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Biomedical subjects

R Dubbelman

Publications and source records attributed to R Dubbelman.

At least 19 recordsLinked to original sources
PubMed1995

Treatment of patients with IVCS and gross oedema and ascites with diuretic combination and ACE-inhibitors: relation to baseline PRA and PAC.

OBJECTIVE: (1) To assess plasma renin activity (PRA) and plasma aldosterone concentration (PAC) in patients with inferior vena cava syndrome (IVCS). (2) To study in an open fashion the efficacy of loop diuretic treatment, single, or in combination with an ACE-inhibitor or with spironolactone. METHODS: In 13 patients PRA and PAC were measured and related to urinary sodium excretion (UNa). RESULTS: Highly elevated PRA and PAC were found in recently developed IVCS. The correlation coefficient between PAC and UNa was -0.61, p < 0.05. In 10 patients the influence of captopril (C)] at maximum tolerable doses with or without furosemide (F) was evaluated. Mean tolerated dose of C amounted to 8.8 mg t.i.d. (range 2-25), achieving a PAC reduction of 26%. Efficacy of F was severely blunted when PAC exceeded the low-normal range. Spironolactone addition at 100 mg/day in non-responders to F or to F and C, induced immediate natriuretic responses except in a patient with 7-70 fold increase in PAC. CONCLUSIONS: (1) In IVCS loop diuretic efficacy is attenuated by aldosterone activation; (2) complete aldosterone suppression with captopril is difficult to achieve due to dose restriction; (3) spironolactone is favoured for a synergistic response.

Adult↗
PubMed1994

Etoposide, leucovorin, 5-fluorouracil (ELF) combination chemotherapy for advanced gastric cancer: experience with two treatment schedules incorporating intravenous or oral etoposide.

BACKGROUND: Because the ELF regimen (etoposide, leucovorin and 5-FU) in advanced gastric cancer was recently advocated as an active, non-toxic schedule, and drug scheduling of etoposide proved to be important, we performed a pilot study using the original ELF regimen (A), followed by a phase II study of a modified ELF schedule (B) using oral etoposide. PATIENTS AND METHODS: Of the 40 patients entered in the consecutive trials 15 were treated according to the original ELF (A) and 25 according to the modified ELF regimen (B). The primary tumor was originally in the stomach in 22 and the oesophago-cardiac junction in 18. In 6 there was locally advanced and in 34 metastatic disease. RESULTS: Toxicity was mild in ELF (A): grade III leukopenia in 6/63 cycles. The ELF (B) caused slightly more myelosuppression: grade III leukopenia in 4/102 and grade IV in 2/102 cycles, resulting in septicaemia in two patients, and toxic death in one. No severe thrombocytopenia was seen. Hemorrhage (4 cases) was exclusively related to tumor progression. Response rates were 7% (0%-21%) and 28% (10%-46%) for ELF (A) and ELF (B), respectively. Subjective response, however, leading to a clinically significant decrease of dysphagia and pain, was seen in 53% and 56% of the patients. CONCLUSIONS: The modified ELF regimen (B) can be applied safely on an out-patient basis, and shows moderate activity in advanced gastric cancer which leads to an improved quality of life.

Administration, Oral↗
PubMed1994

Phase I/II study of intraperitoneal mitoxantrone in refractory ovarian cancer.

