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Biomedical subjects

N H Mulder

Publications and source records attributed to N H Mulder.

At least 253 records · Page 14Linked to original sources
PubMed1987

In vitro chemosensitivity of human lung cancer for vindesine.

Firstly, the effect of Vindesine was studied on four different human lung carcinoma cell lines (two small cell, one adeno and one squamous cell) with the Fast Green dye exclusion assay (FGA) and the clonogenic assay. Both methods demonstrate a clear dose response relationship and the estimated drug efficacy is similar for both assays. In the cell lines with the longest doubling time a plateau was reached in the FGA, most probably due to the short culture time in this assay. Secondly, the effect of Vindesine on human lung carcinoma specimens (n = 64), mainly bronchoscopy biopsies (n = 48), was evaluated with the FGA. The FGA has merits as predictive test in the clinic in the situation that only a small number of cells can be obtained. In this study, due to the high number of bronchoscopy biopsies only in a minority of cases a conclusion could be obtained (37.5%).

Adenocarcinoma↗
PubMed1987

Natural course of bleomycin-induced pneumonitis. A follow-up study.

In this study, long-term pulmonary complications of bleomycin were evaluated in 8 patients with bleomycin-induced pneumonitis (BIP). The lung function parameters: VC, alveolar volume, transfer factor for carbon monoxide of the lungs, diffusing capacity of the alveolocapillary membrane, and pulmonary capillary blood volume were studied in all patients for as long as 2 yr after the development of BIP. Perfusion scans with 133Xe and 99mTc were performed in these patients 2 yr after BIP developed. We concluded that if a patient survives the acute event of BIP, the pulmonary symptoms and the changes in these lung function parameters are completely reversible.

Adult↗
PubMed1987

A phase I and pharmacokinetic study with 21-day continuous infusion of epirubicin.

A phase I study with continuous administration of epirubicin for 21 days using a venous access port and a portable pump was performed. The first dose step was 2 mg/m2/d for 21 days. Interval between courses was 3 weeks. Dose increment per step was 1 mg/m2/d. Twenty-two patients entered the study and received a total of 58 courses with a median of two (range, one to nine). Up to 5 mg/m2/d no toxicity (according to World Health Organization [WHO] criteria) occurred. At 6 mg/m2/d (six pts), one patient had leukopenia grade 3. Two others had some hair loss. At 7 mg/m2/d (four patients), all patients developed mucositis (two grade 3). Three patients had bone marrow depression (one grade 3 anemia, one grade 4 leukocytopenia), and one patient developed the hand-foot syndrome. No other toxicity occurred in the patients. One patient obtained a partial response (18 weeks), ten had stable disease (12 to 54 weeks), seven had progressive disease, and four were not evaluable for response. One patient developed cellulitis around the port, responding to antibiotic treatment; one patient developed a vena cava superior syndrome that resolved with urokinase and removal of the access port. No septicemia occurred. Pharmacokinetic studies were performed by high-performance liquid chromatography (HPLC) with fluorometric detection. Plasma steady state was reached after 57 hours. During steady state there was a linear relationship between epirubicin dose administered and epirubicin level in plasma (r = .58, P less than .05), whole blood (r = .75, P less than .005), and in leukocytes (r = .68, P less than .05). The area under the curve in leukocytes was higher with continuous infusion of 6 mg/m2 for 21 days compared with bolus injection of 80 mg/m2. This method of continuous infusion with epirubicin may be a way to increase intracellular drug-uptake as expressed by intracellular area under curve (AUC). We recommend 6 mg/m2/d for 3 weeks for evaluation of antitumor efficacy in phase II studies.

Adult↗
PubMed1987

Phase I and pharmacokinetic study of trans-N3P3Az2(NHMe)4.

trans-N3P3Az2(NHMe)4, an aziridinyl-substituted cyclophosphazene, was tested for its toxicity, pharmacokinetic behavior, and cytostatic activity in a phase I study in 30 patients. A total of 66 courses of a single iv bolus injection were given in five dose steps. Toxicity consisted of leukocytopenia and thrombocytopenia, dose limiting at 70 mg/m2, mild anemia, and some nausea. Leukocyte and platelet count nadirs fell between 2 and 3 weeks, with recovery at 6 weeks. A tendency for cumulative thrombocytopenia was noticed in three of 13 patients at risk. A three-phase plasma elimination model was applicable with t1/2 alpha of 9.9 minutes, t1/2 beta of 78.5 minutes, and t1/2 gamma of 435.5 minutes; renal drug excretion was substantial. Three partial remissions in 21 evaluable patients suggest some clinical activity for this drug.

Adult↗
PubMed1987

Pharmacokinetics of high-dose teniposide.

