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Biomedical subjects

E A Lien

Publications and source records attributed to E A Lien.

At least 37 records · Page 2Linked to original sources
PubMed1995

Influence of tamoxifen on sex hormones, gonadotrophins and sex hormone binding globulin in postmenopausal breast cancer patients.

Estrone sulphate (E1S) may be an important estrogen source in breast cancers, particularly in postmenopausal women. Recent studies have shown that tamoxifen inhibits the uptake and metabolism of E1S to estradiol (E2) in cell cultures. To evaluate a possible influence of tamoxifen on E1S disposition in vivo, we measured plasma levels of E1S together with unconjugated estrogens (E1 and E2), androgens (T, A, DHEA and DHEAS), SHBG, FSH and LH in 32 postmenopausal breast cancer patients before and during tamoxifen treatment. In a subgroup of 10 patients, we measured 24 h urinary excretion of estrogen metabolites to evaluate the influence of tamoxifen treatment on estrogen metabolism and total estrogen production. Tamoxifen increased plasma levels of E1S (mean increase of 18.1%, P < 0.05) and the ratio of E1S/E1 (mean increase of 25.7%, P < 0.01) and E1S/E2 (mean increase of 34.7%, P < 0.0005). No significant change in plasma E1 was seen, but plasma E2 was reduced (mean reduction of 12.1%, P < 0.005). The fall in plasma E2 was probably secondary to a fall in plasma T (mean reduction of 11.9%, P < 0.05) due to a reduced ovarian excretion of this androgen. The mechanisms may be a reduced gonadotrophin stimulation of the ovary, as plasma FSH and LH fell by mean values of 45.5 and 48.1%, respectively (P < 0.0001 for both). The increase in plasma E1S was accompanied by a reduced ratio of 2OHE1/E1 in urine (mean reduction of 38.2%, P < 0.025) indicating reduced 2-hydroxylation. Possible mechanisms for these alterations are discussed.

Aged↗
PubMed1995

Mechanisms of action of endocrine treatment in breast cancer.

Endocrine treatment plays an important role in the therapy of breast cancer. While the basic mechanisms are understood, additional mechanisms may be of importance to their action and they may also contribute to the mechanism(s) of acquired resistance. Currently, several novel drugs are entering into clinical trials. Observations of the absence or presence of cross resistance to novel 'pure' steroidal antiestrogens and the non-steroidal tamoxifen may add important information to our understanding of the mechanisms of action of both classes of drugs. Similarly, exploration of different aromatase inhibitors in sequence or concert, as well as the combining of different endocrine treatment options may be warranted. Additionally, alterations in different biochemical parameters such as growth factors should not only be carefully explored in relation to treatment options but should also be followed during the course of treatment to asess alterations over time and in relation to the development of drug resistance.

Adrenal Cortex↗
PubMed1995

Determination of droloxifene and two metabolites in serum by high-pressure liquid chromatography.

In this assay of the nonsteroidal antiestrogen droloxifene and two metabolites in human serum, the serum samples were deproteinized with an equal volume of acetonitrile and then injected into an analytical octadecylsilane column. The analytical column was equilibrated with acetonitrile/water (1/1, vol/vol) containing acetic acid and diethyl amine and eluted isocratically with 66% acetonitrile in the same buffer. Droloxifene, N-desmethyldroloxifene, and 4-methoxdroloxifene were post-column converted to fluorophors by ultraviolet illumination while passing through a 10-m transparent knitted polytetrafluorethylene reaction coil. Analytical recovery was close to 100%. Within- and between-day precision corresponded to a coefficient of variation (CV) of 2-5% at serum concentrations of > or 25 ng/ml, except for 4-methoxydroloxifene (CV 7-10% at a concentration of 25 ng/ml). By increasing the injection volume from 50 to 250 microliters, the detection limits could be decreased from approximately 5 to 1 ng/ml. Conjugated droloxifene could be estimated in a second run after treatment of sample with an enzyme preparation containing beta-glucuronidase plus sulphatase. The recovery of droloxifene glucuronide was close to 100%. Sulphate conjugates have not been identified and were not accounted for.

Chromatography, High Pressure Liquid↗
PubMed1995

Relations between sex hormones, sex hormone binding globulin, insulin-like growth factor-I and insulin-like growth factor binding protein-1 in post-menopausal breast cancer patients.