BACKGROUND: Mitoxantrone has demonstrable clinical activity when administered intravenously in a wide range of malignancies. The feasibility and toxicity of intra-peritoneal administration was established in a phase I study. The optimal dose from the phase I was subsequently evaluated in a phase II study. PATIENTS AND METHODS: 19 patients with refractory malignancies and extensive abdominal disease (13 ovarian cancer, 4 breast cancer, 2 mesothelioma) were entered in a phase I study. The dose of intraperitoneal mitoxantrone was escalated from 10 mg/m2, administered in 21 of fluid via a Tenckhoff catheter, to 55 mg/m2, in increments of 5 mg/m2. Cycles were repeated every three weeks. Sixty-seven cycles of mitoxantrone were administered, the maximum tolerable dose being 25 mg/m2. A phase II study at this dose was conducted in 14 patients with refractory ovarian cancer, all of whom had previously received systemic platinum based therapy. Five of the 14 had also previously been treated with intraperitoneal carboplatin. Fifty-one cycles were administered. RESULTS: The dose limiting toxicity in the phase I study was peritoneal irritation and pain. Leucopenia was frequent at doses equal or greater than 30 mg/m2. Three complete remissions were documented in the phase I study (2 breast cancer and 1 ovarian cancer). There was no significant haematological toxicity in the phase II assessment, though local toxicity precluded further therapy in 2 patients. No objective responses were seen in the phase II evaluation. CONCLUSIONS: These studies demonstrate the feasibility of intra-peritoneal mitoxantrone therapy in patients with peritoneal disease, but do not support its routine use in ovarian cancer.

Abdominal Pain↗
PubMed1993

Effects of interleukin-3 on myelosuppression induced by chemotherapy for ovarian cancer and small cell undifferentiated tumours.

Two clinical studies were undertaken to study the toxicity profile and effects of interleukin-3 (rhIL-3) on chemotherapy-induced myelosuppression. Fifteen patients with recurrent ovarian carcinoma were treated with high dose carboplatin (800 mg m-2). All patients received 5.0 micrograms/kg/d rhIL-3 subcutaneously but timing and duration of rhIL-3 treatment differed. Constitutional symptoms were the major toxicity and in addition to the carboplatin-induced nausea and vomiting the combination was poorly tolerated. In 5/15 patients receiving high dose carboplatin rhIL-3 administration was discontinued due to nephrotoxicity (2 x), hypotension, severe malaise and bone pain. In this study, rhIL-3 ameliorated chemotherapy-induced neutropenia as well as thrombocytopenia and reduced the requirement for platelet transfusions in the second cycle of chemotherapy. However, rhIL-3 failed to prevent cumulative platelet toxicity. In the second study 12 patients with small cell undifferentiated cancers were treated with carboplatin, etoposide and ifosfamide. Three dose levels of rhIL-3 were explored (0.125, 5.0 and 7.5 micrograms/kg/d). In this study, toxicity of the treatment was mild, however, no beneficial haematologic effects of rhIL-3 could be demonstrated. In conclusion, the haematological effects of rhIL-3 were modest and dependent on the chemotherapeutic regimen, timing and duration of rhIL-3 treatment (in relation to the expected nadir). In general rhIL-3-induced toxicity was mild, but combination with high dose carboplatin could be hazardous if rhIL-3 is initiated at 24 h after the cytostatic agent.

Adult↗
PubMed1992

Clinical pharmacokinetics of mitoxantrone after intraperitoneal administration.

The pharmacokinetics of intraperitoneally (i.p.) injected mitoxantrone was determined in plasma and peritoneal dialysate taken from five patients presenting with cancer confined to the peritoneal cavity over a sampling period of 1 week. The drug was given through a Tenckhoff catheter as a 15-min infusion and the peritoneal dialysate was removed after a dwell time of 4 h; the doses delivered varied between 20 and 50 mg/m2. Dose-limiting local toxicity was moderate. The HPLC technique used for mitoxantrone determinations proved to be sensitive within the range of 0.3-4,000 ng/ml. Median values obtained for the pharmacokinetic parameters of mitoxantrone in peritoneal dialysate were: t1/2 beta (distribution), 56.4 min (range, 16.8-235.8 min); t1/2 gamma (elimination), 128 h (range, 28.3-171.0 h); Vdss (volume of distribution at steady state), 24.8 l (range, 17.0-232.5 l); delta'ss (volume of distribution at steady state corrected for the body surface area in square meters), 14.4 l/m2 (range, 10.6-129.2 l/m2); and clearance, 0.25 l/h (range, 0.16-0.59 l/h). For plasma the median values were: t1/2 alpha (absorption), 58.8 min (range, 45.6-87.0 min); t1/2 beta (distribution), 2.5 h (range, 1.4-6.3 h); t1/2 gamma (elimination), 44.1 h (range, 9.1-91 h); Vdss, 2,152 l (range, 352-19,733 l); delta'ss, 1,345 l/m2 (range, 220-11,606 l/m2); and clearance, 117 l/h (range, 51-1,609 l/h). After 168 h the median plasma concentration was 1 ng/ml. The median peak concentration in peritoneal dialysate was 490 ng/ml. Considering the moderate toxicity observed and the concentrations achieved in the peritoneal dialysate, removal of the dialysate after certain dwell times seems reasonable to be a reasonable approach for the optimization of i.p. treatment with mitoxantrone.

