawn. Total and free (determined after equilibrium dialysis) plasma concentrations and total synovial fluid concentrations were measured by HPLC. Total plasma piroxicam concentrations (micrograms/ml) were 4.1 (0.5-8.3) [median (range)], free piroxicam plasma concentrations were 0.051 (0.012-0.118), total synovial fluid concentrations were 2.2 (0.3-4.6) and ratios total synovial to total plasma concentration were 0.51 (0.39-0.90). The effect of piroxicam treatment varied among the patients. We found no relationship between drug concentration and change in any of the disease activity parameters nor any correlation between the ratio of synovial fluid to plasma piroxicam concentration and the local knee joint disease activity parameters.

Adult↗
PubMed1992

The synthetic hepatic peptides pyroglutamylglutamylglycylserylasparagine and pyroglutamylglutamylglycylserylaspartic acid inhibit growth of MH1C1 rat hepatoma cells transplanted into Buffalo rats or athymic mice.

Repeated i.p. injections of the synthetic peptides pyroglutamylglutamylglycylserylasparagine and pyroglutamylglutamylglycylserylaspartic acid inhibited the long-term growth of MH1C1 rat hepatoma cells by 50-70% in three in vivo models: metastatic colony growth in the lungs of young Buffalo rats; s.c. tumor growth in young Buffalo rats; and s.c. tumor growth in athymic mice. The amide free peptide pyroglutamylglutamylglycylserylaspartic acid which inhibited the tumor growth in all the models showed a curvilinear dose-response relationship with a maximal effect at 1000 pmol/animal in mice and at 100 pmol/animal in rats. The amidated peptide pyroglutamylglutamylglycylserylasparagine, which was only tested in the lung model, showed growth inhibition with 2, 20, or 200 pmol/animal, but 200 pmol/animal was most effective. We have recently reported that these peptides show cochromatography with hepatic growth inhibitory peptides, isolated from mouse liver.

Animals↗
PubMed1991

Preliminary results of the Norwegian doxazosin postmarketing surveillance study: a twelve-week experience.

The study was designed to investigate the safety and efficacy of doxazosin in the control of blood pressure in general medical practice; the results presented concern the first 748 patients evaluated over a 12-week period. Blood pressure was significantly reduced after treatment with doxazosin (-13/-9 mm Hg), and heart rate was not significantly altered. In addition, doxazosin significantly reduced total cholesterol levels (-6.7%), reduced triglyceride levels (-19.8%), increased high-density lipoprotein cholesterol levels (+2.5%), and the high-density lipoprotein:total cholesterol ratio (+9.7%). The calculated risk of coronary heart disease was reduced by 20.5% over a 12-week period. Thirty-five percent of patients reported at least one side effect, and the number of patients experiencing severe adverse reactions was small. Twenty patients (2.7%) discontinued treatment because of adverse events, and 2.7% had the dose of doxazosin reduced.

Antihypertensive Agents↗
PubMed1991

The peptide pyroGlu-Gln-Gly-Ser-Asn, isolated from mouse liver, inhibits growth of rat hepatoma cells in vitro.

The peptide pyroGlu-Gln-Gly-Ser-Asn, recently isolated from mouse liver, inhibited DNA synthesis and proliferation in vitro of MH1C1 cells, a rat clonal strain derived from a Morris transplantable hepatoma. Both the biological peptide isolated from mouse liver and the synthetic homolog showed bell-shaped dose-response curves. Maximal inhibition (approximately 50%) was observed at two separate dose ranges: one at 10(-7)-10(-10) M, and one at 10(-14)-10(-15) M.

Amino Acid Sequence↗
PubMed1991

Naproxen free plasma concentrations and unbound fractions in patients with osteoarthritis: relation to age, sex, efficacy, and adverse events.

