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Biomedical subjects

D R Uges

Publications and source records attributed to D R Uges.

At least 55 records · Page 3Linked to original sources
PubMed1993

Enhancement of cisplatin and etoposide cytotoxicity after all-trans retinoic-acid-induced cellular differentiation of a murine embryonal carcinoma cell line.

The potential of a combination of differentiation induction and chemotherapy was analyzed. Treatment of the murine embryonal carcinoma (EC) cell line PCC4 in vitro with all-transretinoic acid (RA) was followed by exposure to cisplatin (CDDP) or etoposide (VP-16). The expression of EC-cell-specific markers decreased upon 96 hr exposure to 10(-9), 10(-8), 10(-7) and 10(-6) M RA, indicating a loss of embryonal phenotype of the cells, whereas expression of markers specific for cytokeratins and neurofilaments was increased after this treatment. These data suggest early somatic differentiation of PCC4 cells upon treatment with RA. Cellular growth rate of PCC4 cells was not affected by preincubation with RA at 10(-9) M for 96 hr, but was reduced at 10(-8) and 10(-7) M RA and inhibited at 10(-6) M RA. Culture of PCC4 cells in the presence of 10(-7) M RA for 96 hr led to accumulation in G1 of the cell cycle, whereas at 10(-8) M RA cell-cycle distribution was not affected. RA-treated and -untreated PCC4 cells were compared for CDDP and VP-16 sensitivity. Pre-treatment with 10(-9), 10(-8) and 10(-7) M RA increased CDDP sensitivity, resulting in a 1.9-, 2.7- and 2.6-fold decrease in the concentrations inhibiting survival by 50% (IC50s) respectively. Pre-treatment with 10(-8) and 10(-7) M RA increased VP-16 sensitivity 2.5- and 3.0-fold, respectively. Enhanced CDDP sensitivity at RA concentrations not affecting cell-cycle distribution was not attributable to changes in cellular platinum (Pt) accumulation, or to changes of Pt-DNA binding.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Phase I-II study of the addition of alpha-2a interferon to 5-fluorouracil/leucovorin. Pharmacokinetic interaction of alpha-2a interferon and leucovorin.

5-Fluorouracil (5-FU) activity has been improved by the use of leucovorin (LV) or alpha-2a interferon (alpha-IF). We investigated the feasibility and activity of addition of alpha-IF to a 5-FU/LV regimen. A phase I study with 26 patients (14 previously untreated, 12 previously treated) with disseminated cancer was conducted. 15 patients were treated with 5-FU/LV and 11 with 5-FU/LV/alpha-IF. The 5-FU/LV regimen consisted of escalating doses of 5-FU bolus intravenously on days 2 and 3, combined with repeated oral LV on days 1, 2 and 3. Treatment was every 2 weeks. In the 5-FU/LV/alpha-IF schedule, 18 x 10(6) U alpha-IF subcutaneously daily was added on days 1, 2 and 3. The phase I study was followed by a phase II study of 5-FU/LV/alpha-IF at the established 5-FU dose in 29 previously untreated patients with disseminated colorectal cancer. The optimal 5-FU dose in both parts of the phase I study was 750 mg/m2/day. Mucositis, diarrhea and leucopenia were dose limiting. Although alpha-IF added its own toxicity (fever, flu-like symptoms, fatigue), it did not decrease the optimal dose of 5-FU. In the phase II study 28 patients were evaluable for response: three complete responses and 12 partial responses were observed (response rate 54%, 95% confidence interval, 34 to 72%). Pharmacokinetics of oral LV was performed in patients treated with and without alpha-IF: significantly higher serum levels of LV and 5-methyltetrahydrofolate were found after alpha-IF addition. Influence of alpha-IF on gastrointestinal absorption or renal clearance could be excluded. In conclusion, this 5-FU/LV/alpha-IF combination seems active in metastatic colorectal cancer. The pharmacokinetic interaction between alpha-IF and LV may play a role in the activity of this regimen. Controlled studies are necessary to establish the value of addition of alpha-IF to 5-FU/LV regimens.

Adult↗
PubMed1993

A phase I study of 1,2-diamminomethyl-cyclobutane-platinum (II)-lactate (D-19466; lobaplatin) administered daily for 5 days.

