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Biomedical subjects

J Verweij

Publications and source records attributed to J Verweij.

At least 199 records · Page 11Linked to original sources
PubMed1998

Irinotecan (CPT-11) metabolism and disposition in cancer patients.

The objective of this study was to determine the metabolic fate and disposition of the antitumor camptothecine derivative irinotecan (CPT-11). Ten patients with histological proof of malignant solid tumor received 200 mg/m2 CPT-11 as a 90-min i.v. infusion, followed by a 1.5-h i.v. infusion of cisplatin (60 or 80 mg/m2). Plasma, urine, and feces were collected for 56 h and analyzed by a specific reversed-phase high-performance liquid chromatographic assay for the parent drug and all four metabolites positively identified to date: SN-38; its beta-glucuronide conjugate, SN-38 beta-glucoronide (SN-38G); 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecine (APC); and 7-ethyl-10-[4-N-(1-piperidino)-1-amino]-carbonyloxycamptothecine (NPC). A three-exponential decline was observed in plasma for all compounds, with a clear predominance of the parent drug [25.6+/-5.71 microM x h (CPT-11) versus 15.8+/-3.51 microM x h (total metabolites)]. Total urinary excretion was 28.1+/-10.6% of the dose, with unchanged CPT-11 and SN-38G as the main excretion products. Whereas renal clearance of SN-38 was only a minor route of drug elimination, fecal concentrations of this compound were unexpectedly high (on average, 2.45% of the dose), suggestive of intestinal hydrolysis of SN-38G by bacterial beta-glucuronidase. CPT-11 and the other metabolites could also be identified from fecal extracts, with a very minor contribution overall of the cytochrome P-450-mediated compounds 7-ethyl-10-[4-N-(1-piperidino)-1-amino]-carbonyloxycamptothecine and 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecine. Surprisingly, fecal excretion accounted for only 24.4+/-13.3% of the dose, leading to a total excretion of approximately 52%. These data indicate that half of the dose in urine and feces may constitute some further unknown nonextractable or nonfluorescent metabolites. The findings from this study should be of importance as a guide to further therapeutic evaluation of this drug.

Adult↗
PubMed1997

Determination of irinotecan (CPT-11) and its active metabolite SN-38 in human plasma by reversed-phase high-performance liquid chromatography with fluorescence detection.

Sensitive high-performance liquid chromatographic assays have been developed to determine the levels of the lactone and lactone plus carboxylate (total) forms of the antitumor agent irinotecan (CPT-11) and its active metabolite SN-38, in human plasma. The related compound camptothecin was used as the internal standard. The selective sample pretreatment for the lactone forms involved a single solvent extraction with acetonitrile-n-butyl chloride (1:4, v/v), whereas the sample clean-up for the total forms was a simple protein precipitation with aqueous perchloric acid-methanol (1:1, v/v), which results in the conversion of the carboxylate to the lactone forms. Chromatography was carried out on a Hypersil ODS column, with detection performed fluorimetrically. The methods have been validated, and stability tests under various conditions have been performed. The lower limits of quantitation are 0.5 and 2.0 ng/ml for the lactone and total forms, respectively. The assays have been used in a single pharmacokinetic experiment in a patient to investigate the applicability of the method in vivo.

Antineoplastic Agents, Phytogenic↗
PubMed1997

Determination of the lactone and lactone plus carboxylate forms of 9-aminocamptothecin in human plasma by sensitive high-performance liquid chromatography with fluorescence detection.

Two sensitive reversed-phase high-performance liquid chromatographic fluorescence methods, with simple sample handling at the site of the patient, are described for the determination of the lactone and lactone plus carboxylate forms of 9-aminocamptothecin (9AC). For 9AC lactone, the sample preparation was a liquid-liquid extraction with acetonitrile-n-butyl chloride (1:4, v/v), whereas the sample preparation for 9AC total (lactone plus carboxylate) was a simple deproteinization with 5% perchloric acid-methanol (1:1, v/v), which results in the conversion of the carboxylate into the lactone form. The lower limits of quantitation were 50 pg/ml and 100 pg/ml for 9AC lactone and 9AC total, respectively. The within-run precisions at four tested concentrations were < or = 6.3% for 9AC lactone and < or = 5.3% for 9AC total. The between-run precisions were < or = 8.9% and < or = 5.6%, respectively. The assays were developed to enable pharmacological analysis of 9AC in a bioavailability and oral phase I study in patients with solid tumors.

