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S Kerpel-Fronius

Publications and source records attributed to S Kerpel-Fronius.

At least 37 records · Page 2Linked to original sources
PubMed1987

Chemical reactivity of cisplatin bound to human plasma proteins.

Human plasma was incubated with cisplatin over 24 h. Ultrafilterable platinum and platinum reactive with DDTC were determined at regular time intervals during incubation. At each time point more platinum reacted with sodium N,N1-diethyldithiocarbamate (DDTC) than was available as ultrafilterable platinum. At 24 h 70% of total platinum (10% ultrafiltrable platinum and 60% protein-bound platinum) reacted with DDTC. This means that cisplatin bound to plasma proteins can--at least in part--still react with strong nucleophiles.

Blood Proteins↗
PubMed1987

Phase I-II trial of aclacinomycin A given in a four-consecutive-day schedule to patients with solid tumours. A South-East European Oncology Group (SEEOG) Study.

Aclacinomycin A (ACM) in a daily dose of 30 mg/m2 was infused over 1 h on 4 consecutive days to 50 patients. Myelotoxicity was acceptable, nausea and vomiting was frequent, hair loss was mild. Grade 1-2 cardiac rhythm abnormalities were observed in 12% of the patients. Between days 1 and 4 the heart rate and the corrected Q-T interval increased while the amplitude of the T wave decreased significantly, cardiac contractility remained unchanged. In 24 evaluable breast cancer patients 1 complete remission (4%) and 2 partial remissions (8%) lasting for only 2-3 months were seen. None of the 8 patients suffering from ovarial cancer benefitted from ACM therapy.

Aclarubicin↗
PubMed1987

The excretion of urinary enzymes, proteins and creatinine in patients receiving cisplatinum.

The sensitive parameters of tubular nephrotoxicity during 4-day chemotherapy with new combination schedule of cisplatinum and 5-fluorouracil were followed. The determinations of tubular enzymes beta-glucuronidase (GRS) and gamma-glutamyltransferase (GMT) in 24 hours urine, the excretion of creatinine and proteinuria were assayed before therapy and during 4 consecutive days of treatment. We recorded the significant increase of protein excretion and only slight increase of GMT and GRS activities after chemotherapy. The decrease of the creatinine excretion on the 3rd day of therapy was not statistically significant. Simultaneously followed serum creatinine and urea levels proved the elevation of creatinine only in 1 patient (the 1st grade according WHO classification). Our results suggest that the performed regime of chemotherapy produces only very low nephrotoxicity comparing to the 1-day administration of cisplatinum. These conclusions are confirmed also by the former examinations of GRS activities in cisplatinum therapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

Comparative evaluation of two administration schedules of cis-dichlorodiammineplatinum (DDP) in ovarian and head and neck cancers: a CMEA chemotherapy group study.

The therapeutic effectivity of two administration schedules of DDP were compared. The dose was either 100 mg/m2 infused for 4 h or 20 mg/m2 infused for 1 h on 5 consecutive days. The combined objective remission rate of the two regimens were 37/53 (23% CR ++ 44% PR) for ovarian cancer and 8/35 (9% CR + 14% PR) for head and neck cancer. WHO Grade 1-2 myelo- and nephrotoxicity was observed in 26% and 20%, respectively, out of the 105 cases evaluable for toxicity in the two groups. Nausea and vomiting was moderate to severe. Neither the remission rate nor the toxicity of the two schedules were significantly different.

Adult↗
PubMed1987

Pharmacokinetic studies of [14C]-flumecinol in humans.

The pharmacokinetics of 14C-labelled 3-trifluoro-methyl-alpha-ethylbenzhydrol (flumecinol, RGH-3332, Zixoryn), a hepatic enzyme inducer, has been studied in 6 male healthy volunteers after a single oral dose of 100 mg (11.1 Mbq; 300 microCi). Flumecinol concentration in plasma was determined (0-96 h) by capillary gas-liquid chromatography. Total radioactivity was assayed by liquid scintillation counting. The peak concentration of unchanged flumecinol in the plasma (130.2 +/- 37.7 ng/ml S.D.) was detected 2.1 h after dosing. The maximum total radioactivity concentration (1414.4 +/- 158.9 ng eq./ml) was found at 2.3 h. The ratio of the plasma radioactivity level to unchanged flumecinol indicated a rapid metabolic transformation and a marked first-pass effect in man. A two-compartment open model was constructed to describe the pharmacokinetics of the drug. The unchanged drug was eliminated from plasma with a biological half-life of 20.7 +/- 1.8 h giving a total body clearance value of 100.9 +/- 33.8 l/h. The volume of distribution of flumecinol was found to be 41.4 +/- 18.4 l/kg. However, the biological half-life of total radioactivity was much longer (35.2 +/- 11.9 h) than that of the decrease of unchanged drug. The value of total body clearance (4.1 +/- 0.6 l/h) and volume of distribution (3.2 +/- 1.6 l/kg) were found to be much lower than that of unchanged flumecinol. Radioactivity excreted with urine was 78.8 +/- 5.9% and with faeces 12.0 +/- 5.3% during 120 h.