Plasma samples from 237 patients with osteoarthritis treated with 750 mg naproxen daily were obtained after four weeks of active therapy. The samples were subjected to equilibrium dialysis, analyzed by high-performance liquid chromatography, and free concentrations and unbound fractions were determined. Within the free plasma concentration range in this large patient group, we could detect no association between free naproxen concentration and efficacy score or between free concentrations and adverse events. Free concentrations were 0.295 +/- 0.260 microgram/ml (mean +/- SD) and unbound fractions were 0.33 +/- 0.24%. Females had 65% higher free concentration compared to males (p less than 0.001). For females, but not for males, there was a statistically significant correlation (p less than 0.005) between age and free concentration. The free concentration was estimated to be 88% higher in an 80-year-old female compared to a 50-year-old. Females had a 41% higher unbound fraction than males (p less than 0.005). For females, but not for males, a statistically significant relationship between age and unbound fraction was found. The unbound fraction was estimated to be 62% higher in an 80-year-old female than in a 50-year-old.

Aged↗
PubMed1991

Determination of free concentration of piroxicam and naproxen in plasma. The influence of experimental conditions in equilibrium dialysis.

An equilibrium dialysis method was established in order to investigate possible relationships between free drug concentrations of piroxicam and naproxen and clinical events. Therefore the influence of variations in pH, phosphate concentration and sodium azide concentration of the dialysis buffer on the free concentrations of piroxicam and naproxen was investigated. Piroxicam was found to have a pH-dependent protein binding. Therefore a good control of pH during the dialysis process is necessary. This has been achieved by increasing the buffer capacity of the dialysis buffer, by adding an antibacterial agent to the dialysis buffer and by cleansing the dialysis cells with 70% ethanol before use to prevent bacterial growth. Addition of 0.03% sodium azide as an antibacterial agent and the use of a 0.09 mol/l phosphate buffer gave good pH control. A method to correct for deviations of pH in measurements of free concentrations of piroxicam by a simple mathematical correction has been found. As naproxen was found to have a protein binding independent of pH, a pH-correction is not necessary for this drug. Standardized conditions in determination of protein binding of drugs by equilibrium dialysis are important, as composition of the dialysis buffer and pH of plasma compartment at equilibrium may influence the free concentration measurements. Comparisons of data from experiments using different methods are therefore difficult; the importance of pH-control is stressed. With the methods used in the present investigation, equilibrium dialysis in connection with HPLC, the coefficients of variation for piroxicam and naproxen free concentrations are 5.5% and 7.4%, respectively.

Azides↗
PubMed1991

Pharmacokinetics of intravenous cefetamet and oral cefetamet pivoxil in children.

The pharmacokinetics of cefetamet were determined after intravenous (i.v.) administration of cefetamet and oral administration of cefetamet pivoxil syrup to patients between the ages of 3 and 12 years. The patients were hospitalized for reconstructive urological surgery; to prevent infection, prophylactic i.v. cefetamet was administered on the day of surgery and oral cefetamet pivoxil was administered 2 days later. After i.v. administration, the mean (+/- standard deviation) half-life of cefetamet was 1.97 +/- 0.60 h (n = 18), which was different from the 2.46 +/- 0.33 h reported for nine adults (22 to 68 years old) in a previous study. The average values for the mean residence times were 2.35 +/- 0.94 and 2.83 +/- 0.34 h and the average values for the fraction of the dose eliminated unchanged in the urine were 79.9% +/- 8.99% and 80% +/- 11% in children and adults, respectively. Plots of mean systemic clearance and steady-state volume of distribution versus body weight for the children and comparative adults were linear on log-log coordinates, and the slopes of the plots were 0.661 and 0.880, respectively. These slope values suggested that mean systemic clearance values per unit of body surface area were similar in children and adults and that maintenance doses for children should be the adult maintenance dose multiplied by the child's surface area divided by 1.73 m2. The mean (+/- standard deviation) oral bioavailabilities of cefetamet pivoxil were 49.3% +/- 15.7% in 3- to 7-year-old children who received a 500-mg dose and 37.9% +/- 10.0% in 8- to 12-year-old children who received a 1,000-mg dose. These values were not different from that observed in the adult group after two 500-mg tablets. Likewise, the peak concentration of cefetamet in plasma and its time of occurrence in children were in line with the values which have been observed for adults.

Administration, Oral↗