Antineoplastic Agents↗
PubMed1997

Sensitive determination of docetaxel in human plasma by liquid-liquid extraction and reversed-phase high-performance liquid chromatography.

A sensitive reversed-phase high-performance liquid chromatographic method has been developed and validated for the quantitative determination of docetaxel (I) in human plasma. The concentrations in plasma, for validation procedures spiked with known amounts of I, are read from calibration curves in the range of 10-20,000 ng/ml. The sample preparation involved a liquid-liquid extraction of 1000 microl of sample with a mixture of acetonitrile-n-butylchloride (1:4, v/v). The related compound paclitaxel (II) was used as internal standard. Chromatographic separations were performed an Inertsil ODS-80A column, with UV detection performed at 230 nm. The overall extraction recoveries were 84.3 and 90.0% for I and II, respectively. The lower limit of quantitation was 10 ng/ml, and the accuracy, within-run and between-run precisions at three tested concentrations fell within the generally accepted criteria for bioanalytical assays.

Aged↗
PubMed1997

Tunnelled central venous catheters yield a low incidence of septicaemia in interleukin-2-treated patients.

A retrospective study on the incidence of catheter-related complications and catheter indwelling time (tCI) during treatment with continuous interleukin-2 (IL-2) infusion in patients with metastatic renal cell cancer, who were equipped with tunnelled central venous catheters (CVC). A group of 72 patients were treated with IL-2-based immunotherapy. Two induction treatment cycles of 35 days each were used. Treatment consisted of IL-2 as a continuous intravenous infusion (c.i.v.) with lymphokine-activated killer cells and interferon alpha intramuscularly. A tunnelled CVC was inserted at the start of treatment and was kept in place for the duration of the therapy or until the occurrence of complications. Out of 72 CVC, 30 (42%) functioned uneventfully for a median tCI of 64 days. In another 12 clinically uncomplicated cases (16%), catheter tips were positive in routine culture after a median tCI of 33 days. In 18 patients (25%), CVC-related infections were noted, including 8 (11%) local tunnel infections and 10 (14%) septic episodes. These complications occurred at a median tCI of 28 and 20 days respectively. In 15 (83%) of these 18 catheter infections, Staphylococcus aureus was isolated, whereas in the remaining 3 (17%) Staphylococcus epidermidis was found. Subclavian vein thrombosis was noted in 12 (17%) CVC at a median tCI of 31 days: 5 (36%) of these were diagnosed in the first 14 patients. This prompted us to administer prophylactic heparin 15,000 i.u. c.i.v. daily during IL-2 treatment. Thereafter the incidence of thrombosis dropped to 7 (12%) in the subsequent 58 CVC inserted (P = 0.03). In conclusion, in contrast to previous reports on the high incidence of CVC-related septicaemia and thrombosis, we observed a relatively low incidence of these complications, which we ascribe to the use of tunnelled catheters and prophylactic heparin.

Carcinoma, Renal Cell↗
PubMed1997

A phase II study of weekly high-dose cisplatin combined with oral etoposide in advanced non-small-cell lung cancer.

As a dose-response relationship has been suggested for cisplatin, it appeared attractive to explore high-dose-intensity regimens in non-small-cell lung cancer. In a phase I study of weekly administration of cisplatin combined with oral etoposide we achieved a cisplatin dose intensity of 52.5-60 mg/m2 per week in most patients. We subsequently explored this regimen in advanced non-small-cell lung cancer. Patients were treated with cisplatin infused at 70 mg/m2 on days 1, 8, 15 and 29, 36, 43 in combination with oral etoposide given at 50 mg on days 1-15 and 29-43. Patients showing stable disease or a better response were continued on treatment with oral etoposide given at 50 mg/m2 per day on days 1-21 every 28 days for a maximum of four cycles. In all, 22 patients with stage III disease and 31 patients with stage IV disease entered the study. The median number of cisplatin administration was 6 per patient; 17 patients reached the planned cisplatin dose intensity of 60 mg/m2 per week, 11 patients achieved 52.5 mg/m2 per week, and 7 patients reached 47 mg/m2 per week. Overall, 11 of 21 stage III patients had a partial response [response rate 51%, 95% confidence interval (CI) 36-81%], as did 9 of 28 patients with stage IV disease (32%; 95% CI 15-49%). Toxicity was mainly hematologic, with leukocytopenia being the most frequent cause of treatment delay. Nephrotoxicity of grade 1 was observed in seven patients. Two patients developed clinical hearing loss. With this schedule a high median cisplatin dose intensity of 52.5-60 mg/m2 per week was reached. The 51% response rate achieved in stage III disease makes this schedule attractive for further exploration; however, it is not recommended for routine use in stage IV disease.