A phase I trial was conducted with lobaplatin (D-19466; 1,2-diamminomethyl-cyclobutane-platinum (II)-lactate) i.v. bolus daily for 5 days every 4 weeks. After entering five patients toxicity appeared to be related to renal function, therefore the individual dose (total dose 20-100 mg m-2 over 5 days) of lobaplatin was modified according to creatinine clearance (CRCL) and escalated in patients. Twenty-seven patients with refractory solid tumours received 72 courses. Thrombocytopenia was dose-limiting, its degree was related to dose and CRCL at time of drug administration. With a CRCL of 60-80 ml min-1 the maximum tolerated dose was 40 mg m-2, with a CRCL of 81-100 ml min-1 70 mg m-2, and with a CRCL > 100 ml min-1 it was 85 mg m-2. Platelet and leukocyte nadirs were observed around day 21. The percentual platelet nadir (percentage of day 1 platelet count) correlated with CRCL at different dose levels and could be described by 0.76 x CRCL (ml min-1) - (1.45 x dose (mg m-2) + 43.38. This equation tested in 20 patients (28 courses) produced a correlation between observed and predicted percentual platelet nadir (r = 0.82, P < 0.001). No renal function impairment occurred. Urinary excretion of platinum (by A.A.S) was estimated in six patients and revealed that 91.5% (s.e. +/- 7.9) of the platinum dose was excreted within 4 h. Responses (one PR, one CR) occurred in two patients with ovarian cancer (both pretreated with carboplatin and cisplatin). The recommended dose of lobaplatin i.v. bolus daily for 5 days for phase II studies depends on renal function, namely 30 mg m-2 at CRCL 60-80 ml min-1; 55 mg m-2 at CRCL 81-100 ml min-1; 70 mg m-2 at CRCL > 100 ml min-1.

Adult↗
PubMed1993

Pharmacokinetics of cyclosporine A after intravenous and oral administration in liver transplant patients measured with high-performance liquid chromatography.

Cyclosporine A (CsA) bioavailability after i.v. and oral administration was studied in six stable liver transplant patients with open and clamped bile drain. CsA levels were determined by the high-performance liquid chromatography method (HPLC). External bile drainage decreased CsA absorption considerably. Clamping the bile drain resulted in higher and earlier peak CsA levels. Clamping the bile drain increased the bioavailability (9.6% vs. 7%, p < 0.05), but even then it was considerably lower than the value of approximately 30% generally reported in literature. It is recommended to continue i.v. CsA administration to obtain therapeutic plasma concentrations. Early bile drain clamping or bile refeeding will improve CsA absorption and may also result in continuously therapeutic CsA levels.

Absorption↗
PubMed1992

Clinical and pharmaceutical aspects in acute poisoning.

Today there are several methods for treating intoxicated patients. If these patients arrive in hospital in time, the diagnosis is correct and appropriate therapy is instituted, nearly all survive without any physical damage. This is best achieved by team-work between the hospital pharmacist and the physician treating the patient. Both should have a sound knowledge of the toxicological properties of drugs and other poisons and the clinical features which they produce. This article emphasizes the need for close co-operation between the pharmacist and the physician and discusses specific therapeutic measures, such as prevention of absorption, acceleration of elimination, symptomatic therapy and administration of antagonists.

Acute Disease↗
PubMed1992

Combination therapy with cisplatin: modulation of activity and tumour sensitivity.

Although cisplatin is applied with success in clinical oncology, this success is limited because some cancers are initially unresponsive to cisplatin or become so during treatment. In this review, some strategies to overcome this problem are discussed. Among these are combination with the differentiation inducing agent, retinoic acid, combination with radiotherapy, and the use of hyperthermia.

Animals↗
PubMed1992

Stability of the new anticancer platinum analogue 1,2-diaminomethyl-cyclobutane-platinum(II)-lactate (lobaplatin; D19466) in intravenous solutions.

