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L Slørdal

Publications and source records attributed to L Slørdal.

At least 37 records · Page 2Linked to original sources
PubMed1997

Sudden, unexpected death in subjects with undiagnosed gliomas.

We report two cases in which a medicolegal autopsy disclosed small and previously undiagnosed gliomas. The first case was a 38-year-old woman who was found dead in bed; her autopsy revealed a 1.3-cm low-grade astrocytoma in the right subthalamic area. The second case involved a 32-year-old man who drowned in shallow water after his canoe capsized. A 0.5-cm oligoden-droglioma of the left temporal lobe and a 0.1-cm ganglionic hamartoma of the hypothalamus were found. In both cases the tumors may, directly or indirectly, have been the underlying cause of death. We emphasize the importance of a thorough neuropathological examination for all cases of sudden unexpected death in which no extracerebral cause of death has been found.

Adult↗
PubMed1997

Intrapleurally instilled mitoxantrone in metastatic pleural effusions: a phase II study.

Thirty cases (breast cancer-20 cases, malignant lymphoma-4 cases, different malignancies-6 cases) of histologically/cytologically verified malignant pleural effusion (MPE) in 29 patients were treated with intrapleurally instilled mitoxantrone (30 mg). The therapy was well tolerated. At evaluation, 25 patients had died of progressive disease. The median survival was 3 months (range 0.3-21.3 months). There were 26 responders (12 complete responses (CR), 14 partial responses (PR)), whereas 4 patients relapsed and 3 of these had an early relapse (within 3 months). Patients achieving PR or CR had a low risk (15%) of treatment failure. Five patients were subjected to a pharmacokinetic evaluation. This demonstrated rapidly declining plasma and pleural exudate levels of mitoxantrone within the first 6 hours. At 24 hours after instillation, mitoxantrone was only detected in circulating mononuclear cells. This study shows that mitoxantrone is efficacious in the treatment of MPE, and may represent a cost-effective alternative.

Adolescent↗
PubMed1996

Determination of extracellular methotrexate tissue levels by microdialysis in a rat model.

We used a microdialysis technique to determine tissue methotrexate (MTX) levels during steady state in a rodent model. Two different approaches were employed to measure the actual extracellular MTX concentrations in muscle, liver, and kidney tissues of anesthetized Wistar rats. With the reduced-perfusion-rate technique, the flow in the microdialysis perfusate was gradually decreased toward zero to permit calculation of zero-flow intercepts. Using the net change technique, microdialysis probes were perfused with different MTX concentrations to allow an assessment of equilibrium drug levels. For these two methods to be used, drug concentrations in the matrix to be analyzed must remain unchanged during the experimental procedure. In the animal model, steady state was attained after 1.5 h and maintained throughout the rest of the experiments by the administration of MTX as continuous infusions through a venous catheter. In vitro and in vivo, both the reduced-perfusion-rate and net change techniques gave reproducible data that permitted the estimation of extracellular drug concentrations in the dialyzed tissue compartments.The data suggest that the level of unbound MTX in the circulation is fairly similar to the extracellular concentrations in the muscle and liver. In the kidney, MTX levels were measured to be 3-8 times higher than those of unbound, circulating MTX, and a considerable discrepancy between the two methods used for estimations was apparent. These results demonstrate that both the net change and reduced-flow microdialysis techniques can produce reproducible and precise data. The results may constitute a basis for determining recoveries and, thus, true extracellular drug levels during in vivo microdialysis of MTX. This may be of importance in delineation of the relationship between tissue MTX levels and outcome in a variety of normally inaccessible compartments during cancer pharmacotherapy.

Animals↗
PubMed1995

Quantitation of 6-thioguanine residues in peripheral blood leukocyte DNA obtained from patients receiving 6-mercaptopurine-based maintenance therapy.