OBJECTIVE: Oestrogens, androgens and anti-endocrine drugs such as tamoxifen and aminoglutethimide influence plasma insulin-like growth factor-I (IGF-I). IGF-I, in turn, has been found to stimulate the peripheral aromatase in vitro. The aim of this study was to examine relations between sex hormones, IGF-I and insulin-like growth factor binding protein-1 (IGFBP-1) in post-menopausal women with breast cancer. DESIGN: To measure plasma sex steroids, sex hormone binding globulin (SHBG), IGF-I, IGFBP-1, insulin and urinary oestrogen metabolites in post-menopausal women with breast cancer not receiving any endocrine therapy. PATIENTS: Thirty-two patients had fasting blood samples obtained between 0800 and 1000 h. A sub-group of 10 patients had 24-hour urine oestrogen metabolites determined. MEASUREMENTS: Plasma steroids and proteins were measured by radioimmunoassays. Urinary oestrogens were measured by GC-MS. RESULTS: SHBG correlated negatively with plasma androstenedione (P < 0.001), insulin (P < 0.001), IGF-I, height and plasma oestrone sulphate (P < 0.025 for all), but positively with plasma IGFBP-1 (P < 0.025). IGFBP-1 correlated negatively with IGF-I (P < 0.001) and the testosterone/SHBG ratio (P < 0.05). Neither IGF-I nor IGFBP-1 correlated with any of the plasma or urinary sex hormones or with the oestrone/androstenedione and oestradiol/testosterone ratios. Multivariate analysis revealed plasma SHBG to correlate positively with IGFBP-1 (P = 0.029) and negatively with insulin (P = 0.031). Plasma IGFBP-1 correlated negatively with IGF-I (P < 0.0001) but not with insulin. CONCLUSION: Our results do not suggest any influence of plasma sex steroids in physiological concentrations on IGF-I or IGFBP-1 in post-menopausal breast cancer patients, nor do they indicate IGF-I at physiological concentrations influences the ratios between plasma oestrogens and their androgen precursors.

Aged↗
PubMed1993

Pharmacokinetics of anti-endocrine agents.

Endocrine therapy plays a major part in the systemic treatment of common cancers such as breast and prostatic carcinomas and some gynaecological malignancies. Although more than two million women have been treated with the anti-oestrogen tamoxifen, its disposition is still not completely understood. The absorption fractions for tamoxifen and the progestin drugs are uncertain. Many studies evaluating the plasma pharmacokinetics of tamoxifen and progestin drugs used blood sampling times that may have been too short to allow the determination of the terminal half-life with certainty. For most drugs, information on tissue concentration in general and tumour concentration in particular is lacking. Clinical results obtained with combined treatment may have been confounded by drug interactions, as exemplified by use of the enzyme inducer aminoglutethimide. Aims for further studies will be to compare tissue distribution and tumour distribution in relation to treatment response and to evaluate drug interactions. Increasing use of tamoxifen in premenopausal women highlights the need to study long term effects with special regard to possible teratogenicity.

Androgen Antagonists↗
PubMed1992

Influence of tamoxifen on plasma levels of insulin-like growth factor I and insulin-like growth factor binding protein I in breast cancer patients.

Plasma levels of insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein I (IGFBP-I) were measured in fasting blood samples obtained from 16 postmenopausal breast cancer patients before and during tamoxifen treatment for 1 to 6 months. Tamoxifen suppressed total plasma IGF-I by a mean of 28.5% (P less than 0.001) but elevated plasma IGFBP-I by a mean value of 78% (P less than 0.001). Changes in plasma levels of growth hormone, insulin, or insulin C-peptide were not observed. These findings suggest that tamoxifen exerts its influence on plasma IGF-I and IGFBP-I by mechanisms other than those known to regulate the plasma levels of these peptides, primarily growth hormone and insulin, respectively. A dual effect suppressing plasma IGF-I and elevating plasma IGFBP-I suggests that tamoxifen may have a significant influence on endocrine and possibly paracrine delivery of IGF-I to breast cancer cells in vivo.

Aged↗
PubMed1992

Intermittent high-dose tamoxifen as a potential modifier of multidrug resistance.

In vitro tamoxifen reverses multidrug resistance (MDR). To evaluate the clinical potential of using tamoxifen in this way, intermittent high-dose tamoxifen was combined with oral etoposide in 86 patients. At 320 mg/day tamoxifen for 6 days, mean plasma levels of tamoxifen in 11 patients increased from 453 ng/ml (range 269-664) on day 2 to 984 ng/ml (578-1336) on day 6. Of 31 patients who had plasma tamoxifen measured during the time of etoposide administration (days 4-6), 13(43%) were over 1111 ng/ml (3 mumol/l), an active in vitro level. Potentially active levels of the principal metabolite, N-desmethyl tamoxifen, were also obtained but accumulation was slower. Emesis and thromboembolism were toxicities. Tamoxifen is a modifier of MDR, a role that warrants further clinical studies.

