Approximate spectral functions in thermal field theory.
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Journal Article↗
Biomedical subjects
T Schilling
Publications and source records attributed to T Schilling.
[The diagnosis and therapy of hypoparathyroidism].
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Calcium↗
Immunochemiluminometric assay with two monoclonal antibodies against the N-terminal sequence of human parathyroid hormone.
We have developed an immunochemiluminometric assay (ICMA) with two monoclonal antibodies for the N-terminal sequence of human parathyroid hormone (hPTH). One monoclonal antibody (A1-70) was physically adsorbed onto polystyrene beads, the other (B1-70) was labelled with acridinium ester and synthetic hPTH (1-38) was used as standard. This assay has cross-reactions with synthetic hPTH (1-34) and hPTH (1-84) but no cross-reactions with hPTH (4-16), (28-48), (39-84), (44-68), (53-84) and hPTH-rP (1-86). The assay detection limit is 0.4 pmol/l. The normal range is 1.3-12 pmol/l based on 72 normal volunteers. About 91% of study patients (n = 58) with surgically proven primary hyperparathyroidism (1 degree HPT) had PTH values above normal and one of them showed a low normal intact PTH value but elevated PTH values with use of this assay. After immunoabsorption of plasma samples from patients with secondary hyperparathyroidism (2 degrees HPT) on hemodialysis with polystyrene beads containing antibodies against hPTH (39-84), some patients still showed significant amounts of PTH in this new ICMA but not intact PTH. The data reveal that significant amounts of amino-terminal immunoreactive PTH fragments rarely exist in 1 degree HPT but are present in some patients with 2 degrees HPT. The major advantage of this assay is to measure both amino-terminal PTH fragments and intact PTH with no interference from carboxy-terminal PTH fragments because two anti-N-terminal hormone sequence monoclonal antibodies are used.
Adult↗
Clinical phase I and pharmacokinetic trial of vinorelbine administered as single intravenous bolus every 21 days in cancer patients.
We have performed a high-dose clinical and pharmacokinetic trial with vinorelbine administered as a bolus injection every 21 days. The aim was to evaluate a schedule with longer treatment intervals than one week and to determine the toxicity pattern of such a schedule. A total of 13 patients (pts) with solid tumors (non-small-cell lung [3 pts], unknown primary [3 pts], mesothelioma [2 pts], colon/rectum, sarcoma, thyroid, head/neck and cervix [1 pt each]) were entered [9 male, 4 female, median age: 56 years (range: 37-69)]. Dose levels were 35, 40 and 45 mg/m2 with a total of 26 cycles administered. At 40 mg/m2, 2/6 pts developed grade 4 granulocytopenia. 1/1 pt at 45 mg/m2 developed a grade 4 leuko- and granulocytopenia. Non-hematological toxicities were mild to moderate. Neurologic toxicity except for constipation was mild. Constipation occurred at 35 mg/m2 in 1/6 pts WHO grade 4, at 40 mg/m2 in 2/6 pts WHO grade 3 and at 45 mg/m2 in 1/1 pt WHO grade 4 and was due to neurotoxicity. No objective antitumor response was observed. Vinorelbine pharmacokinetics were analysed in whole blood and plasma and were similar to previously published studies using < or = 30 mg/m2. Our results confirm a high affinity of vinorelbine to corpuscular blood elements. We conclude that the MTD of vinorelbine administered once every 21 days as bolus injection is 40 mg/m2, the dose-limiting toxicities are constipation and granulocytopenia and the recommended dose for subsequent Phase II trials is 35 mg/m2.
Adult↗
Clinical and pharmacokinetic phase I trial of oral dimethylaminoetoposide (NK611) administered for 21 days every 35 days.