The antimetabolite 6-mercaptopurine is widely utilized in maintenance therapy for childhood acute lymphoblastic leukemia. Following p.o. administration, this prodrug undergoes extensive biotransformation, resulting in the generation of a plethora of metabolites including 2'-deoxy-6-thioguanosine triphosphate. Incorporation of 6-thioguanine (6-TG) bases into DNA is generally considered to be central to thiopurine-mediated cytotoxicity. We have developed a novel precolumn derivatization HPLC technique for quantifying 6-TG base accumulation into leukocyte DNA obtained from acute lymphoblastic leukemia patients receiving 6-mercaptopurine maintenance therapy. The method is based on enzymatic degradation of DNA to 2'-deoxyribonucleosides and the derivatization of released 2'-deoxy-6-thioguanosine with a thiol-reactive reagent containing a 7-amino-4-methylcoumarin-3-acetic acid fluorophore. The 2'-deoxy-6-thioguanosine-7-amino-4-methylcoumarin-3-acetic acid adduct is resolved by reversed-phase HPLC and quantified fluorometrically. Assay response is linear from 15 pmol to 60 fmol 6-TG bases/microgram DNA with a limit of quantitation corresponding to the incorporation of 1 6-TG residue per 50,000 bases. In a small cohort of acute lymphoblastic leukemia patients receiving p.o. 6-mercaptopurine-based maintenance therapy, significant interindividual variation in the accumulation of 6-TG bases into leukocyte DNA was revealed. The determined levels of drug base incorporation ranged from 95 to 710 fmol 6-TG bases/microgram DNA (6-TG base:nucleotide ratio 1:32,000 to 1:4,000). The assay may provide a novel methodology for pharmacological monitoring of thiopurine therapy either in the routine clinical setting or during studies of alternative routes of drug delivery.

Cell Line↗
PubMed1995

Pharmacokinetics of different doses of methotrexate at steady state by in situ microdialysis in a rat model.

We used a microdialysis technique to monitor extracellular methotrexate (MTX) levels during the steady state in a rodent model. Microdialysis probes were implanted in the muscle, liver, and kidney of anesthetized male Wistar rats. MTX (18.75-500 mg/kg) was given as a continuous infusion through a venous catheter, and blood samples were obtained through a second venous catheter. Heparinized plasma, ultrafiltered plasma, microdialysis effluent from tissues, and tissue samples (obtained at the end of experiments) were analyzed for MTX content by high-performance liquid chromatography (HPLC). Steady state was demonstrated in the blood and tissues from 2 h until the end of the experiments (6 h). Extracellular drug levels in muscle and liver displayed a linear correlation with doses, whereas kidney levels reached a plateau at an MTX dose of 150 mg/kg per 6 h. Microdialysis-fluid endpoint levels for muscle, liver, and kidney were positively correlated to the endpoint total tissue levels (r2 = 0.80, 0.85, and 0.68, respectively). In the kidneys, the maximal relative tissue MTX accumulation was measured at a total dose of 75 mg/kg per 6 h. At higher doses, the relative drug sequestration declined to less than half of the values observed at this dose. This study demonstrates that the microdialysis technique can provide reproducible data on MTX tissue exposure in an animal model and that it offers a means of serial and reproducible monitoring of extracellular-tissue MTX levels at steady state and over a wide dose range. Pending additional studies, microdialysis may be a helpful technique for elucidating the kinetics of drug delivery to both targeted and toxicity-prone tissues during chemotherapy.

Animals↗
PubMed1995

A high-pressure liquid chromatographic method for measuring mitotane [1,1-(o,p'-Dichlorodiphenyl)-2,2-dichloroethane] and its metabolite 1,1-(o,p'-Dichlorodiphenyl)-2,2-dichloroethene in plasma.