Administration, Oral↗
PubMed1997

Zeniplatin in advanced malignant melanoma and renal cancer: phase II studies with unexpected nephrotoxicity.

The antitumor activity of zeniplatin, a third-generation, water-soluble platinum compound that has shown broad preclinical antitumor activity and no significant nephrotoxicity in phase I trials, was tested in patients with advanced malignant melanoma and advanced renal cancer. Patients who had not previously been treated, except with local limb perfusion and immunotherapy, were given zeniplatin as bolus injections at 125 mg/m2 every 3 weeks. The main hematological toxicity was leukopenia (7/30 patients, WHO grade > or = 3) and the main nonhematological toxicity was nausea and vomiting (21/30 patients, WHO grade > or = 2). Serious nephrotoxicity was observed early in the renal cancer study and, later, also in the melanoma study. Hyperhydration did not prevent the nephrotoxicity, and the studies were stopped after 6 renal cancer patients and 24 malignant melanoma patients had been included. Zeniplatin gave objective responses in 3 of the 21 evaluable malignant melanoma patients [2 complete responses (CRs) in patients with lymph-node metastases lasted 5 and 14 months, respectively; 1 partial response (PR) in a patient with lymph-node and liver metastases lasted 6 months]. In the renal cancer study, only four patients were evaluable for response and none responded. The results show that zeniplatin has some activity (14%) in patients with advanced malignant melanoma, but no conclusion can be drawn regarding the activity of zeniplatin in renal cancer as the number of patients was too low. The main toxicities were leukopenia and nausea and vomiting. Unexpected and serious nephrotoxicity was observed, and for this reason the studies were terminated before the planned number of patients had been included. A possible explanation for the nephrotoxicity may be drug interactions, but no firm conclusion can yet be drawn.

Adult↗
PubMed1997

Pharmacokinetics of the multidrug-resistance-converting drug dexniguldipine and its pyridine metabolite M-1 in the plasma, tumor, and renal tissue of tumor-bearing Wag/Rij rats.

The pharmacokinetics of oral dexniguldipine, a new multidrug-resistance-modifying agent under clinical evaluation, and its pyridine metabolite M-1 were determined in plasma, tumor, and renal tissue in Wag/Rij rats bearing a multidrug-resistant CC531 colon adenocarcinoma tumor under the renal capsule. The pharmacokinetics were studied in four experiments. After a single administration of dexniguldipine (30 mg/kg), tumors and kidneys were collected after 5 (experiment 1), 24 (experiment 2), and 48 h (experiment 3). In the fourth experiment, dexniguldipine was given once daily for 3 consecutive days at a dose of 30 mg/kg. In all experiments, plasma samples were collected at regular intervals. The concentrations of dexniguldipine and M-1 could be determined in plasma in most of the rats at up to 32 h after drug administration. The area under the curve (AUC) of dexniguldipine and M-1 varied by a factor of 2-6 in the four experiments. High tumor-tissue concentrations of dexniguldipine were observed. The concentrations were highest in the multiple-dose experiment (2014 +/- 1005 ng/g tissue). High degrees of correlation (> 0.8) were established between the concentrations of dexniguldipine measured in plasma and tumor as well as renal tissue. Overall, tumor-tissue concentrations of M-1 comprised one-third of the dexniguldipine concentrations measured.

Adenocarcinoma↗
PubMed1997

Phase II study of weekly high-dose cisplatin for six cycles in patients with locally advanced squamous cell carcinoma of the head and neck.