Abdominal Neoplasms↗
PubMed1992

Feasibility study of high-dose carboplatin and etoposide in the salvage treatment of testicular cancer.

Eleven patients with testicular cancer, either relapsing after or refractory to cisplatin-based chemotherapy, underwent salvage chemotherapy with high-dose carboplatin (800 mg/m2 on day 1) and high-dose etoposide (500 mg/m2 on days 1, 3 and 5). A total of 21 courses were administered. The major toxicity consisted of profound myelosuppression. There were two toxic deaths, both caused by infection during neutropenia. Bone marrow recovery was usually complete around day 26 (range 19-129). Other toxicities included mild mucositis, nausea and vomiting, and alopecia. No significant neurotoxicity or hearing loss were observed and only one patient had a moderate decrease in renal function. Nine of ten evaluable patients responded, with one complete remission, 6 partial remissions with normalization of tumor markers, and two partial remissions with over one log decrease of tumor markers. The duration of these remissions was not evaluable, since only three evaluable and responding patients did not receive additional therapy after HD-CE. All three relapsed after discontinuing chemotherapy. HD-CE has activity in relapsing or refractory testicular cancer and can be administered without bone marrow support. The regimen may thus be suitable to be used as a remission induction regimen prior to consolidation with intensive chemotherapy and autologous bone marrow transplantation.

Adult↗
PubMed1992

Replacement of cisplatin with carboplatin in combination chemotherapy against ovarian cancer: long-term treatment results of a study of the Gynaecological Cancer Cooperative Group of the EORTC and experience at The Netherlands Cancer Institute.

Carboplatin-based chemotherapy has been evaluated in three studies of ovarian cancer patients. In the first, combination cisplatin and carboplatin plus doxorubicin/hexamethylmelamine/cyclophosphamide were compared as first-line treatment of ovarian cancer in 341 women with stage IIB to IV disease. There were no observed differences in results between the two treatment groups. In the second study, conventional doses of intravenous carboplatin (350 mg/m2, given on day 1) plus oral cyclophosphamide (100 mg/m2 days 2 to 6) were given to late-relapsing patients (12 to 72 months) previously treated with cisplatin. Mature data showed a 55% overall response rate, acceptable toxicity, and an absence of additive neurotoxicity. Finally, 65 patients with refractory disease or in early relapse after cisplatin therapy (within 12 months) were treated with high-dose carboplatin (800 mg/m2). Toxicity was severe, but the 45% combined response rate was considered encouraging and worthy of further evaluation. It was concluded that carboplatin is an appropriate replacement for cisplatin in the treatment of ovarian cancer.

Adult↗
PubMed1991

Formation of interaction products of carboplatin with DNA in vitro and in cancer patients.

Binding of the cytostatic drug carboplatin to DNA was studied in solution, in RIF-1 and CHO cell lines and in human buccal cells after in vitro or in situ drug exposure. Results were compared with DNA adduction by cisplatin. The rate of binding in solution, determined by atomic absorption spectroscopy, was 35 times lower for carboplatin than for cisplatin. Adduct formation in cells in vitro was determined in a quantitative immunostaining assay. Staining intensities after carboplatin treatment were at least 29 times lower than after an equimolar dose of cisplatin. For RIF-1 and CHO cells, maximum levels of carboplatin-induced DNA modification were obtained 24 h after treatment; these levels correlated with cell killing. Adduct-specific staining in buccal cells from two carboplatin-treated patients increased 5-7 fold between 0 and 14 h after infusion, reaching a maximum at 10-14 h. This strongly contrasts with buccal cells from a cisplatin-treated patient, in which the adduct-specific staining signal increased by only 23% between 0 and 6 h after infusion, and then declined. This difference in the rate of adduct formation in vivo is consistent with the in vitro data.