The adrenolytic agent mitotane [o,p'-DDD or 1,1-(o,p'-dichlorodiphenyl)-2, 2-dichloroethane] has been employed in the nonsurgical treatment of patients with adrenal carcinoma for several decades. Its use is hampered by serious side effects, which may be limited by analytically guided dose modifications in the individual patient. Mitotane analyses have previously been undertaken by gas chromatography with electron capture detection. A sensitive high-pressure liquid chromatographic method for measuring mitotane in plasma is described. After protein precipitation with 1.5 vol of acetone, mitotane and its metabolite 1,1-(o,p'-dichlorodiphenyl)-2,2-dichloroethene (o,p'-DDE) are resolved by isocratic elution from a C18 reversed-phase support and quantified by ultraviolet detection at 230 nm. Recoveries of mitotane and o,p'-DDE after deproteinization were quantitative. Within-run and between-day coefficients of variation were < 4% over the entire therapeutic range. The limit of detection was 0.25 mumol/L and the standard curve was linear in the 1-100 mumol/L range. The method has been evaluated using samples obtained from an adolescent girl who had metastatic adrenocortical carcinoma. Data from this single patient may suggest that systemic absorption of mitotane is adequate, and toxicity possibly decreased, when mitotane is administered by the rectal route.

Absorption↗
PubMed1995

Effect of methotrexate on murine bone marrow cells in vitro: evidence of a reversible antiproliferative action.

Methotrexate (MTX) acts by inducing cellular depletion of reduced folates, which ultimately leads to an inhibition of DNA synthesis. Like many anticancer drugs, this antimetabolite has little selectivity for tumor cells, and its effectiveness is limited by toxicity to normal tissues, particularly gastrointestinal epithelium and bone marrow. Previous studies have shown that MTX inhibits colony formation of the hematopoietic progenitor cells (CFU-C) in vitro. Whether this effect is due to a cytotoxic or a cytostatic mechanism has not been resolved. The present study was undertaken to eludicate the mechanism by which MTX inhibits CFU-C formation. Bone marrow cells in agarose cultures supplemented with recombinant murine granulocyte-macrophage colony-stimulating factor (rmGM-CSF) were incubated for 7 days in the presence or absence of MTX. Exposure to 33 nM to 1 microM MTX reduced colony formation by more than 80% when compared to control cultures. When bone marrow suspension cultures supplemented with rmGM-CSF were incubated for 5 days in the presence or absence of MTX, exposure to 10 nM to 1 microM MTX resulted in a 60 to 80% reduction in cell numbers when compared to untreated cultures. Residual CFU-C numbers were determined in the same cultures by replating into agarose. Exposure to 10 nM MTX was found to enhance CFU-C recovery three-fold as compared to controls and cultures exposed to higher MTX concentrations. Addition of 10 microM of the reduced folate leucovorin (LV; 5-formyl-tetrahydrofolate) prevented CFU-C accumulation in the presence of 10 nM MTX. The kinetics of LV rescue of CFU-C, pre-exposed to 100 nM MTX, were investigated in clonogenic assays. The addition of 1 microM LV to semisolid bone marrow cultures preincubated with 100 nM MTX for up to 8 days completely abolished the inhibition of colony formation seen with 100 nM MTX alone. When the dose range of MTX was expanded from 33 nM to 3.3 microM, we found that administration of 10 microM LV on day 5 rescued the hematopoietic progenitors from MTX inhibition in all groups. These observations suggest that MTX is not cytotoxic to hematopoietic progenitors over its entire dose range but that it can induce a reversible block in the proliferation and differentiation of cells in the progenitor compartment.

Animals↗
PubMed1994

Role of the 75-kDa tumor necrosis factor receptor: inhibition of early hematopoiesis.