We have conducted a clinical and pharmacokinetic trial of the novel podophyllotoxin derivative NK611 administered orally for 21 consecutive days. The treatment was repeated every 35 days. Eighteen patients were included into the study, all of whom were eligible. Due to early progression of tumor disease in two patients, 16 patients were evaluable for toxicity [7 female, 9 male, median age 64 years (range: 44 to 73)]. Dose escalation steps were 5 mg/day [105 mg per cycle (pc)], 10 mg/day (210 mg pc), 12.5 mg/day (265 mg pc) and 15 mg/day (315 mg pc). A total of 37 courses was administered. Toxicity was evaluated using NCI-CTC criteria. Granulocytopenia was the main hematologic toxicity. Other hematologic toxicities were sporadic. Non-hematologic toxicities were mild and consisted of grade 1 nausea and grade 2 alopecia. Pharmacokinetic analyses were performed in six patients each treated with 10 mg/day and 12.5 mg per day, and in one patient treated with 15 mg/day. Using a two-compartment model, t1/2 alpha ranged from 0.47 to 1.54 h and t1/2 beta from 2.0-11.6 h. Mean values for Cmax and AUC were 1.47 +/- 0.331 microgram/ml and 13.67 +/- 3.81 micrograms/ml.h. No objective tumor responses were observed. However, one patient with metastatic breast cancer had stable disease for twelve months. We conclude that the Maximum Tolerated Dose of NK611 administered daily for 21 consecutive days is 12.5 mg/day. The Dose-Limiting Toxicity is granulocytopenia. The recommended dose for further clinical Phase II studies is 10 mg/day.
Administration, Oral↗
Clinical phase I and pharmacokinetic trial of the new titanium complex budotitane.
Budotitane [cis-diethoxybis(1-phenylbutane-1,3-dionato)titanium (IV)] is a novel inorganic metal complex. Preclinical studies in established screening models indicate considerable antitumor activity. We have performed a clinical Phase I and pharmacokinetic trial with budotitane administered as i.v. infusion twice weekly. The starting dose of 100 mg/m2 was derived from a prior single dose Phase I study. Eighteen patients with solid tumors refractory to all other known treatment modalities were entered. 17 patients had received prior chemotherapy. Dose levels ranged from 100 mg/m2 to 230 mg/m2, with a total of 122 budotitane infusions administered. Neither leuko- nor thrombocytopenia were observed. 2/5 pts at 180 mg/m2 and 2/4 pts at 230 mg/m2 developed a 3-fold increase of reticulocytes without signs of hemolysis or bleeding. Nonhematologic toxicity was moderate at doses of < or = 180 mg/m2. Fifteen patients reported loss of taste at the day of infusion. At 230 mg/m2, 2/4 pts developed WHO grade 3 cardiac arrhythmias with polytope premature ventricular beats and nonsustained ventricular tachycardia. A limited pharmacokinetic analysis was performed at dose levels 180 mg/m2 and 230 mg/m2. At 180 mg/m2, Cmax was 2.9 +/- 1.2 microg/ml, t1/2 78.7 +/- 24.4 h, Cltot 25.3 +/- 4.6 ml/min and AUC 203 +/- 71.5 h x microg/ml. At 230 mg/m2, Cmax was 2.2 +/- 0.8 microg/ml, t1/2 59.3 +/- 12.1 h, Cltot 44.9 +/- 23.6 ml/min and AUC was 183 +/- 90.4 h x microg/ml. No objective tumor response was observed. We conclude that the maximum tolerated dose of budotitane administered twice weekly is 230 mg/m2, the dose limiting toxicity is cardiac arrhythmia. Further evaluation of the nature of the cardiac toxicities observed is warranted. Using this schedule, 180 mg/m2 is a safe dose for subsequent clinical studies.
Adult↗
Pharmacokinetics and pharmacodynamics of the new podophyllotoxin derivative NK 611. A study by the AIO groups PHASE-I and APOH.