Animals↗
PubMed1990

Phase I study of mitozolomide on a once daily for 5 days schedule.

In a phase I study mitozolomide was given on a once daily for 5 days schedule to 18 patients with a variety of malignancies. Non-hematological toxicity was negligible. Significant myelosuppression occurred at a total dose as low as 62.5 mg/m2 per course. In particular, thrombocytopenia, which was unpredictable, precluded dose increments beyond 15 mg/m2 per day (or a total of 75 mg/m2). Antitumor effects were not observed. The 5-day schedule of mitozolomide appears to have no advantage over administration once every 3-4 weeks, and may even be more dangerous than the latter schedule.

Adult↗
PubMed1990

Dose-finding studies with carboplatin, ifosfamide, etoposide, and mesna in non-small cell lung cancer.

Carboplatin, a clinically active analogue of cisplatin, was added to a regimen containing ifosfamide and etoposide, two agents with proven activity in non-small cell lung cancer (NSCLC). From August 1986 until November 1988, 43 consecutive patients (29 men and 14 women), mean age 57 years, performance status of 2 or less, with symptomatic, inoperable NSCLC were accrued and received carboplatin 100 mg/m2 on days 1, 3, and 5, or 300 or 350 mg/m2 on day 1; ifosfamide 1,500 mg/m2 and etoposide 60 or 100 mg/m2 every 4 weeks. Thirty-four patients were previously untreated, nine had been irradiated before, and two had also received previous chemotherapy. So far, 154 courses have been administered; 19 patients have received four or more courses. With the combination of 350 mg/m2 carboplatin and 100 mg/m2 etoposide, myelosuppression was dose-limiting; nephrotoxicity and neurotoxicity did not occur. Evaluation of response after two or four courses in 40 patients showed an objective response in 40%, whereas 30% progressed during therapy. Carboplatin added to etoposide and ifosfamide is a feasible combination that warrants further study in a randomized fashion.

Adult↗
PubMed1990

Long-term venous access with a Hickman catheter: complications and patient satisfaction.

Hickman catheters can be used to secure prolonged access to the venous system. We have retrospectively analysed the incidence of complications, risk factors for the occurrence of complications and patient satisfaction in 120 catheters. The total number of complications was 30, leading to the removal of 15 catheters. The majority of complications were infectious, occurring 28 times and leading to catheter removal in 13 patients. Other complications (i.e. catheter thrombosis) were rare. The only identifiable risk factor for the occurrence of complications was the male gender, associated with a higher rate of catheter infection. Patient satisfaction after catheter insertion, assessed by a questionnaire to which 24 of the 30 patients responded, was high. This report indicates that the use of Hickman catheters is associated with an acceptable complication rate and a high level of patient satisfaction.

Adolescent↗
PubMed1988

Monitoring of interaction products of cis-diamminedichloroplatinum(II) and cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II) with DNA in cells from platinum-treated cancer patients.

The formation and stability of interaction products between the anti-cancer drug cis-diamminedichloroplatinum(II) (cis-DDP) and DNA were studied in buccal epithelial and urinary cells from ten cancer patients who received cis-DDP-based therapy. Buccal cells were collected 1 h before and 1-2 h after i.v. infusions with cis-DDP. The interaction products were visualized in an immunocytochemical peroxidase assay, using an antiserum against cis-DDP-modified calf thymus DNA. The nuclear staining density was measured by microdensitometry. Nuclear staining densities in buccal cells after infusions of greater than or equal to 20 mg/m2 cis-DDP were always higher than pretreatment values. Repeated sampling from individual patients treated for 2-5 consecutive days with daily doses of 20-70 mg/m2 cis-DDP indicated that cis-DDP-DNA binding in buccal cells increased in proportion to the cumulative total dose of cis-DDP. The variation in dose-density response between patients was 17%. Apparent adduct loss in buccal cells from four patients, as measured 8-17 days after the last infusion, amounted to 67-86%. Platinum-induced DNA modifications could also be detected in buccal cells from two cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II)-treated patients. In vitro experiments with human buccal cells and lymphocytes indicated linear relationships between DNA modification and either cis-DDP concentration or incubation time. Nuclear staining densities in pretreatment buccal cells from ten cancer patients treated in vitro with 33 microM cis-DDP for 1 h revealed that interpatient variation in in vitro DNA modification by cis-DDP was low. No quantitative correlation was found between in situ and in vitro DNA modification.