Biological effects of tumor necrosis factor alpha (TNF-alpha) are mediated through two cell surface receptors, the 55-kDa TNF receptor and the 75-kDa TNF receptor. The present study investigated the relative roles of the two TNF receptors in normal hematopoiesis. Using agonists (antibodies) specific for the 55- and 75-kDa TNF receptors, we demonstrate differential roles of the two TNF receptors in hematopoiesis in that only the 55-kDa TNF receptor mediates antiproliferative effects of TNF-alpha on mature Lin- hematopoietic progenitor cells responding to granulocyte colony-stimulating factor or interleukin 3 alone. In contrast, the 75-kDa TNF receptor is essential in mediating inhibition of primitive Lin-Sca-1+ high-proliferative-potential colony-forming cells and inhibition of the total number of proliferative clones of individually cultured Lin-Sca-1+Rh123lo and Lin-Sca-1+Rh123hi cells.

Animals↗
PubMed1994

Quantitation of cell-associated doxorubicin by high-performance liquid chromatography after enzymatic desequestration.

A method for measuring cellular concentrations of the anthracycline doxorubicin was developed. The assay involves cell lysis and protein degradation by detergent and proteinase K treatment followed by DNA hydrolysis using DNase I. Prior to high-performance liquid chromatography, samples are deproteinized by the addition of ZnSO4 and methanol. The assay is linear with respect to both the cellular drug content and the number of cells assayed over the ranges tested, and drug recovery is close to 100%. The method has a limit of detection of 50 fmol injected doxorubicin. Within run and between-day coefficients of variation have consistently been found to be in the 5% and 10% range, respectively, in different cell lines exposed to doxorubicin in vitro. The method has been evaluated in analyses of doxorubicin levels in mononuclear blood cells of patients. The assay offers several advantages over commonly used organic extraction techniques and may improve cellular drug monitoring during anthracycline therapy in patients.

Breast Neoplasms↗
PubMed1994

Evaluation of methotrexate tissue exposure by in situ microdialysis in a rat model.

The feasibility of using a microdialysis technique to obtain pharmacokinetic data on tissue exposure to methotrexate (MTX) was investigated. Microdialysis probes were implanted in the jugular vein, femoral muscle, and liver of anesthetized male Wistar rats. MTX (100 mg/kg) was given as a bolus injection through an indwelling venous catheter, and blood samples were obtained through a second venous access and by microdialysis for a total of 6 h. Heparinized plasma, ultrafiltered plasma, and microdialysis effluent from tissue and venous probes were analyzed by high-performance liquid chromatography. Centrifugal ultrafiltration of rat plasma spiked in vitro with MTX (1-100 microM) revealed a mean binding to plasma proteins of 21%. In vitro microdialysis of this spiked plasma resulted in 23% relative recovery of the unbound fraction. In rats receiving MTX, plasma protein binding was 23% and the relative drug recovery as assessed with venous microdialysis probes was 18%. Plotting of unbound (i.e., ultrafiltrate) MTX concentrations in the blood against venous microdialysis perfusate values in the blood gave a good linear correlation with a coefficient of correlation (r2) of 0.98. There was also a linear correlation between the total MTX concentrations in venous blood and the drug levels in microdialysis samples from muscle and liver (r2 = 0.93 and 0.74, respectively). Area under the curve estimations were consistent with an MTX exposure of 30% and 46% for the muscle and liver as compared with the circulation. The present study demonstrates that the microdialysis technique can provide reproducible data on tissue exposure to MTX in an animal model and indicates that the methodology is adaptable to clinical settings.

Animals↗
PubMed1994

Pituitary-gonadal dysfunction in male patients with lung cancer. Association with serum inhibin levels.

Male lung cancer patients with poor performance status have an endocrinological dysfunction shown by decreased serum levels of total and free testosterone (AFTC). The intention was to investigate whether or not inhibin plays a role in gonadal dysfunction observed in male patients with malignant pulmonary disease. Twenty-seven patients with locally advanced non-small cell lung cancer were included. Sixteen patients were within ECOG index 1-2 (group A) and 11 patients within ECOG index 3-4 (group B). Gonadal function was monitored by serum LH, FSH, testosterone, SHBG and inhibin levels. Patients with poor performance status displayed significantly lower inhibin (1.6 +/- 0.8 U/I) and AFTC (0.23 +/- 0.07 nmol/l) levels when compared to patients within ECOG index 1-2 (inhibin 2.4 +/- 1.1 U/I; AFTC 0.66 +/- 0.36 nmol/l). Serum inhibin tended to correlate inversely to FSH with a 4.4-fold higher FSH/inhibin ratio in group B compared to A.