The chemical stability of the new anticancer platinum analogue 1,2-diaminomethyl-cyclobutane-platinum(II)-lactate (D19466) in infusion media was studied in an accelerated stability testing experiment with a selective HPLC-UV method. Variables were time, temperature, light, concentration, and infusion mixture. Mean reaction rate constants of decomposition were, respectively, 0.9555 *10(-2), 2.127 *10(-2), and 4.221 *10(-2) hr-1 at 37, 56, and 66 degrees C at a concentration of 200 mg/L in normal saline. From the Arrhenius equation, shelf lives (5% loss) at 4, 22, 37, and 121 degrees C were, respectively, calculated to be 41.6, 13.2, 5.7, and 0.15 hr. Mean reaction rate constant in 5% dextrose was 3.106 *10(-2) hr-1 (200 mg/L; 56 degrees C) and differed from that in normal saline (P less than 0.005). Mean reaction rate constant in Ringer lactate was 2.084 *10(-2) hr-1 (200 mg/L; 56 degrees C) (P greater than 0.05). There was no influence of normal daylight on the rate of decomposition. It is recommended to prepare D19466 infusions in normal saline. Chemical stability is then maximal 12 hr at room temperature or 24 hr at 4 degrees C. No protection against normal daylight is required. Sterilization by heat is not possible.

Antineoplastic Agents↗
PubMed1991

Sensitive method for the determination of vincristine in human serum by high-performance liquid chromatography after on-line column-extraction.

A column-switching high-performance liquid chromatographic method was developed for the determination of vincristine in serum. Sample preparation was carried out by means of on-line column-extraction, using a C18 reversed-phase preconcentration column. This technique is simple (minimizing manual sampling errors), rapid (reduction of time and costs) and can be easily automated. Both ultraviolet and electrochemical detection are possible, but the latter shows a cleaner chromatogram and is, by the use of a new electrochemical detector, far more sensitive (detection limit 0.3 microgram/l at a signal-to-noise ratio of 3). A matrix study was carried out (using human serum and urine and two kinds of calf's serum). Although it appeared that the system was matrix-dependent, no difference in matrix effects could be found in the serum or plasma of different patients. Controls for human serum analysis should be prepared in human serum. With the method described, pharmacokinetic studies of vincristine in children can be performed.

Chromatography, High Pressure Liquid↗
PubMed1991

In vitro and in vivo modulation of multi-drug resistance with amiodarone.

The modulating effect on drug resistance of amiodarone (AM) and its metabolite desethylamiodarone (DEA) was studied in a P-glycoprotein-positive human colon carcinoma cell line COLO 320, and a human small-cell lung carcinoma cell line GLC4 and its adriamycin (Adr)-resistant subline GLC4-Adr (both P-glycoprotein-negative). AM, DEA and verapamil induced an increase in cytotoxicity of Adr, vincristine and etoposide (VP16) in COLO 320 cells, while in the GLC4 and GLC4-Adr cell line no effect was seen. In the COLO 320 cell line, AM caused more intracellular, and especially intranuclear, fluorescence of Adr and more Adr-induced DNA strand breaks as compared to Adr alone. Moreover, an increase in VP16-induced topoisomerase II-DNA complexes was observed when AM was added. Competition between AM and Adr for the same efflux pump was suggested in efflux studies. The colony-forming unit granulocyte macrophage (CFU-GM) assay showed no increase in cytotoxicity of Adr when AM was added. Fourteen patients with Adr-resistant tumors were treated with Adr and AM. In these patients, peak serum levels of AM plus DEA of 10 microM were reached. Patient serum (20%) obtained after the first i.v. AM infusion induced in vitro significantly more cell kill of Adr in COLO 320 cells. Apart from a transient first-degree AV block in one patient, no cardiac toxicity was observed with the combination of Adr and AM. Bone-marrow toxicity was the same as expected from Adr alone in these patients. One of the 13 evaluable patients obtained a partial remission.

Adult↗
PubMed1991

Continuous infusion carboplatin on a 21-day schedule: a phase I and pharmacokinetic study.