NK 611 is a new podophyllotoxin derivative in which a dimethyl amino group replaces a hydroxyl group at the sugar moiety of etoposide. This results in profound physico-chemical differences: NK 611 is much less hydrophobic than etoposide. Preclinical studies have shown that NK 611 is advantageous in terms of bioavailability and of the potency of its anticancer activity. A clinical phase I study was performed in cancer patients within the framework of the AIO. Additionally, its pharmacokinetics and pharmacodynamics were investigated. NK 611 was given to 26 patients at doses ranging from 60 to 140 mg/m2 [maximum tolerated dose (MTD) 120 mg/m2] in a 30-min infusion. Plasma and urine samples were collected from 25 patients and analyzed using a validated high-performance liquid chromatography (HPLC) assay procedure. The concentration versus time curve of total NK 611 in plasma samples was best described by a three-compartment model. The overall median pharmacokinetic values were as follows (ranges are given in parentheses): mean residence time (MRT) 16.5 (5.4-42.3)h, terminal half-life 14.0 (8.2-30.5)h, volume of distribution at steady state (V(ss)) 11.4 (7.9-18.1) l/m2 and plasma clearance (Cl(p)) 15.1 (3.6-36.4) ml min-1 m-2. The total systemic drug exposure, represented by the area under the curve (AUC), varied between 53.4 and 532.0 micrograms ml-1 h. The mean AUC (+/- SD) increased with the dose from 78.7 +/- 3.7 micrograms ml-1 h at 60 mg/m2 up to 202.8 +/- 157.2 micrograms ml-1 h at 120 mg/m2. The mean urinary excretion (UE) fraction of unchanged drug at 48 h after the end of the infusion varied between 3.0% and 25.8% of the total dose delivered. Analysis of ultrafiltrate samples showed a protein binding of approx.. 99%. The percentage reduction in white blood cells (WBC) and neutrophils (ANC) correlated with the dose, AUC, and AUC(free). The best relationship between the percentage of reduction in ANC and a pharmacokinetic parameter (AUC) took a nonlinear Hill-type form. The laboratory parameter for kidney or liver function did not correlate with the AUC. The variation of pharmacokinetic parameters within each dose level was profound. The reason for this pharmacological behavior remains unclear and should be investigated in further studies.
Adult↗
Glucocorticoids decrease the production of parathyroid hormone-related protein in vitro but not in vivo in the Walker carcinosarcoma 256 rat model.
In 50-90% of cases, humoral hypercalcemia of malignancy (HHM) is due to tumor secretion of parathyroid hormone-related protein (PTHrP). Glucocorticoids are sometimes used as calcium lowering agents and there are in vitro results showing that glucocorticoids diminish PTHrP production. In this study we tested whether the serum-calcium-lowering effect of glucocorticoids is due to decreased PTHrP production by the tumor. As an animal and cell culture model we used the Walker carcinosarcoma (WCS) 256, a rat mammary carcinoma cell line producing PTHrP. In vitro, dexamethasone caused a dose-dependent inhibition of PTHrP production, whereby already 1-5 nmol/L revealed a significant decrease by WCS 256 cells. In contrast to these in vitro results, in WCS 256 tumor-bearing rats, dexamethasone (4 mg/kg body weight on day 4, and 1 mg/kg body weight from day 5 until day 7 after WCS transplantation; circulating dexamethasone levels > 20 nmol/L) did not decrease PTHrP production, PTHrP secretion, serum calcium, or tumor weight in vivo. We conclude that, in this PTHrP-mediated model of humoral hypercalcemia of malignancy, glucocorticoids do not decrease PTHrP production and secretion in vivo and do not show a calcium-lowering effect.
Analysis of Variance↗
Influence of dexamethasone and 1,25-Dihydroxyvitamin D on Walker carcinosarcoma 256 growth and parathyroid hormone-related protein secretion.
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Animals↗
Effects of passive immunization against parathyroid hormone-related protein: PTHrP is the responsible factor in mediating hypercalcemia in the Walker carcinosarcoma 256 rat model.