Administration, Oral↗
PubMed1992

Influence of tamoxifen, aminoglutethimide and goserelin on human plasma IGF-I levels in breast cancer patients.

Plasma insulin-like growth factor-I (IGF-I) was measured in breast cancer patients before and during treatment with tamoxifen, goserelin or aminoglutethimide. 24 out of 27 postmenopausal women treated with tamoxifen 20 or 30 mg daily experienced a decrease in plasma IGF-I levels (mean levels before treatment 14.8 nM, during treatment 10.2 nM, P less than 0.001). In 8 out of 12 premenopausal breast cancer patients there was a reduction in plasma IGF-I during treatment with goserelin (mean levels before treatment 23.3 nM, during treatment 19.4 nM, P = 0.052). Contrary, 15 out of 17 postmenopausal women treated with the aromatase inhibitor aminoglutethimide had an increase in plasma IGF-I level (mean level before treatment 17.0 nM, during treatment 21.1 nM, P less than 0.01). These preliminary results indicate that different forms of endocrine treatment of breast cancer may influence plasma IGF-I levels in different directions.

Aminoglutethimide↗
PubMed1992

High-dose tamoxifen as an enhancer of etoposide cytotoxicity. Clinical effects and in vitro assessment in p-glycoprotein expressing cell lines.

Twenty-six patients with relapsed or drug-resistant cancer were treated with a combination of oral etoposide (300 mg day-1 for 3 days) and high-dose oral tamoxifen as a potential modulator of drug resistance (480 or 720 mg day-1 for 6 days beginning 3 days before etoposide). One patient with relapsed high-grade lymphoma and one with adenocarcinoma of unknown primary site has a partial response. Toxicity consisting of nausea, vomiting and subjective dizziness, unsteadiness of gait and malaise occurred during tamoxifen treatment. Serum levels of tamoxifen averaged 3-3.5 microM on day 4 of all courses of treatment at both 480 and 720 mg day-1. N-desmethyltamoxifen levels were lower than tamoxifen during the first course (2 microM) but increased to equal tamoxifen levels during the second course. Didesmethyltamoxifen levels remained below 1 microM. In vitro, both tamoxifen and the standard modulator of multidrug resistance, verapamil, produced minor enhancement of etoposide cytotoxicity in the MCF-7 wt cell line but produced no enhancement with any other cell line. High, intermittent doses of tamoxifen can be given with acceptable toxicity and produce serum levels that have been shown to modulate drug resistance in vitro. In vitro, however, such levels have no significant effect on etoposide cytotoxicity towards a range of wild-type and MDR cell lines.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Clinical pharmacokinetics of endocrine agents used in advanced breast cancer.

Endocrine therapy is important in the treatment of advanced breast cancer. The prototype antiestrogen tamoxifen and the prototype aromatase inhibitor aminoglutethimide have been in clinical use for more than 2 decades, as have synthetic progestin derivatives. Currently, several novel antiestrogens and aromatase inhibitors are used to treat breast cancer. This paper reviews the present knowledge of the clinical pharmacokinetics of these drugs. Drug monitoring in plasma and other body fluids has been improved over recent years by the introduction of sensitive and specific high performance liquid chromatography and gas chromatography-mass spectrometry methods. However, we still lack information on such basic pharmacokinetic parameters as the bioavailability of several of these drugs. It is important to study not only plasma but also tissue drug concentrations.

Aromatase Inhibitors↗
PubMed1991

Distribution of tamoxifen and its metabolites in rat and human tissues during steady-state treatment.