This paper describes the pharmacokinetics of teniposide (VM-26) after being administered iv in high doses to eight cancer patients (maximum dose, 1.0 g/m2). VM-26 levels in plasma, urine, saliva, duodenal fluid, and cerebrospinal fluid were determined using high-performance liquid chromatography in combination with electrochemical detection. The plasma concentration-time curve of VM-26 showed a triphasic decay with a slow third phase in five patients, whereas in two patients the plasma concentration decay was biphasic. The plasma pharmacokinetics of VM-26 proved to be linear and could be fitted to a three-compartment model (five patients) and to a two-compartment model (two). The steady-state volume of distribution varied from 13.2 to 24.7 L/m2. The total-body clearance ranged from 5.84 to 10.18 ml/minute/m2. Low concentrations of VM-26 were found in saliva, duodenal fluid, cerebrospinal fluid, and urine. Excretion of unchanged VM-26 into the urine varied from 8.8% to 13.9% of the administered dose. No glucuronide of VM-26 could be detected in plasma or other biological fluid.

Adult↗
PubMed1986

Gastrointestinal toxicity of chemotherapy and the influence of hyperalimentation.

The effect of combination chemotherapy on human small intestinal morphology and disaccharidase activities and their relation with clinical and chemical (fecal wet weight and K-excretion) parameters for gastrointestinal toxicity were evaluated in patients with disseminated malignant melanoma receiving enteral normoalimentation (NA). Also evaluated were the supposed protective effects on gastrointestinal toxicity of enteral hyperalimentation (HA) with an elemental diet. After chemotherapy, a comparable decrease in villus height, total mucosal height, and mitotic index was found in jejunal biopsy specimens of both groups. However, in the NA group, the crypt depth decreased (in contrast to the HA group), whereas the disaccharidase activities in the HA group deteriorated to lower values than in the NA group. The authors found no correlation between disaccharidase levels and mucosal morphology, nor was there a correlation between these variables, fecal parameters and clinical diarrhea, suggesting that diarrhea occurring after chemotherapy was not due to loss of mucosal tissue or decrease in enzyme activities. A protective effect of HA with an elemental diet on gastrointestinal toxicity could not be established.

Adult↗
PubMed1986

Detection of DNA cross-links in tumor cells with the ethidium bromide fluorescence assay.

Until now the fluorescence assay with ethidium bromide has only been used on pure DNA. This assay depends on the difference in fluorescence between single- and double-stranded DNA (dsDNA). Cross-links in DNA are measured by the return of fluorescence of dsDNA after heat denaturation at pH 12. Under these conditions denatured DNA gives very low fluorescence. In the present study this assay was applied to tumor cells. The mouse Ehrlich ascites tumor cell line (EAT) and a human small-cell carcinoma line (GLC4) were incubated for 4 hr at 37 degrees C, with the cross-linking agent cis-diamino-dichloro platinum (cDDP). The samples of whole cells were thereafter resuspended in potassium phosphate buffer with 10 mM EDTA, 4M NaCl, 0.1% Sarkosyl pH 7.2, for 16 hr at 37 degrees C. Measurements were performed with a spectrofluorometer with excitation wavelength 525 nm, emission wavelength 580 nm. There was a linear relationship for cDDP concentrations of 0-150 microM and the extent of DNA cross-links in EAT (r = 0.958). In GLC4 there was a linear relationship at low cDDP concentrations of 0-50 microM (r = 0.968) while between 50 and 150 microM a plateau was reached. RNase added to the lysate of whole cells had no influence on the extent of cross-links. This assay was compared with the alkaline elution assay, and results were identical.

Animals↗
PubMed1986

Acute nonlymphocytic leukemia 5 years after treatment with cisplatin, vinblastine, and bleomycin for disseminated testicular cancer.

The combination of cisplatin, vinblastine, and bleomycin (PVB) was used to treat a 25-year-old man for disseminated testicular germ cell cancer, leading to a complete remission. Acute nonlymphocytic leukemia (ANLL), resistant to chemotherapy, developed 5 years later. The secondary nature of this ANLL was corroborated by the detection of nonrandom chromosomal aberrations in bone marrow cells of chromosomes, 7, 5, and 3. This is one of the first reports of possible leukemogenic activity of PVB treatment when applied without additional irradiation or alkylating agents.

Acute Disease↗
PubMed1986

Carbon-11 labelled tyrosine to study tumor metabolism by positron emission tomography (PET).

To measure the rate of protein synthesis in human neoplasms by positron emission tomography, we prepared no carrier added DL-(1-11C)-tyrosine by 11C-carboxylation of the appropriate alpha-lithioisocyanide followed by hydrolysis of the isocyanide function and removal of the protecting methoxy group. The purification, resolution and solvent switch to saline was performed by high performance liquid chromatography (HPLC). DL-(1-11C)-Tyrosine in 0.1 N NaH2PO4 buffer was prepared with a radiochemical yield of 8%-16% (EOS, 35 min). The enantiomeric separation and solvent switch to saline were achieved in 5 min and 10 min respectively. Consequently L-(1-11C)-tyrosine in physiological saline was obtained in 2%-4% radiochemical yield. Tumor accumulation in rats with the experimental WALKER 256 carcinosarcoma was observed for both the L- and D-isomer. Using positron emission tomography a tumor/muscle ratio of two was observed for the L-isomer 15 min after injection. The corresponding figure for the D-isomer was 2.5. The first clinical results with DL-(1-11C)-tyrosine show accumulation of radioactivity in meningioma, a primary breast carcinoma and in liver metastases of a colonic carcinoma.