The Walker carcinosarcoma (WCS) 256 is a well-characterized rat model of humoral hypercalcemia of malignancy (HHM). We addressed the question of whether parathyroid hormone-related protein (PTHrP) is the factor responsible for mediating HHM in this model. WCS 256 cells were subcutaneously implanted in female rats. We examined the plasma at days 0, 2, 4, 6, and 8. The midregional PTHrP measured by radioimmunoassay (RIA) and the plasma calcium increased significantly. Measuring PTHrP by a two-site immunoradiometric assay (IRMA) showed comparable results. There was a strong positive correlation between plasma calcium and midregional PTHrP (r = 0.85, p < 0.0001). A strong positive correlation between tumor weight and both midregional PTHrP (r = 0.83, p < 0.0001) and plasma calcium (r = 0.87, p < 0.0001) was also found. After surgical removal of the tumor at day 5, both plasma calcium and plasma PTHrP levels fell to within the normal range. Ip administration of native polyclonal antiserum against PTHrP(53-84) led to a significant decrease of plasma calcium. Extracted WCS 256 tumor showed 5-fold increased levels of midregional PTHrP compared with liver. Immunohistochemistry and Western blot were positive for PTHrP. RNA from the WCS 256 tumor was positive for PTHrP whereas liver tissue RNA was negative. WCS 256 cells grown in vitro also secreted PTHrP into the medium. We conclude that PTHrP is synthesized and secreted by WCS 256 and that PTHrP is the factor responsible for mediating hypercalcemia in the WCS 256 rat model.
Analysis of Variance↗
The diagnostic value of urinary pyridinium cross-links of collagen, serum total alkaline phosphatase, and urinary calcium excretion in neoplastic bone disease.
Bone metastases strongly affect skeletal metabolism by both their growth and their paracrine activities. However, so far no specific laboratory marker has been found to signal the spread of neoplastic disease to bone. We performed a cross-sectional study of 153 cancer patients and an equal number of healthy controls matched for sex and age, in which we determined serum levels of calcium and total alkaline phosphatase (TAP) as well as the fasting urinary excretion of calcium (uCa) and of the collagen cross-links pyridinoline (uPYD) and deoxypyridinoline (uDPD). The aim of the study was to analyze the diagnostic validity of the biochemical parameters measured with regard to neoplastic bone involvement. In the cancer group, 98 patients had overt bone metastases, as judged from radiographic and radioisotopic bone imaging. The remaining 55 patients were also in an advanced stage of disease, but there was no evidence of malignant bone involvement. In comparison to healthy controls, patients both with and without metastatic bone disease had significantly higher levels of TAP, uPYD, and uDPD (P < 0.0001). Only in cancer patients with bone metastases was the median serum calcium level higher than in the healthy controls (P < 0.02). uCa was the same in cancer patients and the control group. Within the collective of cancer patients, individuals with skeletal metastases had higher levels of serum calcium (P < 0.05), TAP (P < 0.01), and uPYD and uDPD (both P < 0.0001), than patients without evidence of malignant bone disease. uCa did not differ between the 2 groups of cancer patients. The cancer patients were then stratified into 4 subgroups according to the serum calcium level (< or = 2.6 mmol/L >) and the absence or evidence of bone metastases. This stratification revealed that in patients with bone metastases, uPYD and uDPD levels were similar in normocalcemic and hypercalcemic subjects, whereas in hypercalcemic patients, uCa levels significantly exceeded those in normocalcemic patients. When the efficacy of TAP, uCa, uPYD, and uDPD in discriminating between patients with and without bone metastases was evaluated by use of receiver-operating characteristic curves and stepwise multivariate regression analysis, uPYD was found to have the highest diagnostic validity. Using 50 mumol PYD/mol creatinine (i.e. the upper limit of normal range) as the cut-off level, the sensitivity of uPYD was 88.7%, whereas the specificity was only 41.8% (odds ratio, 5.598; 95% confidence interval, 2.547-12.306).(ABSTRACT TRUNCATED AT 400 WORDS)
Adult↗
Modalities of endotoxin binding to CD14.
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Animals↗
Clinical phase I study of paclitaxel followed by cisplatin in advanced head and neck squamous cell carcinoma.
