Biomedical subjects

H E Rugstad

Publications and source records attributed to H E Rugstad.

At least 37 records · Page 2Linked to original sources

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↗

PubMed1991

Long-term toxicity of preoperative 4'-epidoxorubicin (Epi-adriamycin) in partially hepatectomized rats.

4'-Epidoxorubicin (Epi-A) administered immediately prior to liver resection has been suggested as treatment for patients with primary liver carcinoma. Long-term toxicity was studied in rats given a single dose of Epi-A intravenously immediately prior to a standard partial hepatectomy (PH). After 52 weeks only 9% of the rats given 5 mg/kg + PH were alive, 79% of the rats given 2 mg/kg + PH and 92% of the PH control survived. The weight gain of the rats given 5 mg/kg + PH was only 17% of that of PH controls. Signs of congestive heart failure were observed in some rats while in others moderate kidney lesions. No histopathological lesions were detected by light microscopy in heart, liver, spleen and bone marrow. For the rats given 2 mg/kg + PH body weight gain, microscopic observations and blood chemistry data (total protein, albumin, alkaline phosphatase, alanine aminotransferase, total bilirubin, creatinine and urea) were comparable to the PH controls. No significant differences in survival were registered between partially hepatectomized and sham-operated rats. The results indicate that Epi-A may be given preoperatively to liver resection without inducing long-term effects on vital organs.

Animals↗

PubMed1990

The influence of partial hepatectomy on the pharmacokinetics of preoperatively injected 4'-epidoxorubicin in rats.

Preoperative administration of 4'-epidoxorubicin (Epi-A) has been suggested as adjuvant therapy in patients undergoing liver resection for hepatocarcinoma. To assess the influence of partial hepatectomy on the pharmacokinetics of Epi-A, an experimental study in rats was undertaken in which 5 mg/kg Epi-A was given i.v. 10 min prior to a 2/3 hepatic resection or sham operation. Epi-A levels in liver tissue and plasma were determined using a sensitive and specific HPLC method. A marked uptake of Epi-A in liver tissue was found at 10 min after injection. The partially hepatectomized rats showed a 2-fold increase in AUC between 4 and 72 h as compared with the sham-operated controls. The terminal half-life from 24 to 72 h was not significantly changed by the partial hepatectomy. The plasma binding of Epi-A was measured at 4 h post-surgery. The fraction of unbound Epi-A was 0.16 in partially hepatectomized animals and 0.20 in sham-operated rats. The results indicate that when Epi-A is given prior to liver resection, a dose reduction might be necessary to avoid increased side effects due to the rise in AUC.

Animals↗

PubMed1990

Verapamil potentiates 4'-epidoxorubicin cytotoxicity in a rat hepatoma cell line and in a substrain resistant to 4'-epidoxorubicin.

We have examined the influence of verapamil (VP) on the in vitro effect of 4'-epidoxorubicin (Epi-A) in a rat hepatocarcinoma cell line (MHlCl) and in an Epi-A resistant substrain. A VP concentration of 500 ng/ml (1.1 mumol/l) markedly potentiated the cytotoxic effect of Epi-A in the parent line. The resistant cells grow at an Epi-A concentration of 7500 ng/ml (12.9 mumol/l). This is approximately 15-fold higher than the concentration tolerated by parental cells. In these cells VP reversed the acquired resistance to Epi-A in a concentration dependent manner; thus, a concentration in the range of 500-750 ng/ml (1.1-1.7 mumol/l) of VP restored the sensitivity to Epi-A in the resistant cells. Our results demonstrate that VP increases the sensitivity to Epi-A in hepatocarcinoma cells never exposed to this drug, as well as in hepatocarcinoma cells with acquired Epi-A resistance.

Animals↗

PubMed1990

Acute effects of paracetamol on prostaglandin synthesis and renal function in normal man and in patients with renal failure.

