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  • 1
    Electronic Resource
    Electronic Resource
    Multifractality in human heartbeat dynamics (1999)
    [s.l.] : Macmillan Magazines Ltd.
    Nature 399 (1999), S. 461-465 
    Details
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] There is evidence that physiological signals under healthy conditions may have a fractal temporal structure. Here we investigate the possibility that time series generated by certain physiological control systems may be members of a special class of complex processes, termed multifractal, which ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/20924
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  • 2
    Electronic Resource
    Electronic Resource
    Phase I study of cancer therapy with recombinant interleukin-2 administered by intravenous bolus injection (1989)
    Springer
    Biotherapy 1 (1989), S. 215-226 
    Details
    ISSN: 1573-8280
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Sixty-six patients with disseminated malignancy were treated with recombinant interleukin-2 (IL-2) on a three times a week (M, W, F) IV-bolus injection schedule. Doses ranged from 0.001 to 14.0 × 106 units/M2 body surface area. Consecutive groups of 3-5 patients were placed on each dose level and were maintained on that level except for dosage de-escalation for toxicity. Toxicity to all major organ systems were noted with major toxicity including fever and chills, anorexia, fatigue and malaise, arthralgias and arthritis as well as hepatic and renal toxicity. All toxicity reversed within one week of drug cessation. Renal toxicity manifested by azotemia, arthritis and fatigue were the common dose limiting toxicities and the maximally tolerated dose was 12 × 106 units/M2. Pharmacokinetic studies indicated a short half-life (T 1/2α = 7–23 minutes). At doses over 0.5 × 106 units/M2 increases in absolute lymphocytes and eosinophil counts were noted. All T lymphocyte subsets increased. Maximal increases were seen at 4–8 × 106 units/M2 with a lesser increase at 10–14 × 106 units/M2 dosage level. Circulating NK cells also increased while circulating LAK cells were detected during therapy. Partial responses were noted in 3 patients with melanoma. These lasted 4, 6 and 16 months and involved pulmonary, pulmonary plus mesenteric and retro-orbital plus hepatic metastases respectively in these patients.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02170890
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  • 3
    Electronic Resource
    Electronic Resource
    Effects of endotoxin on the pharmacology of antineoplastic agents (1981)
    Springer
    Cancer chemotherapy and pharmacology 5 (1981), S. 227-231 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Patients with cancer often develop serious gram-negative bacterial infections. Since bacterial endotoxins have been shown to affect the in vitro hepatic metabolism of antineoplastic agents, significant infection may adversely affect drug pharmacokinetics and metabolism in these patients. To evaluate the clinical significance of these effects, bacterial endotoxin (0.5 mg/kg, IV) was administered to male beagle dogs 1 or 24 h prior to the administration of radiolabeled 5-fluorouracil (5-FU), methotrexate (MTX), arabinosylcytosine (Ara-C), or vinblastine (VLB) as an IV bolus. Drug levels in plasma and urine were measured at various times after administration and standard pharmacokinetic parameters were calculated. The pharmacokinetics of all four agents were found to be significantly altered by the administration of bacterial endotoxin. However, there were no detectable patterns to these changes so that no predictions could be made. In studies on rats, chronic, nonlethal endotoxin administration (0.8 mg · kg-1 · day-1 for 10 days) resulted in a dramatic decrease in the distribution of [14C]methylglyoxal bis(guanylhydrazone) (MGBG) in liver, kidney, intestine, heart and lung tissue. This suggests that bacterial endotoxin may also affect drug pharmacokinetics by altering drug penetration into various organs. In studies on hepatic microsomes isolated from rats, bacterial endotoxin incubation affected aniline hydroxylase activity only at concentrations greater than 0.4 mg/ml, at least tenfold higher than the LD50 of endotoxin in rats. It therefore seems likely that the endotoxin may require in vivo metabolism to affect changes in drug metabolism and disposition.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00434389
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  • 4
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and metabolism of β-2′-deoxythioguanosine and 6-thioguanine in man (1982)
    Springer