We performed a clinical phase I trial of the combination of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and cisplatin in patients with recurrent or metastatic squamous cell carcinoma of the head and neck, using a 3-hour infusion of paclitaxel followed by a 1-hour infusion of cisplatin. Treatment with this combination was repeated every 21 days. Patients who had received prior treatment with platinum-containing regimens were excluded. However, patients who had received two or fewer courses of radiochemotherapy not including platinum compounds were eligible. At present, 21 patients have been entered into this ongoing study. Doses ranged from paclitaxel 135 mg/m2 plus cisplatin 75 mg/m2 to paclitaxel 250 mg/m2 plus cisplatin 100 mg/m2. The maximum tolerated dose was reached at paclitaxel 250 mg/m2 and cisplatin 100 mg/m2. The dose-limiting toxicity of this regimen was myelosuppression (leukopenia, granulocytopenia). Clinically, neurosensory toxicity was moderate. However, preliminary analyses of threshold electrotonus studies indicate the presence of subclinical neurotoxicity in most patients. One patient receiving paclitaxel 200 mg/m2 plus cisplatin 100 mg/m2 developed grade 3 motor neurotoxicity. Profound orthostatic hypotension was observed in five patients receiving paclitaxel 200 mg/m2 plus cisplatin 100 mg/m2 or higher. Neurotoxicity was of delayed onset and slowly reversible, and its severity appeared to be dose related. Twelve patients are currently evaluable for response. Of these, three partial remissions were observed (6, 6+, and 3+ months). Five additional patients had stable disease. We conclude that the combination of paclitaxel administered as a 3-hour infusion followed by cisplatin is an active regimen in advanced head and neck cancer. In addition to myelosuppression, orthostatic hypotension may be a potentially significant clinical toxicity. Clinical phase II studies have been initiated, using a dose of paclitaxel 200 mg/m2 and cisplatin 100 mg/m2.
Adult↗
In vivo models of hypercalcemia of malignancy.
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Animals↗
Comparison of a semiquantitative and a quantitative method for assessing vertebral fractures in osteoporosis.
There is no agreed definition for the assessment of vertebral fractures and deformities in patients with osteoporosis. Radiographs of 66 patients randomized for therapy with etidronate or placebo were analyzed at baseline and during follow-up (60/120/150 weeks) independently using two procedures. The first method of spinal deformity index (SDIG) and vertebral deformity score (VDSG) is based on a semiquantitative visual reading of each vertebra between T4 and L4. The second method of spine deformity index (SDIM) and vertebral deformity index (VDIM) is based on vertebral height measurements of T4 through L5 and each measurement from T5 to L5 (anterior, middle and posterior height) is related to T4 and compared with the respective T4-related normal range. There was good agreement between the mean vertebral deformation from T5 to L4 graded by VDSG and VDIM, with correlation coefficients between R = 0.52 (p < 0.0001) and R = 0.9 (p < 0.0001) respectively. Spinal deformation at baseline as measured by SDIM and SDIG was correlated with R = 0.76 (p < 0.0001). For diagnosing a vertebra as fractured or not, VDIM reached a sensitivity of 82% and a specificity of 85% using VDSG as a standard, and on the other hand VDSG reached a sensitivity of 78% and a specificity of 88% in relation to VDIM. The changes in spinal deformation from week 0 to 150 were correlated with R = 0.58 (p < 0.0002) between SDIM and SDIG. To detect vertebral fracture progression the sensitivity of VDIM was 74% and the specificity 86%, when changes in VDSG were used as a standard.(ABSTRACT TRUNCATED AT 250 WORDS)
Etidronic Acid↗
Parathyroid hormone-related protein and life expectancy in hypercalcemic cancer patients.
