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Biomedical subjects

D R Uges

Publications and source records attributed to D R Uges.

At least 73 records · Page 4Linked to original sources
PubMed1989

Influence of docosahexaenoic acid on cisplatin resistance in a human small cell lung carcinoma cell line.

In a sensitive, human, small cell lung carcinoma cell line (GLC4) and a cisplatin (CP)-resistant subline (GLC4-CP), the effect of co-culturing with docosahexaenoic acid (DCHA) on CP cytotoxicity was studied. Cells were cultured for 4 days, with 32 microM of DCHA added on days 1 and 3. Incorporation of DCHA into the cellular phospholipids was demonstrated by fatty acid analysis. Supplementation with DCHA led to almost a threefold decrease of resistance in GLC4-CP and had no influence on CP cytotoxicity in GLC4. After culturing with DCHA, cellular platinum (Pt); total Pt bound to DNA; and Pt-GG, Pt-AG, G-Pt-G, and Pt-GMP adduct contents increased in both lines, whereas interstrand cross-link formation was elevated only in GLC4-CP. These experiments demonstrate that DCHA reduces CP resistance. Although an effect on cellular membranes resulting in an increased CP uptake apparently was present, this mechanism does not seem to be responsible for resistance modulation. Rather, an effect on nuclear, probably DNA-related, structures is likely and leads to an increased formation of interstrand cross-links in GLC4-CP.

Carcinoma, Small Cell↗
PubMed1989

Blood concentrations after accidental cyclosporin overdose.

Two cases of children are reported with an accidental oral overdose of cyclosporin in whom blood concentrations were monitored. Despite a tenfold oral overdose, the peak blood concentrations of cyclosporin in both patients were only moderately increased above therapeutic levels. Apart from a transient rise in blood pressure in one patient, no toxic effects of cyclosporin were noticed.

Biological Availability↗
PubMed1989

A phase I pharmacokinetic study of 21-day continuous infusion mitoxantrone.

A phase I study of mitoxantrone given as a continuous infusion for 21 days using a venous access port and a portable pump was performed. The first dose step was 0.3 mg/m2/d for 21 days. Courses were repeated every 6 weeks. Dose increment per step was 0.1 mg/m2/d in the first three dose steps and 0.2 mg/m2/d in the latter dose steps. Twenty-five patients entered the study and received a total of 50 courses, with a median of two courses (range, one to five). Up to 0.5 mg/m2/d, no toxicity (according to the World Health Organization [WHO] criteria) occurred. At 0.7 mg/m2/d, one patient experienced grade 2 leukocytopenia and at the 0.9 mg/m2/d dose step, one patient experienced grade 2 leukocytopenia, grade 1 thrombocytopenia, and grade 1 hair loss. At 1.1 mg/m2/d, two of six patients had grade 3 leukocytopenia, and in one patient treatment was discontinued after two days because of myocardial infarction. In both patients receiving 1.3 mg/m2/d, treatment was discontinued after 2 weeks because of grade 3 leukocytopenia. Three patients at the 1.1 mg/m2/d, dose step and two patients at the 1.3 mg/m2/d dose step experienced some nausea in the last week of the infusion period. One patient developed subclavian vein thrombosis. No infectious complications occurred. Pharmacokinetic studies were performed by high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection. Plasma steady-state was reached after 35 hours. During steady-state there was a linear relationship between the mitoxantrone dose administered and the level of mitoxantrone in plasma (r = .93, P less than .005). The mitoxantrone level in leukocytes increased significantly during the infusion period at the 0.9 mg/m2, the 1.1 mg/m2, and the 1.3 mg/m2 dose steps. The area under the curve (AUC) in leukocytes was higher with continuous infusion of 1.1 mg/m2/d for 21 days compared with bolus injection of 12 mg/m2. Mitoxantrone could be detected in plasma for at least five days after the end of the 21-day infusion period and in leukocytes for at least 14 days. Continuous infusion mitoxantrone may increase intracellular drug uptake as expressed by intracellular AUC. We recommend a dose of 1.1 mg/m2/d for 3 weeks for evaluation of antitumor efficacy in phase II studies.

