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H J Keizer

Publications and source records attributed to H J Keizer.

67 records · Page 4Linked to original sources
PubMed1988

Bioanalysis of (E)-5-(2-bromovinyl)-2'-deoxyuridine.

(E)-5-(2-Bromovinyl)-2'-deoxyuridine is an antiviral drug that is experimentally used for modulation of the antitumour effect of fluoropyrimidines, such as ftorafur and 5-fluorouracil. The isolation of the analyte, in the presence of 5-fluorouracil, from the matrix is performed either by means of a simple protein precipitation (plasma) or by means of a liquid-liquid extraction with ethyl acetate (urine). Following pretreatment, the analyte is analysed by reversed-phase chromatography and quantified by absorbance detection at 307 nm. The minimum detectable concentration in plasma and urine samples is ca. 6 ng/ml. The recovery after deproteination of plasma samples is 75%, while after liquid-liquid extraction of urine the recovery amounts 92%. The degree of protein binding of the analyte, measured by ultrafiltration, is found to be 97%. These data allow the bioanalysis of (E)-5-(2-bromovinyl)-2'-deoxyuridine for pharmacokinetic studies.

Antiviral Agents↗
PubMed1988

Combined effects of bromovinyldeoxyuridine and fractionated or continuous administration of 5-fluorouracil in P388 leukemia-bearing mice.

The combined effects of fractionated administration of the antiviral agent (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) and fractionated (4 injections at a 48-h interval) administration or continuous (7-day) infusion of 5-fluorouracil (FU) have been investigated in P388 leukemia-bearing mice. The LD50 of continuous FU infusion in normal mice was approximately 330 mg/kg, while that for the fractionated treatment was 160 mg/kg. When combined with BVDU (200 mumol/kg, 90 min before each FU injection; 4 injections at a 48-h interval), the LD50 of FU was decreased from 330 to 115 mg/kg and from 160 to 30 mg/kg, respectively. The 7-day continuous infusion of FU (up to a dose of 210 mg/kg) did not exert a therapeutic effect in P388-leukemic mice, and, similarly, combination of continuous FU infusion (at lower doses) with BVDU failed to increase the survival of the leukemic mice. If, however, FU was administered in fractionated doses, there was a dose-dependent increase in survival time of P388-leukemic mice, and simultaneous fractionated BVDU treatment allowed a 4-6-fold lower dose of FU to achieve the same increase in survival time, indicating that BVDU effectively increased the antitumor activity of FU in the leukemic mice.

Animals↗
PubMed1985

Cancer chemotherapy: alternative routes of drug administration. A review.

This review covers recent developments in regional cancer chemotherapy, including the pharmacological background, technical progress, and clinical experience. Intrathecal chemotherapy is an approach that has acquired an established place, although its ultimate potentials are not known yet. The therapeutic value of hepatic intraarterial drug infusion is still unclear, although this route has been used for more than 20 years. Furthermore, the evaluation of alternative routes via the pleural and peritoneal cavities and other arteries is still in an experimental phase. Interest in these treatment modalities has been stimulated by a number of recent developments in separate fields. Major technical advances have been made, including surgically placed and totally implantable elastic catheters and subcutaneous portals and pumps. In addition, a pharmacokinetic model describing the fate of drugs administered via an artery or cavity has been developed. These developments have made it possible not only to design randomized studies and treat a larger number of patients in a relatively short time with reduced morbidity, but also to improve greatly the selection of drugs, target organs, and administration schedules. Ongoing clinical studies can be expected to lead to improved treatment results as well as provide data on dose-response relationships and drug schedule dependency for specific tumor types.

Antineoplastic Agents↗
PubMed1984

Feasibility study on daily administration of cis-diamminedichloroplatinum(II) in combination with radiotherapy.

In experimental models cis-diamminedichloroplatinum(II) (cis-platinum) showed to have a radioenhancing effect. The feasibility of daily administration of cis-platinum in combination with radiotherapy was studied in 21 patients with locally advanced inoperable cancers (head and neck 7, esophagus 5, bronchus 3 and others 6). The tumours were squamous cell (15), or adenocarcinoma (6). Radiotherapy was delivered in one (180 cGy; 5 patients) or two (each of 125 cGy; 16 patients) fractions per day to a cumulative dose of 3000-6800 cGy, while cis-platinum was administered at a total daily dose of 8 mg/m2 (14 patients) or 6 mg/m2 (7 patients), in one single or two divided injections (total dose 168-352 mg cis-platinum). Fourteen patients received a total daily cis-platinum dose of 8 mg/m2 with 4 l of i.v. hydration. Severe myelosuppression occurred in 10/14 patients (range white blood cell count nadirs 0.6-2.1 X 10(9)/l) after 3-5 weeks of treatment, while seven developed severe thrombocytopenia (less than 75 X 10(9)/l). All patients became anaemic. Due to this myelosuppression, radiation treatment had to be postponed in four patients for 18-35 days. Eight patients developed bronchopneumonia, two of them had a septicaemia and one died. One patient with a bronchial carcinoma developed necrotizing pneumonitis with a cavity outside the tumour area and subsequent severe pulmonary fibrosis within the radiation field. Seven patients received cis-platinum at 6 mg/m2 per day without i.v. hydration. A moderate leukopenia (white blood cell count nadirs 1.8-2.1 X 10(9)/l) was observed in three patients requiring postponement of treatment in one of them.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1976

Preferential inhibition of DNA synthesis in mouse hemopoietic cells by halothane.

The effect of prolonged light halothane anesthesia (0.8%) on the proliferation rate of different mouse tissues was investigated, using [5-125I]5-iodo-2-deoxyuridine uptake into DNA as the test parameter. It was found that DNA synthesis in spleen, femoral bone marrow, and, occasionally, the small intestine was significantly depressed after exposure for 24 hr to halothane in vivo. The time course of DNA synthesis inhibition was then investigated by utilizing a shorter (6-hr) exposure time. This period was found to be insufficient to cause DNA synthesis inhibition in any of test tissues. Because anesthesia was found to be associated with hypothermia at normal room temperatures, it was established that the inhibition of DNA synthesis was not due to cooling of the mice under anesthesia by demonstrating that inhibition in sensitive tissues occurred at warmer temperatures as well. To examine the specificity of this finding, the DNA synthesis rate of cells in other normal tissues, e.g., skin and muscle, and in s.c.-growing tumor cells of a mouse mammary carcinoma, L1210 leukemia, and a first transplant AKR lymphoma were examined. In none were responses noted with 24 hr of halothane exposure. However, halothane was found to inhibit DNA synthesis in regenerating marrow. Finally, it was found that after significant exposure to halothane, complete recovery was seen in the spleen after 24 hr, whereas femur DNA synthesis was still depressed by 20% at the same time.

Animals↗
PubMedDate not supplied

Pharmacokinetics of ifosfamide, 2- and 3-dechloroethylifosfamide in plasma and urine of cancer patients treated with a 10-day continuous infusion of ifosfamide.

The cytotoxic drug ifosfamide is subject to an extensive metabolism. This study reports the results of a pharmacokinetic study of the parent drug and the two dechloroethylated metabolites in 22 patients on a 10-day continuous infusion of ifosfamide. Ifosfamide causes a substantial induction of the enzymes responsible for its metabolism, resulting in a two-fold increase of the clearance. The maximal IF concentration is reached after 24 h, after which the concentration decreases to a steady-state. The dechloro-ethylated compounds can be detected in the plasma about 8 h after the start of the infusion with plasma half-lives longer than for IF. Urinary excretion studies revealed that at least a quarter of the IF dose is excreted as inactive compounds.

Adult↗