We determined the effect of raised serum levels of midregional (53-84) parathyroid hormone-related protein (PTHrP) on life expectancy in 59 cancer patients with first presentation of hypercalcemia. The patients were stratified according to the serum PTHrP levels measured on day 0 after fluid repletion prior to bisphosphonate therapy. Twenty-nine patients were assigned to group N (PTHrP < or = 21 pmol/L) and 30 to group E (PTHrP > 21 pmol/L). Breast cancers were more common in group N, squamous cell cancers predominated in group E (p < 0.02). More patients with normal PTHrP had skeletal metastases, whereas group E was characterized by a higher incidence of prognostically unfavorable visceral involvement (p < 0.001). Bisphosphonates (pamidronate or BM.210955) were administered on day 0. Within one week, normocalcemia (serum calcium < or = 2.6 mmol/L) was restored in 96% of patients in group N, compared to 70% of patients in group E (p < 0.01). On day 12, 7 patients with elevated PTHrP were still hypercalcemic. Although a comparable number of patients in the two groups received cytostatic treatment after day 12, objective tumor responses were seen only in group N (n = 6; p < 0.05). Calculated from the first occurrence of hypercalcemia, the median survival was 66 days in group N and 33 days in group E (log-rank test: p = 0.0456; Wilcoxon-Breslow test: p = 0.0475). We conclude that in hypercalcemia of malignancy raised serum levels of PTHrP indicate a reduced hypocalcemic response to bisphosphonates, a more advanced tumor state and, therefore, an extremely poor prognosis.
Adult↗
Parathyroid hormone-related protein (PTHrP) does not regulate 1,25-dihydroxyvitamin D serum levels in hypercalcemia of malignancy.
We investigated in humoral hypercalcemia of malignancy whether parathyroid hormone-related protein (PTHrP) elevation causes a rise in 1,25-dihydroxyvitamin D (1,25-(OH)2 D) serum levels. We assessed 41 patients with hypercalcemia of malignancy in a prospective study. There were 19 patients who had serum PTHrP levels in the normal range; 22 patients had elevated serum PTHrP levels. All patients were treated with the bisphosphonate pamidronate resulting in a drop of serum calcium (p < 0.0001) and serum phosphate (p < 0.0023) within 12 days, independent of the group. Parathyroid hormone (PTH) was suppressed at the start of therapy and rose to within the normal range during therapy (p < 0.0001), regardless of the PTHrP levels. PTHrP levels were not influenced by calcium lowering therapy. The serum levels of 1,25-(OH)2 D were either suppressed or in the low normal range at the beginning of the study, without any significant difference between both groups. All patients showed a rise in 1,25-(OH)2 D during bisphosphonate therapy (p < 0.0001), independent of their PTHrP levels. Thus PTHrP did not influence the calcium, phosphate-, or PTH-dependent regulation of 1,25-(OH)2 D during calcium lowering therapy. We conclude, that PTHrP does not stimulate renal 1-hydroxylase activity in humoral hypercalcemia of malignancy.
Adult↗
Effect of clodronate treatment on bone scintigraphy in metastatic breast cancer.
Because of their high affinity for bone, bisphosphonates are used both in the treatment of benign and malignant bone disease and in radiopharmaceutical bone imaging. A prospective study was undertaken to evaluate whether intravenous clodronate (dichloromethylene bisphosphonate) therapy might affect the results of bone scintigraphy with 99mTc-labeled methylene diphosphonate (MDP). In 11 female patients with breast cancer and metastatic bone disease, quantitative bone scans were obtained using a region of interest (ROI) method on Days 0 and 22. After intravenous clodronate therapy from Day 1 to Day 21, all metastatic bone lesions were still detectable, and median ROI ratios did not differ to a statistically significant extent from baseline values. Serum calcium levels decreased (p = 0.0449), whereas parathyroid hormone concentrations showed an increase (p = 0.0053). Mean serum levels of creatinine, inorganic phosphorus, osteocalcin, gamma glutaminyl-transpeptidase and alkaline phosphatase remained unchanged. However, a more than twofold rise in the serum activity of alkaline phosphatase was measured in three patients. We conclude that 3 wk of intravenous clodronate treatment did not impair the sensitivity of 99mTc-MDP bone scintigraphy in detecting bone lesions in patients with metastatic breast cancer.
Bone Neoplasms↗