    Cancer chemotherapy and pharmacology 8 (1982), S. 119-123 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Resistance to the antileukemic agent 6-thioguanine (TG) inevitably develops in animal tumors. However, a new agent, β-2′-deoxythioguanosine (β-TGdR) can overcome TG resistance in animal tumor models and is therefore of potential clinical use. The pharmacokinetics of radiolabeled TG were compared with those of β-TGdR in patients with cancer after intravenous administration. [35S]-β-TGdR (5.4 mg/kg, 200 mg/m2, 200 μCi total) was administered to five patients; the radiolabel in the plasma declined with an initial half-life (t1/2) of 14 min and a terminal t1/2 of 19.3 h. Within 24 h, 65% of the radiolabel was excreted in the urine. In contrast, after administration of [35S]-6-TG (3.4 mg/kg, 125 mg/m2, 200 μCi total) the average initial t1/2 was 40 min while the terminal phase t1/2 was 28.9 h. Urinary excretion of the radiolabel was 75% of the dose 24 h after administration. Both thiopurines were rapidly and extensively degraded and excreted as 6-thioxanthine, inorganic sulfate, S-methyl-6 thioxanthine, and 6-thiouric acid in addition to other products. Small amounts of unchanged drug were also excreted. These studies suggest that β-TGdR is merely a latent form of TG.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00292882
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  • 5
    Electronic Resource
    Electronic Resource
    A potent and specific immunotoxin for tumor cells expressing disialoganglioside GD2 (1991)
    Springer
    Cancer immunology immunotherapy 34 (1991), S. 198-204 
    Details
    ISSN: 1432-0851
    Keywords: Monoclonal antibodies ; Toxins ; Immunotoxins ; Cytotoxicity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Monoclonal antibody 14G2a (anti-GD2) reacts with cell lines and tumor tissues of neuroectodermal origin that express disialoganglioside GD2. mAb 14G2a was coupled to the ribosome-inactivating plant toxin gelonin with the heterobifunctional cross-linking reagentN-succinimidyl-3(2-pyridyldithio)propionate. The activity of the immunotoxin was assessed by a cell-free translation assay that confirmed the presence of active gelonin coupled to 14G2a. Data from an enzyme-linked immunosorbent assay demonstrated the specificity and immunoreactivity of the 14G2a-gelonin immunotoxin, which was identical to that of native 14G2a. Assays for complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) revealed that these functional properties of the native 14G2a antibody were also preserved in the 14G2a-gelonin immunotoxin. The gelonin-14G2a immunotoxin was directly cytotoxic to human melanoma (A375-M and AAB-527) cells and was 1000-fold more active than native gelonin in inhibiting the growth of human melanoma cells in vitro. The augmentation of tumor cell killing of 14G2a-gelonin immunotoxin was examined with several lysosomotropic compounds. Chloroquine and monensin, when combined with 14G2a-gelonin immunotoxin, augmented its cytotoxicity more than 10-fold. Biological response modifiers such as tumor necrosis factor α and interferon α and chemotherapeutic agents such as cisplatinum andN,N′-bis(2-chloroethyl)-N-nitrosourea (carmustine) augmented the cytotoxicity of 14G2a-gelonin 4- to 5-fold. The results of these studies suggest that 14G2a-gelonin may operate directly by both cytotoxic efforts and indirectly by mediating both ADCC and CDC activity against tumor cells; thus it may prove useful in the future for therapy of human neuroectodermal tumors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01742313
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  • 6
    Electronic Resource
    Electronic Resource
    Characterization of murine and humanized anti-CD33, gelonin immunotoxins reactive against myeloid leukemias (1994)
    Springer
    Cancer immunology immunotherapy 39 (1994), S. 367-374 
    Details
    ISSN: 1432-0851
    Keywords: Myeloid leukemia ; CD33 ; Immunotoxin ; Gelonin ; M195 ; HuM195
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract M195 antibodies recognize CD33, an antigen present on acute myeloid leukemia blasts as well as some myeloid progenitor cells, but not on the ultimate hematopoietic progenitor stem cell. Immunotoxins (IT) reactive with human myeloid leukemias were constructed by conjugating gelonin, a single-chain ribosome-inactivating protein, to murine and genetically engineered, humanized M195 antibodies via anN-succinimidyl-3-(2-pyridyldithio)-propionate linkage. No losses of gelonin cytotoxic activity or M195 binding activity were observed after conjugation of up to two toxin molecules per antibody. Toxin conjugates displayed specific, potent toxicity for CD33+ cells. The murine and humanized IT were not toxic to CD33− cells and were 600 and 4500 times more potent, respectively, than free gelonin in inhibiting CD33+ HL60 cells. Treatment of HL60 cells with 1 μg/ml HuM195-gelonin resulted in more than 1000 times lower colony formation; normal bone marrow mononuclear cell colonyforming units treated with HuM195-IT were reduced by a factor of 10. HL60 leukemia cells could be effectively purged from an excess of normal bone marrow cells. Exposure of target cells to IT for as little as 30 min was as effective as continuous exposure of IT for up to 6 days. However, measures of the efficacy of the immunotoxin were directly related to the length of time of observation after IT exposure and were inversely related to cell concentration. M195-gelonin immunoconjugates are potential candidates for therapeutic use in in vivo or ex vivo bone marrow purging of myeloid leukemias.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01534423