Aged↗
PubMed1993

A high-performance liquid chromatographic method for the determination of 6-thioguanine residues in DNA using precolumn derivatization and fluorescence detection.

An HPLC method is described for the determination of 6-thioguanine (6-TG) residues in DNA. The assay is based on the release of 2'-deoxy-6-thioguanosine 5'-monophosphate (S6dGMP) by P1-nuclease digestion and its derivatization with the thiol-reactive fluorophore monobromobimane (mBBr). Following treatment with alkaline phosphatase, the resultant 2'-deoxy-6-thioguanosine-mBBr adduct is resolved by isocratic elution from a C18 reversed-phase support and quantified fluorometrically. The chromatographic procedure provides good adduct resolution without interference from reagent peaks or endogenous components present in the DNA. Recoveries of S6dGMP following DNA digestion were quantitative and the assay displayed a linear response from 18 pmol 6-TG bases/microgram DNA down to the lowest concentration tested (0.56 pmol 6-TG bases/microgram DNA). Within-run coefficients of variation were 2.6 and 3.1% for samples containing 18 and 0.9 pmol 6-TG bases/microgram DNA, respectively. Between-day coefficients of variation were 3.1% at 18 pmol and 4.4% at 0.9 pmol 6-TG bases/microgram DNA. In the standard procedure, derivatized sample corresponding to 5 micrograms of DNA (approximately 5 x 10(5) cells) was injected per analysis. This allowed the quantification of < 2.8 pmol adduct and permitted an assessment of 6-TG base incorporation into the DNA of cells exposed to 6-mercaptopurine concentrations as low as 30 nM. This method may be useful in clarifying the relationship between drug metabolite uptake into DNA and the anticancer effect mediated by 6-thiopurines. In addition it may form the basis of improved methods for clinical monitoring during pharmacotherapy with these agents.

Chromatography, High Pressure Liquid↗
PubMed1993

Reversal of sexual impotence in male patients with chronic obstructive pulmonary disease and hypoxemia with long-term oxygen therapy.

Erectile impotence is commonly encountered in male patients with respiratory failure and hypoxia. In this study, 42% of the patients experienced reversal of sexual impotence during long-term oxygen therapy (LTOT). We examine the association between sexual impotence, gonadal axis hormones, hypoxia, and oxygen therapy. Nineteen sexually impotent male patients eligible for LTOT (pO2 < 7.3 kPa during stable disease) and with sexual impotence received oxygen therapy for 1 month (n = 12) or 24 h (n = 7). pO2, LH, FSH, testosterone, and SHBG (sex hormone binding globulin) were monitored. Five of 12 patients receiving oxygen for 1 month regained sexual potency. The responders showed a significant increase in arterial pO2 and serum testosterone, and a decline in SHBG compared to non-responders. None of the patients receiving oxygen for 24 h experienced reversal of sexual impotence, despite a significant increase in pO2. In these patients, serum testosterone did not increase significantly. Reversal of sexual impotence may be achieved in some patients with respiratory failure. The oxygen therapy must, however be administered for an adequate length of time.

Aged↗
PubMed1993

A sensitive high-performance liquid chromatographic method for the determination of 6-mercaptopurine in plasma using precolumn derivatization and fluorescence detection.

