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Biomedical subjects

H E Rugstad

Publications and source records attributed to H E Rugstad.

At least 19 recordsLinked to original sources
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↗
PubMed1989

Epidemiology of NSAID-related gastrointestinal side effects.

Finding the true incidence of gastrointestinal side effects due to non-steroidal anti-inflammatory drugs (NSAIDs) is extremely difficult. Included in every clinical trial is the spontaneous and NSAID-unrelated occurrence of gastrointestinal problems. On the basis of several different clinical studies (cohort, case control, case review, and double-blind studies) we feel that the following frequency estimate adequately describes the clinical situation: one-third of all patients using NSAIDs will experience gastrointestinal symptoms during a 3-month course of therapy. When specifically asked for, all kinds of unspecific gastrointestinal symptoms will be encountered, ranging from vague complaints about intestinal distension to typical duodenal ulcer symptoms. In approximately half of the symptomatic patients these symptoms can be classified as dyspeptic. Serious gastrointestinal hemorrhage or perforation can be expected in 1%, and less than half of these patients will have experienced dyspeptic symptoms before the serious incident. More than 10% of all patients will withdraw from the planned treatment owing to intolerable symptoms.

Adult↗
PubMed1989

Renal side effects of high and low cyclosporin A doses in patients with rheumatoid arthritis.

Thirty-nine patients with classical or definite rheumatoid arthritis (RA) entered a randomized double-blind placebo controlled study with low dose cyclosporin A (CyA) (mean whole blood CyA level after 26 weeks 282 +/- 33 micrograms/l) or placebo treatment for 48 weeks. The placebo treatment had to be withdrawn before 48 weeks in 9 out of 19 patients because of a deterioration of their arthritis symptoms. All 20 patients in the CyA group completed 26 weeks of treatment. Fourteen of them were followed up for 48 weeks of treatment on CyA and then 12 weeks after CyA treatment was withdrawn. The side effects in the CyA group were compared with the results from another study with high CyA doses (mean whole blood CyA level 419 +/- 71 micrograms/l) for 26 weeks in 11 other patients with RA. Serum creatinine increased 19.7% (p less than 0.01) in the low CyA dose group after 26 weeks as compared with 59.5% in the high CyA dose group. Creatinine clearance was reduced by 17.9% (low dose) (p less than 0.01) and 26.2% (high dose), respectively. Twelve weeks after withdrawal of the low dose CyA treatment, serum creatinine values were still higher than before treatment (p less than 0.05), but creatinine clearance had normalized. Eight of the 20 patients treated with low CyA doses also started with nonsteroidal anti-inflammatory drugs (NSAIDs) after 20-36 weeks of CyA treatment. Serum creatinine was 16.6% above baseline 4 weeks before NSAIDs compared with an increase of 40.4% (p less than 0.05) 4 weeks after start of NSAID treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Epidemiology of NSAID-induced gastrointestinal problems and the role of cimetidine in their prevention.

It is difficult to ascertain the incidence of gastrointestinal side-effects associated with intake of non-steroidal anti-inflammatory drugs (NSAIDs). In retrospective studies, some NSAIDs have been reported to be associated with a higher incidence of gastrointestinal side-effects than others. However, this has not been verified either in a prospective case-review study or in a large double-blind study. Serious side-effects, such as bleeding, perforation and heart failure, occur in approximately 1% of patients using NSAIDs. One-third of all patients receiving NSAIDs will have gastrointestinal complaints. Since at least 10% of patients terminate treatment with NSAIDs as a result of side-effects, even reduction of those that are not life-threatening would be of great benefit. H2-receptor antagonists have proved effective in ulcer treatment, and their use as prophylaxis against the side-effects of NSAIDs is being widely studied. In a recent study, 63 patients who had experienced serious upper gastrointestinal side-effects were given cimetidine while continuing their NSAID therapy. All but 4 of the 47 who had gastric or duodenal ulcer on first admission were healed at 8 weeks, and none of the remaining 16 with diffuse bleeding gastritis experienced further clinical episodes of bleeding or ulcer-related dyspepsia.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1988

Partial cross-resistance between auranofin and sodium aurothiomalate in cultured human cells.

Cross-resistance between auranofin and sodium aurothiomalate was tested in two substrains of cultured human epithelial cells. The HEAF cells were previously made resistant to the otherwise lethal concentration of 2 mumol auranofin per litre of culture medium. The HEmyo cells were made resistant to the otherwise lethal effect of 300 mumol sodium aurothiomalate/l. After 4 days of continuous treatment with 2 mumol auranofin/l, 4.6% of the parent HE cells, 55.7% of the HEAF cells and 51.7% of the HEMyo cells continued to grow, compared with controls grown without drug supplement. After 4 days on 300 mumol sodium aurothiomalate/l, 17.6% of the HE cells, 101.0% of the HEMyo cells and 45.3% of the HEAF cells continued to grow. Thus, there was an almost complete cross-resistance to auranofin in the HEMyo cells, and a relative cross-resistance to sodium aurothiomalate in the HEAF cells. The cross-resistance was not found to be related to decreased cytosolic concentration of total gold in the cross-resistant lines.

Auranofin↗
PubMed1988

Mapping of synovial fibroblast proteins by high resolution two-dimensional polyacrylamide electrophoresis.

The highly sensitive protein separation technique two-dimensional polyacrylamide gel electrophoresis was used to study the cellular protein synthesis in 1) cultured human rheumatoid and 2) normal synovial fibroblasts and 3) normal skin fibroblasts. No reproducible differences were found that could be ascribed to cellular origin, the disease or in vitro cellular aging. The reasons for that probably were related to the cell cultures and not to failure of protein detection.

Arthritis, Rheumatoid↗