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  • 7
    Electronic Resource
    Electronic Resource
    Pharmacokinetics, tissue distribution, and in vivo antitumor effects of the antimelanoma immunotoxin ZME-gelonin (1995)
    Springer
    Cancer immunology immunotherapy 40 (1995), S. 339-345 
    Details
    ISSN: 1432-0851
    Keywords: Key words: Monoclonal antibodies ; Immunotoxin ; Immunotherapy ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Antibody ZME-018 is directed against the gp240 glycoprotein on the surface of more than 80% of human melanoma cell lines and fresh biopsy specimens. Previous studies in our laboratory described the in vitro cytotoxicity and specificity of an immunoconjugate composed of mAb ZME-018 and the plant toxin gelonin. The present study describes the in vivo pharmacokinetics and therapeutic effects of ZME-gelonin in human xenograft/nude mouse models. Pharmacokinetic studies of 125I-labeled ZME-018 and ZME-gelonin demonstrated a shorter terminal-phase plasma half-life of the immunoconjugate than native ZME (20.6 h compared to 41.3 h). The initial volume of distribution of the ZME-gelonin was also higher compared to that of ZME alone (2.85 ml compared to 1.91 ml) suggesting an enhanced distribution of the conjugate outside the vasculature. The corresponding area under the concentration/time curve for the ZME-gelonin conjugate was 40% lower than that of ZME alone (80.8 compared to 139.6 μCi ⋅ ml-1×min). In nude mice bearing well-developed human tumor A375 melanoma xenografts, administration of 125I-labeled ZME and ZME-gelonin resulted in tumor-to-blood ratios of 1.9±0.5 and 1.5±0.6 respectively by 72 h. Compared with ZME, ZME-gelonin conjugate caused an increase in the content of radiolabel in kidney, spleen and liver. Treatment of nude mice bearing well-developed (150 mm3) s.c. A375-M xenografts with divided doses of ZME-gelonin, ZME, gelonin, or saline resulted in suppression of tumor growth in the immunotoxin group but virtually no retardation of tumor growth in the control groups. Using a murine model for a rapidly growing lethal metastatic human melanoma, treatment with ZME-gelonin resulted in a mean survival of 44 days, a 213% increase in mean survival time compared with the saline treatment (14.2±2 day survival). Given these encouraging results, we are proceeding with further preclinical development of this immunotoxin.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01519635
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  • 8
    Electronic Resource
    Electronic Resource
    Comparative cytotoxicity and pharmacokinetics of antimelanoma immunotoxins containing either natural or recombinant gelonin (1999)
    Springer
    Cancer chemotherapy and pharmacology 44 (1999), S. 343-348 
    Details
    ISSN: 1432-0843
    Keywords: Key words Immunotoxins ; Gelonin ; Melanoma ; Recombinant toxins ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Immunotoxins are a class of targeted therapeutic agents under development by various research groups. The murine monoclonal antibody designated ZME-018 recognizes a high molecular weight glycoprotein present on most human melanoma cells and biopsy specimens and has been utilized for clinical imaging studies in patients with melanoma. The plant toxin gelonin is a ribosome-inactivating protein (RIP) with n-glycosidase activity similar to that of ricin A chain. In previous studies by our group, the gelonin toxin was sequenced, cloned and expressed in E. coli. The purified recombinant gelonin (RG) was found to have identical protein synthesis inhibitory activity to that of natural gelonin (NG). For comparative purposes, chemical conjugates of antibody ZME and either RG or NG were produced using the heterobifunctional crosslinking reagents SPDP and SMPT. The ZME-NG and ZME-RG immunotoxins were found to be 104- to 105-fold more cytotoxic to antigen-positive human melanoma cells than free toxin. NG toxin alone was cytotoxic to intact cells (IC50 = 100 nM) while RG was nontoxic to cells at doses up to 1 μM. Both ZME-NG and ZME-RG immunoconjugates were nontoxic to antigen-negative (Me-180) cells. ZME-RG immunotoxins constructed with the more stable SMPT reagent were slightly more