Adult↗
PubMed1988

Continuous infusion of low-dose doxorubicin, epirubicin and mitoxantrone in cancer chemotherapy: a review.

With the recent development of reliable portable pumps and safe venous access systems, continuous infusion of chemotherapeutic agents on an out-patient basis has become feasible. Advantages of continuous infusion are the long-term exposure of tumour cells to the drug and the fact that most toxic effects are reduced for doxorubicin, epirubicin and mitoxantrone due to elimination of the high peak plasma levels. Preliminary data for doxorubicin suggest that its antitumour activity is maintained. Pharmacokinetic studies with epirubicin and mitoxantrone showed a linear relationship between drug dose infused and the steady-state plasma level for these drugs. The area under the curve for leukocytes drug level was higher during continuous infusion than after an equitoxic bolus injection of epirubicin and mitoxantrone. Well-randomized clinical trials will be necessary to investigate the role of continuous infusion of antracyclines and mitoxantrone in cancer chemotherapy in the future.

Doxorubicin↗
PubMed1988

Characterization of a human small cell lung carcinoma cell line with acquired resistance to cis-diamminedichloroplatinum(II) in vitro.

A 6.4-fold cis-diamminedichloroplatinum(II) (CDDP) resistant human small cell lung carcinoma cell line (GLC4-CDDP) was developed to study acquired CDDP resistance in vitro. Compared to the sensitive cell line (GLC4), the GLC4-CDDP showed an increase in doubling time and a decrease in cloning efficiency, cellular size, double minutes per cell, cellular protein, and nuclear protein content. While a complete cross-resistance for tetraplatin and a partial cross-resistance for doxorubicin, melphalan, cadmium chloride, carboplatin, and cis-dichloro-trans-dihydroxo-cis-bis(isoprolylamine)platinum (IV) (resistance factor, respectively,4.0,5.8,2.1,1.5,2.9) was found, no cross-resistance for vincristine was found. In the GLC4-CDDP line in comparison to the GLC4 line, glutathione and total amount of sulfhydryl compounds was significantly increased, while glutathione S-transferase and glutathione reductase was the same. The platinum content in cells and nuclei was lower in the resistant line, but after correction for cellular protein or volume no difference was found. The amount of platinum bound to DNA was significantly lower in the GLC4-CDDP line. After a 1-h incubation with CDDP, the amount of Pt-GG adducts was the same and the amount of interstrand cross-links was reduced in the GLC4-CDDP line as compared to GLC4. In conclusion, in the GLC4-CDDP line the phenotype and genotype are changed and various mechanisms, such as decreased Pt-DNA binding, elevated glutathione, and reduced interstrand cross-links, play a role in the development of the CDDP resistance.

Amino Acids↗
PubMed1988

Plasma or serum in therapeutic drug monitoring and clinical toxicology.

The relative merits of plasma and serum in blood analysis are reviewed. The expression 'plasma concentration' is often used in the literature, although serum samples have been taken. In most cases serum and plasma concentrations of analytes are the same. The choice depends mostly on the policy of the hospital or the availability of the test tubes in the ward. Some of the advantages of plasma over serum are large volume, no delayed clotting, less risk of haemolysis. In addition, the sample is often suitable for both whole blood and plasma monitoring. Some of the disadvantages of plasma over serum are the (unknown) influence of the anticoagulant on the assay, on the protein binding and on the stability of the sample, the (unknown) influence of additives or impurities in the anticoagulants on the assay and on the concentration, the risk of the formation of small clots and dilution of the sample.

Humans↗
PubMed1988

Renal dysfunction following high-dose carboplatin treatment.

A case history is reported or renal failure during and after treatment with carboplatin for 3 days, total dose 750 mg/m2, in a conditioning regimen prior to autologous bone marrow transplantation. Pretreatment renal function was compromised after nephrectomy and chemotherapy with cisplatin. A decrease in glomerular filtration rate concurred with a decrease in excretion of platinum in the urine and an increase in urinary beta 2 microglobulin. Treatment with high-dose carboplatin in patients with impaired renal function and previous treatment with cisplatin may lead to further loss of renal function.