A phase I study with continuous infusion carboplatin for 21 days every 6 weeks using a venous access port and portable pump was performed over a dose range of 12 to 32 mg/m2/d, with increments of 2 mg/m2/d. Forty-four patients received 107 courses (median, two; range, one to nine). World Health Organization (WHO) grade III/IV leukopenia and thrombocytopenia occurred in one of seven patients at 30 mg/m2/d, and in two of six and four of six patients at 32 mg/m2/d. Cumulative platelet depression was found at dose levels of 28 mg/m2/d or more. Median glomerular filtration rate (GFR) and effective renal plasma flow, monitored by radioisotope clearances at doses greater than or equal to 20 mg/m2/d, decreased 8.2% (P less than .05) and 10.9% (P less than .01) after two courses. There was a relationship (r = .50, P less than .0002) between the percentage of platelet depression and GFR. No other toxicity was observed. Of the 17 patients who were evaluable, one complete response and four partial responses were observed. In addition, six patients had stable disease. Pharmacokinetic analysis of total and ultrafiltrable platinum (UFPt) was performed by atomic absorption spectrophotometry. Steady-state plasma levels for UFPt were reached after 8 hours. These levels could be detected from the 20 mg/m2/d dose. During steady state, carboplatin dose and UFPt plasma levels were not correlated, but steady-state UFPt and GFR (r = -.27, P less than .05) were. Twenty-four percent of total platinum (Pt) was present as UFPt during steady state (x = 160 +/- 10 micrograms/L). Total body clearance of UFPt exceeded GFR 2.2 times. Mean area under the curve (AUC) for UFPt during continuous infusion was 4,921.8 +/- 301.72 mg.min/L. For total Pt, steady-state plasma levels were not reached; total Pt plasma levels increased between day 7 and day 21 (P less than .0001). There was a significant relation between total Pt serum levels day 7, 14, and 21 and the drug dose administered. Immunohistochemical analysis of DNA-bound Pt in leukocytes showed a linear increase from day 7 to day 14 to day 21 (r = .97) between DNA-bound Pt and duration of infusion in individual patients. The maximum-tolerable dose of carboplatin is 30 mg/m2/d for 21 days (total dose 630 mg/m2) and is recommended for phase II studies.

Adult↗
PubMed1990

A study of human small-cell lung carcinoma (hSCLC) cell lines with different sensitivities to detect relevant mechanisms of cisplatin (CDDP) resistance.

The cisplatin(CDDP)-resistant cell line GLC4-CDDP shows a variety of differences from the parent line GLC4. The aim of this study was to determine which of the observed changes correlated with the degree of resistance and was therefore relevant to the phenomenon of CDDP resistance. For these experiments we used cells of the sensitive hSCLC cell line GLC4 and the in vitro-acquired CDDP-resistant sublines GLC4-CDDP3 and GLC4-CDDP11, with a resistance factor (RF) of 3 and 11 respectively for CDDP and of 1.8 and 7.4 respectively for carboplatin. Carboplatin was used, in addition to CDDP in seeking relevant mechanisms. No consistency was found between the RF and the growth pattern or antigen expression, cellular volume, doubling time, cellular or nuclear platinum (Pt) content or the level of Pt-non-histone chromatin protein (NHCP) binding. A correlation was found between the RF and the level of glutathione (GSH), and a trend was found for the level of Pt-DNA binding, Pt-GG adduct content and the amount of interstrand cross-links (ISC). These changes might therefore be relevant for the development of resistance. These findings are compatible with a GSH-induced reduction of the amount of reactive Pt in the resistant cell, resulting in a lower net platination and toxic Pt-DNA adduct formation.

Antibodies, Monoclonal↗
PubMed1990

The uncoupling of biliary lipid from bile acid secretion by organic anions in the rat.

A number of organic anions has been shown to inhibit biliary phospholipid and cholesterol secretion without affecting bile acid secretion. However, the mechanism of this uncoupling phenomenon is still unclear. This study shows a comparison of the effects of ampicillin (18 mumol/100g body wt), sulfated taurolithocholic acid (0.2 and 1.0 mumol/100 g body wt), and indocyanine green (0.6 mumol/100 g body wt) in control and Groningen Yellow-Wistar rats with chronic (8 days) biliary drainage. Groningen Yellow rats have a hereditary defect in hepatobiliary transport of various organic anions. Bile secretion, but not hepatic uptake, of the three organic anions was strongly impaired in Groningen Yellow rats compared with controls. Ampicillin and sulfated taurolithocholic acid caused a strong uncoupling in control rats but had no effect or a much smaller effect on lipid secretion in Groningen Yellow rats. Indocyanine green did not affect lipid secretion, in either control or in Groningen Yellow rats. Gel-filtration chromatography of bile showed a specific coelution of ampicillin and sulfated taurolithocholic acid with the bile acid fraction, whereas indocyanine green coeluted with the phospholipid/cholesterol fraction. This study concludes that the uncoupling by ampicillin and sulfated taurolithocholic acid occurs after their secretion into bile and is caused by interaction of these compounds with bile acids. It is hypothesized that this interaction inhibits the capacity of bile acids to induce secretion of phospholipids and cholesterol into the bile.