Adult↗
PubMed1986

Pharmacokinetic study in a phase I trial with an alkylating agent, diacetyldianhydrogalactitol (DADAG).

Diacetyldianhydrogalactitol (DADAG), a new alkylating hexitol derivative, was given in 30-min infusions for 5 consecutive days or as a single high-dose administration. The parent drug was eliminated in a biphasic manner, with a terminal half-life of 30-40 h. Dianhydrogalactitol (DAG), the main, pharmacologically active metabolite, appeared after a lag time of about 0.2-0.6 h. Its peak concentration was reached 1-2 h after termination of the infusion. The terminal elimination of DAG followed that of the parent compound. During the 5-day schedule slight accumulation was observed, and the plasma concentrations of both compounds approached the steady state. Over a dose range of 75-1050 mg/m2 the daily mean plasma concentrations of DADAG increased by only about 3-4 times. Dose-dependent expansions of the distribution volumes of the drug (Vc, V lambda, Vss) were observed. The behavior of DADAG and DAG in the body could be adequately described by a three-compartment open model. After equilibration the plasma levels of the parent compound and its metabolite were determined by the rate of return of DADAG from the peripheral compartment and its conversion to DAG.

Adult↗
PubMed1986

Relation between dose, plasma concentration and toxicity in a phase I trial using high dose intermittent administration of an alkylating agent, diacetyldianhydrogalactitol (DADAG).

Diacetyldianhydrogalactitol (DADAG), a new alkylating sugar alcohol derivative, was administered as single, 30-min infusions in doses ranging from 390 to 1200 mg/m2. The dose-limiting toxicity was myelosuppression. The median times to WBC nadir and regeneration were 16 and 21 days, and to platelet nadir and recovery 20 and 27, respectively. Nausea and vomiting occurred frequently and were of moderate severity. For phase II studies 900 mg/m2 DADAG given every 4-6 weeks is recommended. The area under the plasma concentration time curve (AUC) for DADAG did not increase in proportion with dose escalation; it changed only from 235.5 +/- 70.7 to 262.4 +/- 71.5 micrograms h ml-1 between doses of 690 and 1050 mg/m2. No correlations between the dose administered and the nadir values for haemoglobin concentration, WBC and platelet counts, or the number of episodes of vomiting were demonstrable in this dose range. Such an association was revealed, however, when the above biological variables were related to the individual AUC for DADAG.

Adult↗
PubMed1986

Dibromodulcitol-based combined postoperative chemotherapy of malignant astrocytomas and glioblastomas.

Continuing our earlier studies with dibromodulcitol (DBD), in a series of 38 evaluable consecutive patients who were operated on for malignant supratentorial gliomas, radiotherapy with smaller daily but higher total doses of DBD has been started 3-5 weeks after surgery. This was followed alternately by a combination chemotherapy of CCNU and DBD or CCNU and Procarbazine. No severe myelotoxicity occurred. Survivals were compared with a group of patients who got irradiation alone. Statistical analysis showed a significantly better survival in the presently treated group: median survival was 55 weeks, p = 0.02. These values were very similar to those groups which were treated by intermittent DBD schedule during irradiation. This study seems to confirm our previous suggestion that the concurrent use of DBD during irradiation might be an important factor in improving survival times.

Adult↗
PubMed1986

Pharmacokinetics and metabolism of dianhydrogalactitol DAG in patients: a comparison with the human disposition of dibromodulcitol DBD.

Dianhydrogalactitol (DAG), labelled with 3H, was administered in single intravenous or oral doses to six patients (three in each group) with cancer. Kinetic parameters were calculated for the unchanged DAG and its biotransformation products. Elimination of the drug by metabolism and excretion was described by a catenary model. In order to elucidate the role of DAG as a mediator of the alkylating action of the cytostatic drug dibromodulcitol (DBD), the pharmacokinetic parameters of DAG and DBD were compared. The mean residence time for pharmacologically active molecules in the body was six times shorter for DAG (1.9 hr) than for DBD (11.4 hr). Alkylating action and metabolic degradation proceeded about 8-9 times faster for DAG than for DBD. The process of DBD alkylation implies a slow solvolytic conversion of the parent drug into the more reactive bromoepoxide and DAG. The preformed DAG would be rapidly consumed by intracellular alkylation and degradation, while unchanged DBD could form a depot in the cells and exert its cytostatic activity through the epoxides released in situ by solvolytic activation. Thus DBD entering the cells in unchanged form may have a more important role in its therapeutic effects than had been assumed earlier.