Adult↗
PubMed1988

Impairment of organ function after oral ingestion of refined petrol.

After oral ingestion of 600 ml of refined petrol a 23-year-old male developed multiple organ failure. Acute renal insufficiency due to nephrotoxic tubular necrosis requiring hemodialysis was a major manifestation. Moreover, respiratory failure, seizures, hemolysis, disseminated intravascular coagulation, liver damage and erosions of mucous membranes occurred. The patient subsequently recovered completely. In spite of the poor absorption from the gastrointestinal tract and the high first-pass effect in the liver, massive petrol intoxication may lead to reversible multisystemic lesions.

Acute Kidney Injury↗
PubMed1987

Comparison of the precision of seven analytical methods for the H2O concentration in human serum and urine.

In order to calculate a true renal H2O clearance (U X V/P), serum and urine H2O concentrations have to be known. In this investigation we compared the precision (repeatability) and the ease of performance of 7 H2O assays in human serum and urine. The 3 gravimetric assays (oven-drying, freeze-drying or freeze-drying as well as oven-drying) had a very high precision (coefficients of variation (CV) 0.2-0.4%) and were easy to perform. The precision of mass spectrometry, gas chromatography and titrimetry (Karl Fischer) was better in urine than in serum (ranges of CV 1.2-1.5% in urine vs. 2.4-4.3% in serum), but the precision of osmometry was better in serum than in urine (CV 1.0 vs. 1.6%). Accuracy was not determined as storage effects at 4 degrees C and at -20 degrees C caused insuperable logistic problems. Only small sample volumes are used in titrimetry and gas chromatography, making them more suitable for determinations in babies and animal studies. With titrimetry determinations can be done in a short time. The gravimetric assays appear to reflect the true H2O content of serum and urine, thus enabling calculation of the true renal H2O clearance, which can be of clinical importance in liver, renal and cardiac disease.

Body Water↗
PubMed1987

[Regional isolation perfusion with cisplatinum in dogs with osteosarcoma of an extremity].

In the treatment of osteosarcoma, it is possible to differentiate between systemic therapy and local regional treatment. Systemic treatment of human patients with osteosarcomas consists in adjuvant chemotherapy. This has considerably improved the prognosis in these cases. The primary object in local regional treatment is to prevent local recurrences and to preserve function. As regards extremities, the aim is to preserve the limbs. In the present investigations, the value of regional chemotherapy by isolated regional perfusion with cis-platinum to dogs is studied. This approach was based on the hypothesis that considerable necrosis of tumours may be produced after perfusion with cis-platinum, thus making extremity-saving surgery possible. Isolated regional perfusion with cis-platinum (30 mg/litre of extremity volume) was performed in nine dogs with osteosarcomas of an extremity. A marked effect on the tumour was detectable on the basis of clinical, radiological and histological parameters. In the opinion of the present authors, regional perfusion with cis-platinum may contribute to extremity-saving treatment of osteosarcomas in dogs and human subjects. However, further studies will be required in order to achieve more adequate quantitation an improvement of local effects. In view of the synergy with cis-platinum, the latter may possibly be attained by the addition of hyperthermia (temperatures above 41.5 degrees C).

Animals↗
PubMed1987

Changed pharmacokinetics under the influence of age.

Age significantly affects therapeutics in both general and specific ways. In newborns and in infants various physiological processes are still developing, whereas in elderly there may be decreased efficiency or capacity of physiological processes. Unexpected or 'idiosyncratic' responses to drugs in the very old or in the very young often can be explained by age-related changes in absorption, distribution, metabolism, end-organ responsiveness and excretion. Adolescence is often associated with rapid growth and changing body composition. Special problems with adolescents are poor compliance and drug abuse. Adults show a rather stable pharmacokinetic profile, although the cardiac output diminishes and the peripheral resistance increases about 1% annually. Exposure to enzyme-inducing agents (nicotine, cimetidine) influences the pharmacokinetic parameters of both adolescents and adults.

