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  • DKFZ Publication Database  (4)
  • 1
    Keywords: CELLS ; IN-VITRO ; BLOOD ; CELL ; COMBINATION ; Germany ; MODEL ; THERAPY ; VITRO ; DRUG ; METABOLISM ; PATIENT ; MACROPHAGES ; murine ; CONTRAST ; treatment ; antibody ; TARGET ; NUMBER ; DELIVERY ; PHARMACOKINETICS ; DOUBLE-BLIND ; PERIPHERAL-BLOOD ; T lymphocytes ; MONONUCLEAR-CELLS ; METHOTREXATE ; COLLAGEN-INDUCED ARTHRITIS ; albumin ; DRUG-DELIVERY ; rheumatoid arthritis ; RHEUMATOID-ARTHRITIS ; II COLLAGEN ; LOW-DOSE METHOTREXATE ; PLACEBO-CONTROLLED TRIAL ; RHEUMATOID-ARTHRITIS PATIENTS
    Abstract: Objective. To evaluate the anti-arthritic effects of the new inflammation-targeted drug MTX-HSA and to investigate whether peripheral blood mononuclear cells (PBMC) are potential target cells for albumin-mediated drug delivery. Methods. The murine model of collagen-induced arthritis (CIA) was used to measure the anti-arthritic effect of MTX, MTX-HSA or a combination of both (n = 30 to 35 per group). In addition, the uptake of fluorescence-labelled albumin (AFLc-HSA) in PBMC of 14 patients with RA was measured by fluorescence-activated cell sorting (FACS). Results. In equivalent doses of 7.5 mg/kg intravenously (IV) twice a week, MTX-HSA is significantly (P〈0.02) superior to MTX in inhibiting the development of CIA and reducing the joint count as well as the number of affected paws. When given in lower doses as combination therapy, both drugs act synergistically (P〈0.03). A mean of 96, 72 and 64% of the CD14-, CD16- and CD20-positive cells from peripheral blood of rheumatoid arthritis (RA) patients showed an uptake of albumin after incubation with AFLc-HSA in vitro. This finding was not significantly different in comparison to healthy controls. In contrast, the number of CD3-positive cells taking up albumin is increased significantly in RA patients in comparison to controls (26.3 +/- 12.9% s.d. vs 11.6 +/- 7.3% s.d.; P = 0.005). Conclusion. The data show that the effectiveness of MTX-HSA in CIA is superior to MTX and that both drugs act synergistically. In addition, albumin appears to be taken up by peripheral blood cells, suggesting that they might be one of the potential target cells of this novel anti-arthritic treatment approach
    Type of Publication: Journal article published
    PubMed ID: 15199219
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  • 2
  • 3
    Keywords: CANCER ; CELLS ; EXPRESSION ; IN-VITRO ; tumor ; CLINICAL-TRIAL ; human ; IN-VIVO ; MODEL ; liver ; PROTEIN ; PROTEINS ; DRUG ; TISSUE ; TUMORS ; MICE ; PATIENT ; SERA ; fibroblasts ; treatment ; MOUSE ; EFFICACY ; drug delivery ; CONJUGATE ; PHARMACOKINETICS ; BEARING RATS ; COLLAGEN-INDUCED ARTHRITIS ; FIBROBLAST-LIKE SYNOVIOCYTES ; LOW- DOSE METHOTREXATE ; SYNOVIAL FIBROBLASTS
    Abstract: We reported recently that albumin is a suitable drug carrier for targeted delivery of methotrexate (MTX) to tumors. Due to pathophysiological conditions in neoplastic tissue, high amounts of albumin accumulate in tumors and are metabolized by malignant cells. MTX, covalently coupled to human serum albumin (MTX-HSA) for cancer treatment, is currently being evaluated in phase II clinical trials. Because synovium of patients with rheumatoid arthritis (RA) shares various features observed also in tumors, albumin-based drug targeting of inflamed joints might be an attractive therapeutic approach. Therefore, the pharmacokinetics of albumin and MTX in a mouse model of arthritis was examined. Additionally, uptake of albumin by synovial fibroblasts of RA patients and the efficacy of MTX and MTX-HSA in arthritic mice were studied. The results show that when compared with MTX, significantly higher amounts of albumin accumulate in inflamed paws, and significantly lower amounts of albumin are found in the liver and the kidneys. The protein is metabolized by human synovial fibroblasts in vitro and in vivo. MTX-HSA was significantly more effective in suppression of the onset of arthritis in mice than was MTX. In conclusion, albumin appears to be a suitable drug carrier in RA, most likely due to effects on synovial fibroblasts, which might increase therapeutic efficacy and reduce side effects of MTX
    Type of Publication: Journal article published
    PubMed ID: 12707361
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  • 4
    Keywords: INVASION ; Germany ; human ; IN-VIVO ; MODEL ; VIVO ; MICE ; GENE-TRANSFER ; REDUCTION ; INDUCTION ; CONTRAST ; fibroblasts ; treatment ; MOUSE ; score ; IMMUNODEFICIENT MICE ; DEGRADATION ; MOUSE MODEL ; METHOTREXATE ; BEARING RATS ; albumin ; fibroblast ; rheumatoid arthritis ; RHEUMATOID-ARTHRITIS ; CYTOKINE INHIBITORS ; DESTRUCTION ; INTERLEUKIN-1
    Abstract: Objective: To investigate the effect of methotrexate (MTX) and albumin coupled with methotrexate (MTX-HSA) on cartilage invasion and induction of perichondrocytic degradation by rheumatoid arthritis synovial fibroblasts ( RA SF) in vivo. Methods: Human cartilage and RA SF were co-transplanted in three groups of severe combined immunodeficient mice ( SCID), which received 1 mg/kg free MTX (n = 9), 1 mg/kg MTX-HSA ( n = 6), or 0.9% NaCl ( n = 5), respectively, intraperitoneally twice a week. After 4 weeks' treatment, the mice were killed and the implants analysed histologically. Results: The control group had a mean (SEM) score for cartilage invasion of RA SF of 2.0 (0.26) and for perichondrocytic cartilage degradation of 1.5 (0.34). In contrast, mice which received MTX showed a significantly reduced invasion (0.78 (0.14), p〈 0.01) and a reduction in perichondrocytic cartilage degradation scores (0.69 (0.2), p〈 0.05) in comparison with the control group. Mice treated with MTX-HSA also had significantly reduced scores for RA SF invasion into the cartilage (0.92 (0.41), p〈 0.05) and for cartilage degradation (0.83 (0.44), p〈 0.05) compared with controls. The effects of MTX and MTX-HSA were not significantly different between these two groups. Conclusion: Treatment with MTX or MTX-HSA significantly ameliorates cartilage destruction in the SCID mouse model for human RA
    Type of Publication: Journal article published
    PubMed ID: 15194591
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