A sensitive high-performance liquid chromatographic (HPLC) method for measuring plasma concentrations of 6-mercaptopurine (6-MP) is described. After protein precipitation with 5-sulfosalicylic acid, samples are subjected to precolumn derivatization using the thiol-reactive fluorophore monobromobimane (mBrB). The drug-mBrB adduct is then resolved by isocratic elution from a C18 reversed-phase support and quantified by fluorescence detection. Recovery of 6-MP after protein precipitation was consistently > 85% and the drug-mBrB adduct was found to be stable for at least 2 weeks at room temperature. With plasma samples containing 30 nM 6-MP, the assay displayed within-run (n = 6) and between-day (n = 6) coefficients of variation of 2.2 and 10.6%, respectively. The limit of detection for 6-MP in plasma was 3 nM (500 pg/ml) and the standard curve was linear up to 3 microM. Using this method, we have observed that 6-MP is stable in heparinized whole blood for at least 24 h provided samples are maintained on ice. Since this method requires few manipulations during sample preparation and is readily adaptable to automated techniques, it may prove useful in the routine clinical laboratory setting.

Bridged Bicyclo Compounds↗
PubMed1993

A sensitive and simple high-performance liquid chromatographic method for the determination of mitoxantrone in plasma.

A sensitive high-performance liquid chromatographic (HPLC) method for measuring the anthracene derivative, mitoxantrone, in plasma is described. After protein precipitation with 5-sulfosalicylic acid, samples are resolved by isocratic elution from a C18 reverse phase support and quantified by ultraviolet (UV) detection. Recovery of mitoxantrone after deproteinization was > 70%. Within-run and between-day coefficients of variation (CVs) were 5.1 and 13.7%, respectively, at mitoxantrone concentrations of 20 nM (n = 6). The limit of detection was 2.5 nM and the standard curve linear up to 1 microM. Stability studies have shown that mitoxantrone is stable in spiked whole blood for 3-6 h, provided the samples are kept on ice. The drug is stable in plasma and deproteinized plasma samples for at least 24 h. The method requires few manipulations and is readily adaptable to automation.

Blood Specimen Collection↗
PubMed1993

A sensitive and simple high-performance liquid chromatographic method for the determination of doxorubicin and its metabolites in plasma.

A sensitive high-performance liquid chromatographic (HPLC) method for the measurement of doxorubicin and its metabolites in plasma is described. After precipitation with zinc sulphate and methanol, samples are resolved by isocratic elution from a C18 reverse phase support within 20 min and quantified by endogenous fluorescence. Recoveries over a concentration range from 5 to 1,000 nM of doxorubicin, doxorubicinol, doxorubicinone, doxorubicinolone, and 7-deoxydoxorubicinolone were 80-110%, while recovery for 7-deoxydoxorubicinone was approximately 60%. At concentrations of 5 nM, within-run and between-day coefficients of variation for each compound were < 8 and < 16%, respectively. Limits of detection for the compounds were 1-2 nM and standard curves were linear up to at least 1,000 nM. The drug and its metabolites are stable in deproteinized plasma samples at room temperature and in the dark for at least 24 h. The method requires few manipulations and is readily adaptable to automated analysis of large series of samples.

Chromatography, High Pressure Liquid↗
PubMed1993

Effect of nitrous oxide on haematopoiesis in vitro: biochemical and functional features.

Prolonged exposure to nitrous oxide (N2O) can induce dyshaematopoiesis by causing a functional cobalamin-deficiency state through oxidation of methyl-cobalamin (vitamin B12). Herein, we demonstrate that N2O exposure of murine bone marrow cells in vitro results in both functional and biochemical perturbations. In haematopoietic and bone marrow stromal cells, N2O exposure results in a decrease in methionine synthetase activity with a corresponding increase in homocysteine efflux. In semisolid cultures, N2O inhibits colony formation by cells belonging to the colony forming unit in culture (CFU-C) compartment. In contrast, N2O-exposed stromal cell layers maintain the ability to bind and support the differentiation of haematopoietic progenitor cells upon reseeding. Together, these data suggest that the dyshaematopoiesis seen after exposure to N2O is mediated through a direct inhibitory effect on haematopoietic cells.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