Adult↗
PubMed1984

A sensitive assay for the pharmacokinetic investigation of a rapidly hydrolyzing alkylating agent Lycurim (ritrosulfan; R-74; NSC-122 402).

Lycurim [1,4-di(2'-methanesulfonyloxyethylamino)-1,4-dideoxymesoerythri tol dimethane sulfonate] is rapidly hydrolyzed in aqueous media to inactive products according to a second-order reaction. The respective rate constants are: k1 = 9.82 X 10(-2) and k2 = 1.76 X 10(-2) mumol/ml/min. The concentrations of the parent compound and alkylating intermediate(s) were measured by chemical trapping with N,N-diethyldithiocarbamic acid (DDTC). The rate of this reaction is substantially higher: k1 = 2.61 X 10(-1) and K2 = 4.76 X 10(-2) mumol/ml/min. By using 35S-labeled DDTC, alkylating compounds in concentrations as low as 0.04 microgram/ml could be detected in spiked plasma samples. After intracavitary application of 60 mg Lycurim no alkylating activity could be demonstrated in the plasma of patients at any time point.

Alkylating Agents↗
PubMed1983

Effect of a single high dose and repeated small doses of dianhydrogalactitol (DAG; NSC-132313) on rat intestinal mucosa.

The influence of the treatment schedule of dianhydrogalactitol on its effect on the activity of mucosal enzymes in rat intestine was studied. The effect of a single high dose (10 mg/kg) was compared with that of repeated small doses (4 x 2.5 mg/kg) given at daily intervals. At 48 h after a single high dose the activities of thymidine kinase, which is a marker of dividing crypt cells, and of alkaline phosphatase, sucrase, maltase, xanthine oxidase, which are markers of mature enterocytes, were strongly depressed. Even 96 h after the treatment low enzyme activities could be observed. Repeated small doses caused milder enzyme inhibition and almost total recovery had occurred by 96 h after administration of the last dose. The results indicate that fractionation of drug administration can reduce the toxic side-effects on the intestinal mucosa and might be partly responsible for the higher therapeutic index of such schedules in experimental tumor models.

Alkaline Phosphatase↗
PubMed1983

The distribution of [3H]-dibromodulcitol in the central nervous system of patients with brain tumour.

The uptake of [3H]-dibromodulcitol ( [3H]-DBD) into glioblastomas, white matter and cerebrospinal fluid was studied in 10 patients. Single-tissue samples were taken from different subjects at 4, 15 and 24 hr after [3H]-DBD administration. The level of 3H-compounds in the central nervous system was similar after a single (400 mg/m2), or 3 smaller daily oral doses of 150-180 mg/m2 of [3H]-DBD. The distribution of radioactivity was uniform in the tumour, white matter and muscle. Between 3 and 15 hr after administration of DBD the concentration of radioactivity did not change significantly and was between 5 and 13 micrograms of DBD/g tissue wet wt. At the same time the level in the cerebrospinal fluid (CSF) remained between 1 and 4 micrograms/ml. Meanwhile, the average concentration of radioactivity in the plasma fell from 11 to 3 micrograms/ml. The elimination half-life of the labelled compounds from the tissues was about 1 day as judged from the limited number of non-serial data obtained 4 and 24 hr after the last dose of repeated drug administration.

Administration, Oral↗
PubMed1982

Pharmacokinetic studies of flumecinol in man and dog.

The pharmacokinetics of flumecinol (Zixoryn) a new hepatic enzyme inducer has been studied in four beagle dogs and six healthy volunteers. The beagle dogs and the volunteers received the drug orally in a dose of 40 mg/kg of body weight and of 100 mg single dose respectively. Flumecinol was extracted from plasma with diethyl ether and analysed by gas-liquid chromatography using a flame ionisation detector (FID). The pharmacokinetic parameters of flumecinol were determined by computer evaluation of the plasma concentration-time curves. The peak plasma concentrations were found to be 5.3 and 2.1 hours in dogs and humans, respectively. Flumecinol is eliminated from the plasma of dogs and humans with half-lives of 38.95 and 17.16 hours, corresponding to a clearance of 53.2 litres/hour and 94.0 litres/hour, respectively.

Adult↗