In a phase I study of weekly administered cisplatin, we observed a major response in 8 of 9 patients with locally far advanced head and neck cancer. Therefore, a phase II study was initiated to explore the activity and tolerance of this weekly cisplatin regimen. 59 patients with locally advanced head and neck cancer were entered into this phase II study. Cisplatin was administered at a dose of 80 mg/m2 weekly for 6 cycles. Cisplatin was administered in hypertonic saline (3% NaCl) as a 3-h infusion with standard pre- and posthydration. 51 patients were evaluable for response and 55 for toxicity. Only 9 patients were able to complete the treatment with the planned dose intensity of 80 mg/m2/week. Complete disappearance of the tumour was observed in 8 patients and a partial response in 22 (response rate 59%; 51% of all eligible patients 95% CI limits 37-63%). Stable disease was observed in 12 patients, and the tumour progressed in 9 patients. 47 patients subsequently received high-dose radiotherapy, 1 radiotherapy and surgery and 4 patients second-line chemotherapy. The median progression-free survival and median overall survival for all patients were 32 weeks and 56 weeks, respectively. Haematological toxicity consisted of anaemia, leucocytopenia (grade 3 + 4 in 17 patients) and thrombocytopenia (grade 3 + 4 in 17 patients). Because of leuco- and/or thrombocytopenia, treatment was delayed in 30 patients while 13 were taken off the study because of delayed bone marrow recovery. Non-haematological toxicities were: ototoxicity grade 1 in 3 patients, grade 2 in 7 and grade 3 in 3 patients; nephrotoxicity grade 1 in 13 patients, grade 2 in 2 and grade 3 in 1 patient. Neurotoxicity grade 1 was observed in only 8 patients. Cisplatin, as a single agent, administered at high-dose intensity, has an antitumour activity comparable with that of combination regimens in locally advanced head and neck cancer. The pattern of toxicity is different: leuco- and thrombocytopenia jeopardize the dose intensity concept; for patients ototoxicity is the more relevant toxicity. Further studies with weekly cisplatin are of interest particularly with newer measures to reduce toxicity.

Adult↗
PubMed1997

The use of a systemic therapy checklist improves the quality of data acquisition and recording in multicentre trials. A study of the EORTC Soft Tissue and Bone Sarcoma Group.

The aim of this study was to verify whether the introduction of a systemic therapy checklist in the performance of multinational multicentre studies improves the quality of data acquisition and recording. We retrospectively analysed the results obtained through the use of this checklist in a study of the EORTC Soft Tissue and Bone Sarcoma Group. During the clinical trial, data were recorded in the hospital record with optional use of a predesigned EORTC Systemic Therapy Checklist. After completion of the study, 11 centres were monitored for the use of this checklist. Monitors were highly experienced medical oncologists. Items checked included all aspects of patient eligibility, drug administration, biochemical and haematological values, variables related to toxicities of treatment and response parameters. Data of 183 cycles given to 51 patients were checked. A total of 8983 items were checked. 91% of the data was reported correctly, 1% was missing and 6% was reported on the case record from (CRF) but could not be retrieved in the hospital record file. Compared with data obtained before the introduction of the checklist (68% correct, 4% incorrect, 0.1% missing and 28% on CRF but not in hospital files), these results show marked improvement generally. In centres where no Systemic Therapy Checklist was used, 85.9% of data were correct 2.8% incorrect, 0.7% missing and 10.6% only on CRF, which compares unfavourably with those where the Systemic Checklist was completely used (97.7% correct, 0.7% incorrect, 1% missing, 0.6% only on CRF). In addition the time required for data checking largely decreased by the use of the checklist-without this, a median of 3.5 cycles could be checked per hour, whilst if the checklist was used, this number increased to 6.5 cycles per hour. The use of a Systemic Therapy Checklist as an integral part of the hospital file for data recording in multicentre multinational trials is highly recommended and leads to a major improvement in data quality.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

Matrix metalloproteinase inhibitors: present achievements and future prospects.

Matrix metalloproteinases (MMPs) are a class of structurally related enzymes that function in the degradation of extracellular matrix proteins that constitute the pericellular connective tissue and play an important role in both normal and pathological tissue remodelling. Increased MMP activity is detected in a wide range of cancers and seems correlated to their invasive and metastatic potential. MMPs thus seem an attractive target for both diagnostic and therapeutic purposes. Several synthetic matrix metalloproteinase inhibitors (MMPIs) are currently being developed. Preclinical studies are promising as they suggest inhibition of several steps in the metastatic process. Marimastat is the first MMPI to enter comparative phase III trials after early clinical trials established the safety profile. Clinical trials will need to be specifically designed to optimally evaluate the therapeutic potential of this novel class of cytostatic drugs. Safety studies should consider the markedly different toxicity profile and determine the range of biologically active dosage, while efficacy studies should be performed in selected clinical settings with appropriate end-points. We review the present achievements in preclinical and clinical studies with MMPIs, discuss specific considerations for appropriate study design and reflect on the future prospects of this novel class of agents.