Ampicillin↗
PubMed1990

Pharmacokinetics of carboplatin at a dose of 750 mg m-2 divided over three consecutive days.

Pharmacokinetics of the cisplatin analogue carboplatin were studied in patients with disseminated ovarian and testicular cancer. Carboplatin 750 mg m-2 divided over three consecutive days was given as part of an ablative combination regimen followed by autologous bone marrow transplantation. Platinum (Pt) in plasma, plasma ultrafiltrate and urine was determined up to 96 h after the last drug dose by atomic absorption spectrometry. Carboplatin was measured by high performance liquid chromatography. The curves of ultrafiltrated Pt and carboplatin decayed in a bio-exponential way with t1/2 alpha of respectively 65 and 70 min and t1/2 beta of respectively 378 and 1014 min. The volumes of distribution (Vdss) were 18 and 25 l m-2, respectively, and total body clearances (ClTB) 79 and 65 ml min-1 m-2. Both curves overlapped when corrected for the Pt content of carboplatin. A diversion with the three-exponential curve of total Pt occurred between 3 and 6 h. After 10 h approximately 30% of the plasma Pt was protein bound. Total Pt had a larger Vdss (117 l m-2) and a lower total body clearance (14 ml min-1 m-2) than free Pt and carboplatin. Fifty-three per cent of the i.v. administered carboplatin was excreted in the urine in the first 6 h. Plasma ultrafiltrated Pt and carboplatin decreased to undetectable levels within 48 h, but total Pt was detectable until 96 h after the last carboplatin dose. However, this Pt is already bound to protein and unlikely to be cytotoxic to reinfused haemopoietic stem cells, so bone marrow reinfusion can be safely performed at 48 h after repeated dosing of carboplatin on three consecutive days.

Adult↗
PubMed1990

The role of glutathione in resistance to cisplatin in a human small cell lung cancer cell line.

The role of glutathione (GSH) in resistance to cisplatin (CDDP) was studied in a human small cell lung carcinoma cell line (GLC4) and a CDDP-resistant subline (GLC4-CDDP). In addition to studying the steady state of GSH, the kinetics of this defence system were also studied via the monitoring of the GSH status of the cells under continuous pressure of CDDP. GLC4-CDDP maintained its elevated GSH level whereas GLC4 (under pressure of CDDP) quickly synthesised GSH to about twice its initial level, corresponding with 80% of the GSH level of GLC4-CDDP. D,L-buthionine-S,R-sulphoximine (BSO) was used to analyse the role of GSH in resistance to CDDP. Pretreatment with BSO (48 h, 50 microM, GSH not detectable) increased the CDDP-induced cytotoxicity 2.8-fold in GLC4-CDDP and 1.7-fold in GLC4. In GLC4 no changes in the amount of platinum (Pt) bound to DNA could be observed after GSH depletion. Changes in formation of interstrand cross-links or the main Pt-containing intrastrand cross-link in digested DNA, the Pt-GG adduct, were also not observed. In GSH depleted GLC4-CDDP cells, an increase in the amount of Pt bound to DNA and in the Pt-GG adduct was observed. Pretreatment with BSO substantially reduced the repair of Pt bound to DNA in both cell lines. We conclude that an increased GSH level and GSH synthesis capacity were demonstrated in CDDP resistant cells. The observations after BSO treatment suggest two roles for GSH in CDDP resistance, namely that of a cytosolic elimination resulting in less DNA platination and a nuclear effect on the formation and repair of DNA platinum adducts.