effective in culture than conjugates made with SPDP. Tissue distribution studies in tumor-bearing nude mice demonstrated that tumor uptake of the ZME-RG immunotoxin was similar to that of the intact ZME antibody with reduced distribution to normal organs compared to an immunoconjugate produced with NG. Pharmacokinetic studies showed that the terminal-phase plasma half-life of ZME-RG was similar to that of ZME itself (42 h vs 50 h) and almost threefold higher than that of ZME-NG (11.5 h). The area under the concentration curve (Cxt) for ZME-RG was 50% lower than that for ZME due to an increased apparent volume of distribution (Vda) but was almost tenfold higher than the Cxt for ZME-NG. These studies suggest that immunoconjugates comprising RG demonstrate identical in vitro cytotoxic effects to immunoconjugates produced with NG and immunotoxins with RG display improved in vivo pharmacodynamics and tissue distribution compared to immunotoxins containing NG.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050987
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  • 9
    Electronic Resource
    Electronic Resource
    Clinical pharmacology of the biological response modifier maleic anhydride divinyl ether copolymer (MVE-2) (1986)
    Springer
    Cancer chemotherapy and pharmacology 18 (1986), S. 243-246 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The anionic pyran copolymers represent a novel class of high molecular weight biological response modifiers with antitumor activity. Clinical pharmacology studies were performed on MVE-2, a polymer with an average molecular weight of 15.5 Kd. MVE-2 was analyzed in plasma and urine by HPLC. In addition, pharmacology studies were also performed using [14C] labeled MVE-2. The clearance of unlabeled MVE-2 from plasma was monophasic and the t1/2 for MVE-2 was extremely short (between 10 and 26 min). The apparent volume of distribution (Vd) varied from 12–18 l. Both the t1/2 and the Vd did not appear to be dose-dependent. The plasma clearance for [14C] labeled MVE-2 was studied in seven patients. The clearance of [14C] labeled MVE-2 fit a biphasic mathematical model. The alpha phase half-life was between 11 and 18 min while the beta phase half-life was between 70 and 85 min. Urinary excretion for either unlabeled drug or the [14C] label was between 30 and 45% of the administered dose. These studies show that, in man, the polyanionic macromolecule MVE-2 is cleared rapidly from plasma and excreted extensively in urine.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00273395
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  • 10
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and tissue disposition of the biological response modifier BAY i 7433 (copovithane) in patients with cancer (1986)
    Springer
    Cancer chemotherapy and pharmacology 18 (1986), S. 247-251 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Copovithane is an uncharged, water-soluble, synthetic polymer with an average molecular weight of 5800 daltons. It demonstrates antitumor activity in vivo against a variety of tumors in animal models but is inactive in vitro. This agent has been found to have immunorestorative activity in man. In concert with its phase I clinical trial, copovithane concentrations were analyzed by HPLC in plasma, urine, and autopsy and in tumor biopsy specimens obtained from patients. Copovithane was cleared from plasma biphasically with a mean t1/2α of 11.1±4 min and a t1/2β of 246±78 min at the dose of 1 g/m2, while the plasma half-lives increased to 57.7±12 and 718±149 for the alpha and beta phases, respectively, at the 10 g/m2 dose, demonstrating clear, dose-dependent pharmacokinetics. There were no significant differences between dose 1 and dose 4 pharmacokinetics. The apparent volume of distribution (Vd) was 14.5±1. at the 1 g/m2 dose and increased to 73 1. at the 33 g/m2 dose. The calculated mean clearance rate for copovithane in plasma was between 2.4 and 5.4 mg/kg x min and did not appear to be dose-dependent. The urinary excretion of copovithane was approximately 5% of the administered dose over 120 h at the 1 g/m2 dose and decreased to 1% at the 33 g/m2 dose. In seven tumor biopsy samples, concentrations of drug in tumor varied from 1- to 1000-fold higher than that found in concurrent plasma samples. In three autopsy samples, the highest concentrations were found in kidney, intestine, and liver, in decreasing order. These studies show that copovithane exhibits dose-dependent changes in pharmacokinetics at doses between 1 and 33 g/m2. However, copovithane does penetrate well to tumor tissues, achieving high tumor/plasma ratios. In addition, copovithane concentrations were highest in kidney tissue, which may be a site for potential organ toxicity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00273396
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