The effects of oral dosing with paracetamol (40 mg/kg/day for 3 days) on serum thromboxane B2 (TXB2), glomerular filtration rate (GFR), sodium homeostasis, urinary excretion of prostaglandin E2 (PGE2) and on some other renal function parameters were investigated in 10 healthy young controls aged 23-26 years, 9 healthy elderly persons with normal renal function aged 66-78 years and 9 patients with chronic stable impaired renal function. Plasma paracetamol concentration was unaffected by age and GFR, whereas the sulphate and glucuronide metabolites of paracetamol accumulated substantially in patients with renal failure, and to a lesser degree in elderly controls. Serum TXB2 was significantly reduced 1 and 4 hours after oral ingestion of a single dose of paracetamol (18 mg/kg), but the values were normalized after 12 hours. Urinary sodium excretion was reduced by 23.4% on the first treatment day in elderly controls, but unchanged in young controls and in patients with renal failure. Urinary excretion of PGE2 was unchanged in young controls, but reduced by 35.9% on the first day on paracetamol treatment in elderly controls and from 22-29% on the 3 days on paracetamol in patients with impaired renal function. Paracetamol was without effect on potassium homeostasis or on the excretion of glandular kallikrein or proteins in urine. Our study indicates that oral treatment with paracetamol in therapeutic doses reversibly reduces serum TXB2 for at least 4 hours after ingestion both in healthy controls and in patients with impaired renal function. Our data also suggest that paracetamol effects renal PGE2 excretion, especially in patients with impaired renal function. Renal glomerular and tubular function parameters were unchanged by paracetamol.

Acetaminophen↗

PubMed1990

Pharmacokinetics of oral 6-mercaptopurine: relationship between plasma levels and urine excretion of parent drug.

Plasma levels and cumulative urine excretion of 6-mercaptopurine (6-MP) were measured using a specific and sensitive high-performance liquid chromatographic assay in seven children with acute lymphoblastic leukemia (ALL) as well as in one healthy volunteer. The dose of 6-MP varied in the range of 25-75 mg/m2 of body surface area and was administered with a standard breakfast. A 4- to 11-fold variation between individuals was found in the pharmacokinetic parameters: peak concentration, time to reach peak, area under the plasma concentration-time curve (AUC), and fraction of dose excreted in the urine. Three repeated determinations in one individual revealed that AUC also varied more than sixfold following an overnight fast. In three individuals, the reducing agents glutathione (10 mg/kg) and ascorbic acid (15 mg/kg) were coadministered with 6-MP to evaluate their possible role in the protection of 6-MP from oxidation and degradation in the intestinal lumen. No consistent effect was observed, however, on the AUCs of either of these agents. A clear relationship was found between AUCs and the 24-h urinary excretion of unchanged drug (r = 0.9381), indicating that determinations of 6-MP in the urine may replace the painful procedure of repeated blood sampling. Further studies are necessary to determine the factors contributing to the unpredictable plasma levels following oral doses of 6-MP and to determine the value of pharmacokinetic monitoring in ALL patients.

Administration, Oral↗

PubMed1989

Effect of preoperative 4'-epidoxorubicin (epi-adriamycin) treatment on the regeneration and function of the liver in partially hepatectomized rats.

The early effects of 4'-epidoxorubicin (Epi-Adriamycin) on liver regeneration and late effects on liver function were studied after a standard partial hepatectomy in rats. 4'-epidoxorubicin was given intravenously immediately preoperatively. Neither suppression nor delay in DNA synthesis (analyzed by incorporation of 3H-thymidine) during the first 72 h postoperatively was registered after a dose of 5 mg/kg body weight. Four weeks following the dose of 5 mg/kg a slight decrease was found in liver weight (8%), body weight (8%) and plasma albumin values (9%) compared with the partial hepatectomized controls. Total protein, alkaline phosphatase, total bilirubin and alanine aminotransferase were not changed. A dose of 2 mg/kg did not alter any of the parameters. No histological signs of liver and kidney damage were seen. The results indicate that preoperative treatment with 4'-epidoxorubicin combined with partial hepatectomy may possibly be used in humans without clinically significant impairment of liver regeneration and function of the remaining liver and without histological detectable nephrotoxicity. The dosage of 4'-epidoxorubicin must, however, be adjusted according to species differences in pharmacokinetics.

Animals↗