Adolescent↗
PubMed1987

A phase I and pharmacokinetic study with 21-day continuous infusion of epirubicin.

A phase I study with continuous administration of epirubicin for 21 days using a venous access port and a portable pump was performed. The first dose step was 2 mg/m2/d for 21 days. Interval between courses was 3 weeks. Dose increment per step was 1 mg/m2/d. Twenty-two patients entered the study and received a total of 58 courses with a median of two (range, one to nine). Up to 5 mg/m2/d no toxicity (according to World Health Organization [WHO] criteria) occurred. At 6 mg/m2/d (six pts), one patient had leukopenia grade 3. Two others had some hair loss. At 7 mg/m2/d (four patients), all patients developed mucositis (two grade 3). Three patients had bone marrow depression (one grade 3 anemia, one grade 4 leukocytopenia), and one patient developed the hand-foot syndrome. No other toxicity occurred in the patients. One patient obtained a partial response (18 weeks), ten had stable disease (12 to 54 weeks), seven had progressive disease, and four were not evaluable for response. One patient developed cellulitis around the port, responding to antibiotic treatment; one patient developed a vena cava superior syndrome that resolved with urokinase and removal of the access port. No septicemia occurred. Pharmacokinetic studies were performed by high-performance liquid chromatography (HPLC) with fluorometric detection. Plasma steady state was reached after 57 hours. During steady state there was a linear relationship between epirubicin dose administered and epirubicin level in plasma (r = .58, P less than .05), whole blood (r = .75, P less than .005), and in leukocytes (r = .68, P less than .05). The area under the curve in leukocytes was higher with continuous infusion of 6 mg/m2 for 21 days compared with bolus injection of 80 mg/m2. This method of continuous infusion with epirubicin may be a way to increase intracellular drug-uptake as expressed by intracellular area under curve (AUC). We recommend 6 mg/m2/d for 3 weeks for evaluation of antitumor efficacy in phase II studies.

Adult↗
PubMed1987

Phase I and pharmacokinetic study of trans-N3P3Az2(NHMe)4.

trans-N3P3Az2(NHMe)4, an aziridinyl-substituted cyclophosphazene, was tested for its toxicity, pharmacokinetic behavior, and cytostatic activity in a phase I study in 30 patients. A total of 66 courses of a single iv bolus injection were given in five dose steps. Toxicity consisted of leukocytopenia and thrombocytopenia, dose limiting at 70 mg/m2, mild anemia, and some nausea. Leukocyte and platelet count nadirs fell between 2 and 3 weeks, with recovery at 6 weeks. A tendency for cumulative thrombocytopenia was noticed in three of 13 patients at risk. A three-phase plasma elimination model was applicable with t1/2 alpha of 9.9 minutes, t1/2 beta of 78.5 minutes, and t1/2 gamma of 435.5 minutes; renal drug excretion was substantial. Three partial remissions in 21 evaluable patients suggest some clinical activity for this drug.

Adult↗
PubMed1984

Effective treatment of verapamil intoxication with 4-aminopyridine in the cat.

To study the value of 4-aminopyridine as an antidote to verapamil intoxication, we subjected 12 adult cats to verapamil poisoning by administering doses of 4.0-25.0 mg/kg verapamil by intravenous infusion. Six animals were given 4-aminopyridine 2 X 0.5 mg/kg i.v. after the verapamil infusion was stopped and the other six animals (the control group) were not. Verapamil caused profound cardiovascular depression and also partial neuromuscular block, both of which were completely reversed by 4-aminopyridine within 50 min, in spite of extremely high serum verapamil concentrations (ranging between 3,700 and 13,500 ng/ml). The six animals that received 4-aminopyridine survived the verapamil intoxication, whereas four of the six animals in the control group died. The results suggest that 4-aminopyridine may be useful in the treatment of verapamil intoxication.

4-Aminopyridine↗