Carboplatin↗
PubMed1988

Pharmacokinetics of carboplatin after intraperitoneal administration.

The pharmacokinetics of carboplatin, ultrafilterable platinum, and total platinum after intraperitoneal (i.p.) administration were studied in peritoneal fluid, plasma, red blood cells (RBCs), and urine during a phase-I trial in patients with minimal, residual ovarian cancer. Samples were collected from 7 patients who had received carboplatin (200-500 mg/m2) in 21 dialysis fluid. The fluid was withdrawn after a 4-h dwell. Platinum concentrations were measured by flameless atomic absorption spectrometry, and intact carboplatin was determined by HPLC with electrochemical detection. Peak concentrations of carboplatin in plasma were obtained 2 h after the end of instillation. The mean ratio of peak concentrations of carboplatin in instilled fluid and plasma was 24 +/- 11. The peritoneal clearance of carboplatin was 8 +/- 3 ml/min, which was 12 times less than the plasma clearance (93 +/- 32 ml/min). Due to this clearance ratio, the AUCs for the peritoneal cavity were about 10 times higher than those for plasma. On average, 34% +/- 14% of the dose was still present in the instillation fluid that had been withdrawn after a dwell time of 4 h. In plasma, the mean value of AUC/Dnet (Dnet = Dose - amount recovered from the peritoneal cavity) after i.p. administration was comparable with that of AUC/D after i.v. administration. This means that unrecovered carboplatin (66%) was completely absorbed from the peritoneal cavity. It may be expected from this bioavailability that the maximum tolerated dose (MTD) of i.p.-administered carboplatin with a 4-h dwell is around 1.5 times higher than that after i.v. administration. Overall pharmacokinetic parameters of carboplatin and platinum in plasma were comparable after i.p. and i.v. administration.

Aged↗
PubMed1988

Complications of Tenckhoff catheter implantation in patients with multiple previous intraabdominal procedures for ovarian carcinoma.

In patients with minimal residual ovarian carcinoma after aggressive surgical and chemotherapeutic treatment, nephrotoxicity and/or peripheral neuropathy often prohibit continued treatment with intravenous combination cisplatin-based chemotherapy. It is attractive to continue treatment of these patients with intraperitoneal (ip) delivered chemotherapy. From 1981 through 1984 a Tenckhoff catheter was implanted in 59 women for ip chemotherapy after a staging laparoscopy or laparotomy. Minor complications occurred in 8 patients and could be treated conservatively. Ten patients suffered major complications, leading to three (re)laparotomies and catheter extraction in 7 of 10 patients. No patient died of complications, but mean hospitalization time of patients with major complications was 25 days as compared to 11 days for patients without complications. An analysis of nine factors that could lead to postoperative complications failed to reveal a statistically significant risk factor. From this study no profile of a typical high-risk patient emerges.

Adolescent↗
PubMed1985

Phase I study and pharmacokinetics of intraperitoneal carboplatin.

In the early stages of this phase I study the tolerance of carboplatin intraperitoneally was good. Pharmacokinetic profiles suggest a possible therapeutic advantage for giving the drug intraperitoneally for the treatment of tumour nodules situated in the peritoneum. The extent of penetration of carboplatin through tumour nodules has not yet been assessed but tumour nodules are being processed for nuclear activation analysis.

Antineoplastic Agents↗