A procedure for the extraction of tamoxifen and metabolites from various rat and human tissues was developed and verified. With this method, we determined the drug and metabolite concentrations during one dosing interval in various tissues (brain, fat, liver, heart, lung, kidney, uterus, and testes) of rats given tamoxifen once daily for 3 or 14 days, and in various normal and malignant tissues obtained during surgery or at autopsy from patients with breast cancer treated with tamoxifen. In the rat, the concentrations of tamoxifen and metabolites in most tissues were 8- to 70-fold higher than in serum. The highest levels were observed in lung and liver; substantial amounts were also recovered from kidney and fat. Fluctuations of metabolites and tamoxifen content in most tissues were observed during one dosing interval, corresponding to a ratio of 4:8 between Cmax and Cmin, except in fat and testicular tissues, where the drug concentrations were relatively stable. In addition to tamoxifen, N-desmethyltamoxifen, followed by 4-hydroxytamoxifen, 4-hydroxy-N-desmethyltamoxifen, and N-desdimethyltamoxifen, were abundant in most tissues. In contrast, adipose tissue contained only small amounts of these metabolites. The concentrations of tamoxifen and metabolites found in human normal and malignant tissues confirmed and extended the conclusions made in the experiments with rats. In humans, levels were 10- to 60-fold higher in tissues than in serum, and relatively high concentrations were detected in liver and lung. Additionally, pancreas, pancreatic tumor, and brain metastases from breast cancer and primary breast cancer retained large amounts of drug. Again, the amounts of demethylated and hydroxylated metabolites were high in most tissues, except in fat. Tamoxifen and some metabolites were also present in specimens of skin and bone tissue. In one patient, significant amounts of drugs could be detected in lung, heart, ovary, and intestinal wall 14 months after withdrawal of tamoxifen, demonstrating efficient retention and slow washout of these compounds in human tissue.

Adipose Tissue↗
PubMed1991

Distribution of tamoxifen and metabolites into brain tissue and brain metastases in breast cancer patients.

We determined the amount of tamoxifen, N-desmethyltamoxifen (metabolite X), N-desdimethyltamoxifen (metabolite Z), and hydroxylated metabolites (Y, B, BX) in brain metastases from breast cancer and in the surrounding brain tissues. Specimens were collected from the breast cancer patients who received tamoxifen for 7-180 days and with the last dose taken within 28 h before surgical removal of the tumour. The concentrations of tamoxifen and its metabolites were up to 46-fold higher in the brain metastatic tumour and brain tissue than in serum. Metabolite X was the most abundant species followed by tamoxifen and metabolite Z. Small but significant amounts of the hydroxylated metabolites, trans-1(4-beta-hydroxyethoxyphenyl)-1,2-diphenylbut-1-ene (metabolite Y), 4-hydroxytamoxifen (metabolite B) and 4-hydroxy-N-desmethyltamoxifen (metabolite BX) were detected in most specimens. The ratios between the concentrations of tamoxifen and various metabolites were similar in tumour, brain and serum. This is the first report on the distribution of tamoxifen and metabolites into human brain and brain tumour, and the data form a basis for further investigation into the therapeutic effects of tamoxifen on brain metastases from breast cancer.

Adult↗
PubMed1990

Decreased serum concentrations of tamoxifen and its metabolites induced by aminoglutethimide.

The antiestrogen tamoxifen and the aromatase inhibitor aminoglutethimide show similar response rates when used in the endocrine management of advanced breast cancer. However, numerous clinical trials have demonstrated no increase in response rate from treatment with the drug combination of tamoxifen plus aminoglutethimide. We investigated the possibility of a pharmacokinetic interaction between these two drugs in six menopausal woman with breast cancer. All patients were investigated under three different conditions (termed phases A, B, and C). The steady state kinetics of tamoxifen were determined when administered alone (phase A) and after coadministration of aminoglutethimide for 6 weeks (phase B). In phase B, the pharmacokinetics for aminoglutethimide were determined and compared with these parameters after a tamoxifen washout of 6 weeks (phase C). The serum concentration of tamoxifen and most of its metabolites ([trans-1(4-beta-hydroxy-ethoxyphenyl)-1,2-diphenylbut-1-ene], 4-hydroxytamoxifen, 4-hydroxy-N-desmethyltamoxifen, N-desmethyltamoxifen, and N-desdimethyltamoxifen) were markedly reduced following aminoglutethimide administration, corresponding to an increase in tamoxifen clearance from 189-608 ml/min. The amount of most metabolites in serum increased relative to the amount of parent tamoxifen. These data are consistent with induction of tamoxifen metabolism during aminoglutethimide exposure. We found no effect of tamoxifen on aminoglutethimide pharmacokinetics or acetylation. We conclude that this aminoglutethimide-tamoxifen interaction should be taken into account when evaluating the clinical effect of this drug combination relative to monotherapy.

Acetylation↗
PubMed1989

[Prognosis of diabetes mellitus type 1. A follow-up study].