Animals↗
PubMed1986

Evaluation of gastrointestinal toxicity following cytostatic chemotherapy.

A number of clinical and chemical parameters related to the gastrointestinal tract in patients treated with intensive chemotherapy for disseminated malignant melanoma were evaluated in order to find quantitative indicators for gastrointestinal toxicity and to investigate the cause of diarrhea after chemotherapy. In 11 patients 17 courses of polychemotherapy with bleomycin, DTIC, vindesine, and actinomycin D were administered, while the patients received complete liquid enteral nutrition. As clinical parameters for toxicity the diarrhea grading system according to the WHO criteria and the daily fecal consistency were used. Furthermore, in the feces Na+, K+, and Cl- (mmol/24 h), Na+/K+ ratio, dry and wet weight (g/24 h), lactate and bile acids (mmol/24 h), fat (g/24 h), pH, and osmolarity were determined. Both clinical parameters were closely correlated. The most important effects of the chemotherapy on the chemical parameters were an increased fecal fluid, K+, and fat excretion. The fecal wet weight and K+ excretion showed a high correlation with the two clinical parameters for gastrointestinal toxicity. We conclude that mucosal injury resulting from chemotherapy probably leads to increased small intestinal fluid and electrolyte secretion inducing diarrhea and that fecal wet weight and K+ excretion are probably the best quantitative indicators for gastrointestincal toxicity.

Adult↗
PubMed1986

Bone marrow toxicity of cyclophosphazenes is related to their structure and the treatment schedule.

For three aziridinyl-substituted inorganic heterocycles belonging to the cyclophosphazene group, the tendency for cumulative bone marrow toxicity was studied in mice. In a one-day regimen, one of these drugs, gem-N3P3Az4Pyr2 (Az = aziridinyl, Pyr = pyrrolidinyl) (AZX), led to an increased death rate after a repeated injection, the number of bone marrow stem cells (CFUgm) being decreased 5 weeks after the second injection of this drug. In a four-day regimen two drugs, (NPAz2)2 NSOAz (Soaz) and AZX, led to an increased death rate after the second treatment course. In surviving animals leucocyte and thrombocyte counts were significantly lower in the second than in the first course. CFUgm counts were decreased for both drugs. For the third drug, trans-N3P3(Az)2(NHMe)4 (AZP), no evidence of cumulative bone marrow toxicity was demonstrated. It is suggested that whereas cytostatic activity of these compounds seems to be comparable, their tendency to cause cumulative marrow toxicity may vary.

Animals↗
PubMed1986

Pharmacokinetics of high dose etoposide (VP 16-213).

This paper describes the pharmacokinetics of etoposide in cancer patients after high dose administration (up to 3.5 g/m2). High performance liquid chromatography with electrochemical detection was used to determine etoposide, cis etoposide and the glucuronide of etoposide in plasma, bile, cerebro-spinal fluid, urine, saliva and ascites, the detection limit being 2 ng etoposide/ml plasma. The plasma concentration time curve shows a tri-phasic decay. The terminal phase is very slow. It was concluded that etoposide is strongly bound in the peripheral compartment. The volume of the central compartment varied from 7.4 to 20.1 l and the steady state volume of distribution from 3.1 to 7.8 l/m2. Relatively high concentrations of etoposide were found in saliva, bile, ascites and urine and low concentrations in cerebro-spinal fluid. The total body clearance varied from 12.0 to 26.8 ml/min/m2, and 26.2 to 53.4% was excreted as unchanged etoposide into the urine and 8.3 to 17.3% as glucuronide into the urine. Very low amounts of the trans hydroxy acid of etoposide and the cis etoposide were detected in the urine. Glucuronides were found in urine and duodenal fluid but not in plasma.

Adult↗
PubMed1986

Phase II study of bleomycin, actinomycin D, DTIC and vindesine in disseminated malignant melanoma.

Twenty-seven patients with disseminated malignant melanoma were treated with combination chemotherapy consisting of bleomycin, actinomycin D, DTIC and vindesine. There were 4 complete responses in patients with pulmonary metastasis, 5 patients had a partial remission, 2 of them had mainly lung lesions. Toxicity consisted mainly of leuco- and thrombocytopenia of short duration and sporadic severe mucositis.

Adult↗
PubMed1986

Isomer-dependent cytostatic activity of bis(1-aziridinyl)cyclophosphazenes.

A number of recently synthesized mono- and bis(1-aziridinyl) derivatives of the inorganic ring systems (NPCl2)3 and (NPCl2)4 was tested for their cytostatic activity in vitro (L1210 and L5178Y cells) and in vivo (intraperitoneal leukemia L1210 in CDF1 mice). Generally, the nongeminal bis(1-aziridinyl) isomers (either trans or cis) appear to be potent tumor growth inhibitors in contrast to their geminally substituted and mono(1-aziridinyl)-substituted analogues. A relationship between the biological activity and the number of alkylating centers (i.e., P atoms carrying one or two aziridinyl groups) is proposed.

Animals↗