Antimetabolites↗
PubMed1990

Euthanasia: a challenge for the forensic toxicologist.

People die daily in the hospital. Mostly, they die because their illnesses were no longer treatable (natural death). Unfortunately, some people die an unnatural death, in particular, as the result of euthanasia. In contrast to the situation in most countries, in the Netherlands euthanasia is accepted by the courts under strict conditions. It can be very difficult for the legal authorities to establish whether a person has died from natural causes or from suicide, euthanasia, or murder. In addition to the pathologist and the lawyer, the toxicologist also has a number of problems in showing whether euthanasia has been carried out. These can consist of the following analytical problems: (a) interactions--the patients involved have frequently been receiving a large number of toxic and nontoxic drugs simultaneously; (b) identification--not all drugs administered are included in general screening procedures; (c) metabolites--a large number of metabolites may have accumulated toward the end of a long therapeutic regimen; and (d) determination--determination of quaternary muscle relaxants and their various metabolites, as well as other drugs, can be problematic. There are also toxicokinetic problems; because of poor kidney and liver function, low serum albumen, general malaise, and interactions between these factors and other drugs, the kinetics of a given drug can differ from normal. This makes it all the more difficult to determine whether the patient died from an accumulation of medication or from a so-called "euthanetic" drug mixture.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1989

The use of an alum irrigation in the treatment of massive bladder haemorrhage.

Severe, massive bladder haemorrhage is a difficult and often frustrating clinical problem. The aetiologies are numerous and include irradiation, malignancy, severe infection and drug-induced changes. Among the numerous modalities of treatment that have been reported formalin, phenol and silver nitrate instillations have often been associated with significant side effects, morbidity and mortality and have had varying degrees of success. During the last two years we have used continuous closed irrigation of a sterile 0.5% alum solution in 16 patients. Alum is an astringent and acts by protein precipitation over the bleeding surface. Because of a low cell permeability its action is limited to the cell surface and interstitial spaces. The permeability of the cell membrane is reduced but remains viable. The preparation and the pharmaceutical aspects of the 0.5% alum irrigation will be discussed. The conclusion is that the technique of managing massive bladder haemorrhage is simple, efficient, nontoxic and less expensive than previously reported therapies. Therefore, irrigation with alum before instituting invasive means to control bleeding is recommended.

Aged↗
PubMed1989

High-dose cyclophosphamide or melphalan with escalating doses of mitoxantrone and autologous bone marrow transplantation for refractory solid tumors.

As the dose-limiting toxicity of mitoxantrone is hematological, the drug is suitable for dose escalation and use in intensive chemotherapy followed by autologous bone marrow rescue. Adult patients with therapy-resistant solid tumors received a regimen of high-dose cyclophosphamide (7 g/m2) and escalating doses of mitoxantrone in dose steps of 30, 45, 60, and 75 mg/m2. Both drugs were given i.v. on 3 consecutive days. Despite the addition of mesnum (3.5 to 7 g/m2), hemorrhagic cystitis occurred on the second day in four of eight patients, irrespective of the mesnum or mitoxantrone dose. Therefore, the cyclophosphamide in the combination regimen was replaced by high-dose melphalan (180 mg/m2). Mucositis was dose limiting at 75 mg/m2 of mitoxantrone. Responses were seen in eight of ten evaluable patients with four complete responses. Three responders received, after the autologous bone marrow transplantation program, radiotherapy or surgery on pretreatment bulky tumor localizations. Five patients still have disease-free survival after 9 to 36 mo. Pharmacokinetic studies of mitoxantrone were performed by high-performance liquid chromatography with UV detection. The plasma disappearance of mitoxantrone fitted into a three-compartment model with a mean t1/2 alpha of 10 min, a mean t1/2 beta of 96 min, and a slow elimination phase of 172 h. The mean distribution volume was 4294 +/- 3836 liters. We conclude that the high-dose cyclophosphamide-mitoxantrone regimen led to unexpected bladder toxicity, but the combination of melphalan (180 mg/m2) and mitoxantrone (60 mg/m2) can probably be given without major extramedullary toxicity. However, more patients should be evaluated at this dose before definite conclusions can be drawn about toxicity.

Adult↗