Animals↗
PubMed1997

Differential modulation of cisplatin accumulation in leukocytes and tumor cell lines by the paclitaxel vehicle Cremophor EL.

BACKGROUND: Several clinical studies have shown that polychemotherapy with the taxanes paclitaxel or docetaxel preceded or followed by cisplatin is associated with important schedule-dependent differences in toxicities, such as leukocytopenia. In general, the pharmacokinetics of both drugs during the combined treatment are unaltered, suggesting that a pharmacodynamic interaction might have occurred. MATERIALS AND METHODS: In order to gain insight into this pharmacologic interaction, we performed in vitro drug accumulation studies using peripheral blood leukocytes and a panel of tumor and non-malignant cell lines with paclitaxel and docetaxel, as well as with their respective formulation vehicles Cremophor EL and Tween 80. RESULTS: Our results show a significant reduction in the intracellular cisplatin concentration in leukocytes of up to 42% in the presence of Cremophor EL and Tween 80 as compared to the control. This pharmacodynamic interaction of these surfactants with cisplatin seems to be specific for haematopoietic cells, and does not occur in solid tumor cells. CONCLUSION: The present data suggest that the pharmaceutical vehicles Cremophor EL and Tween 80 might contribute to the reduced cisplatin-associated myelotoxicity observed in the clinical combination chemotherapy studies with paclitaxel and docetaxel.

Antineoplastic Agents↗
PubMed1997

Experience with independent radiological review during a topotecan trial in ovarian cancer.

BACKGROUND: The results of phase II clinical trials are usually based on response of tumours to new oncolytic agents as evidenced by radiological imaging techniques. In this trial, all claimed responders were reviewed at a specially convened meeting by the peer group of study investigators and a radiologist, independent of the study institutions. PATIENTS AND METHODS: One hundred eleven patients with advanced epithelial ovarian cancer who had previously been treated with a platinum based regimen and had subsequently relapsed and who had measurable disease were treated with topotecan at a dose of 1.5 mg/m2/day i.v. on five consecutive days repeated every 21 days to assess efficacy and tolerability. Ninety-three were considered eligible for the study per protocol and lesions were assessed by either computerised tomography (CT) or ultrasound (US). At the meeting, scans from all 24 (25.8%) claimed responders were reviewed, lesions remeasured by the radiologist and a group discussion led to a final response classification. RESULTS: Ninety-two patients were found to be eligible for the study and 14 (15.2%) were confirmed as responders. Ten were rejected as responders, mainly because the lesion did not decrease in size by < or = 50%, but one patient failed to meet the entry criteria. Remeasurement of CT scans was more objective than US scans. Difficulties were encountered during review of some CT scan sequences because of non-uniform imaging parameters. CONCLUSIONS: Independent radiological review in conjunction with the peer review group in this trial enabled rigorous and consistent application of response criteria. This decreased the response rate from 25.8% to 15.2%, but this represents a more objective assessment. CT scanning is an objective technique for assessing response rates in phase II studies whereas US is subjective and dose not necessarily allow accurate lesion assessment on subsequent examinations, nor allows independent review at a later date. For these reasons it should not be used in such studies for accurate lesion assessment. Cross-sectional imaging techniques such as CT and magnetic resonance imaging (MRI) do allow accurate lesion assessment and independent review at a later date, but standard protocols need to be instituted, to allow consistency and a comparison to be made with subsequent studies using the same agent and a broad comparison to be made with other agents.

Antineoplastic Agents↗
PubMed1997

Clinical characteristics of severe peripheral neuropathy induced by docetaxel (Taxotere).

BACKGROUND: Docetaxel, a semi-synthetic taxane may cause a usually mild sensory neuropathy. We describe the clinical characteristics of five patients who developed a more severe neuropathy following treatment with docetaxel. PATIENTS AND METHODS: All patients were treated in phase II studies with 100 mg/m2 docetaxel in three weekly cycles, without steroid administration. RESULTS: The clinical picture in these patients was dominated by a sensory neuropathy, but in one case severe weakness was present. Another patient developed Lhermitte's sign. Signs and symptoms are usually reversible after discontinuation of docetaxel administration, but in three patients symptoms worsened for some time after the end of treatment before improvement occurred. CONCLUSION: Severe docetaxel neuropathy may especially occur following treatment with cumulative dosage over 600 mg/m2; in patients treated with this dosage a moderate or severe neuropathy may not be rare.

Adult↗