A follow-up of 92 patients with diabetes mellitus, who were hospitalized at the Department of Pediatrics, University of Bergen, during the years 1950-63, was conducted in June 1986. The mean age of the 76 living patients was 38 years, and the mean duration of diabetes 30 years. Sixteen patients had died. According to the death certificates the causes of death were as follows: Myocardial infarction, uremia, pneumonia, diabetes not further specified, suicide, sudden death not further specified, ketoacidosis, accident to the head, and convulsions (epilepsy). The 39 patients living in the county of Hordaland (including Bergen) were invited to a clinical examination. Twenty-nine patients (mean age 37 years, mean duration of diabetes 29 years) accepted. In eleven, the disease had influenced the choice of occupation. Twelve experienced professional difficulties due to diabetes, and thirteen had major complaints due to the disease. Three used antianginal drugs, and a further three were receiving antihypertensive treatment. Four women had hypothyreosis. Twelve had proteinuria or pathologic microalbuminuria. Only two of 27 patients examined by means of fluorescein-angiography showed no retinopathy. Evidence of cardiovascular autonomic neuropathy was observed in ten patients. Since only three patients had used fast-acting insulin regularly during the last ten years, it should be possible to give patients with type 1 diabetes better treatment in the future.

Adolescent↗
PubMed1989

Distribution of 4-hydroxy-N-desmethyltamoxifen and other tamoxifen metabolites in human biological fluids during tamoxifen treatment.

Several metabolites of tamoxifen, including 4-hydroxy-N-desmethyltamoxifen (metabolite BX), 4-hydroxytamoxifen (metabolite B), N-desmethyltamoxifen (metabolite X), the primary alcohol (metabolite Y), and N-desdimethyltamoxifen (metabolite Z) were identified and their concentrations determined in fluids and feces from patients receiving chronic tamoxifen treatment. The biological samples investigated were serum, pleural, pericardial and peritoneal effusions, cerebrospinal fluid, saliva, bile, feces, and urine. In serum, tamoxifen itself, and the metabolites X and Z were the prevailing species, but significant amounts of the metabolites Y, B, and BX were also detected. About 3 h after drug intake tamoxifen as well as Y, B, BX, X, and Z showed a peak in serum. This may be explained by efficient metabolism of the metabolite precursor before being distributed to peripheral compartments. Upon drug withdrawal all metabolites showed first-order elimination curves which paralleled that of tamoxifen suggesting that their rate of elimination exceeded that of tamoxifen and that the serum levels are production rate limited. The protein binding of tamoxifen and its major serum metabolites (Y, X, Z) was determined and found to be higher than 98%. Albumin was the predominant carrier for tamoxifen in human plasma. The concentrations of tamoxifen and its metabolites in pleural, pericardial, and peritoneal effusions equalled those detected in serum, corresponding to an effusion/serum ratio between 0.2 and 1. Only trace amounts of tamoxifen and metabolite X were detected in cerebrospinal fluid (CSF/serum ratio less than 0.02). In saliva, concentrations of tamoxifen and X exceeded the amounts of free drug in serum, suggesting active transport or trapping of these compounds in the salivary gland. Bile and urine were rich in the hydroxylated, conjugated metabolites (Y, B, and BX), whereas in feces unconjugated metabolite B and tamoxifen were the predominating species.

Adult↗
PubMed1989

Evaluation of the enhanced rapid identification method for Gardnerella vaginalis.

The enhanced rapid identification method (RIM; Austin Biological Laboratories), a micromethod for the identification of Gardnerella vaginalis, is based on starch and raffinose fermentation and hippurate hydrolysis. We tested 105 clinical isolates of G. vaginalis with both the RIM and standard biochemical tests. The RIM agreed with the standard biochemical methods for 96 (91.4%) of the strains; nine isolates which were hippurate hydrolysis positive by standard biochemical tests were hippurate hydrolysis negative in the RIM. RIM may serve as a useful adjunct to Gram stain and colony morphology for the identification of G. vaginalis.

Female↗
PubMed1988

Identification of 4-hydroxy-N-desmethyltamoxifen as a metabolite of tamoxifen in human bile.

The occurrence of tamoxifen metabolites in bile was investigated in a 57-year-old female patient receiving chronic treatment with tamoxifen. In bile treated with beta-glucuronidase, two major peaks were detected using a chromatographic system developed for the quantitation of tamoxifen metabolites in human serum. One sharp peak coeluted with 4-hydroxy-tamoxifen whereas a second broad peak eluted slightly ahead of tamoxifen and was separated from all major serum metabolites. This latter peak was identified as the cis (about 30%) and trans (about 70%) isomers of 4-hydroxy-N-desmethyltamoxifen. The identification was based on (a) coelution with authentic standard on reversed-phase chromatography and formation of fluorescent material after photoactivation, (b) a molecular ion (M + 1)+ of 374 m/z as determined with liquid chromatography-mass spectrometry, and (c) a fragmentogram identical to that of the authentic standard, as obtained by gas chromatography-mass spectrometry.

Bile↗