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ABSTRACT: The subtype of the proliferating cells in the synovial fluid of patients with rheumatoid arthritis (RA), ankylopoietic spondylarthrosis (SPA), and osteoarthritis (OA) was studied with auto-radiography-immunoperoxidase double staining. Of all spontaneously proliferating synovial fluid cells in chronic arthritis, 59±4% displayed T8 differentiation marker, whereas T4 (21±4%) and B (2±1%) cells were few. Of all T4+ and all T8+ lymphocytes, 0.55±0.1% and 0.90±0.1%, respectively, incorporated [3H]thymidine. The [3H]thymidine labelling index for B cells was 0.30±0.1%. This was in contrast to OA, in which no proliferating lymphocytes were observed in the synovial fluid. Our findings suggest that the predominance of proliferating T8+ cells in the synovial fluid reflects an underlying chronic inflammation. Because RA and SPA synovium is a site of intense immunoglobulin production, our finding of the predominance of activated, proliferating T8+ cells may also reflect a dissociation between phenotype and function as a reason for the chronicity of the joint inflammation.
Scandinavian Journal of Immunology 06/2006; 22(4):383 - 388. · 2.23 Impact Factor
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ABSTRACT: Colon-specific drug-delivery systems have been extensively investigated over the last decade. The aim of the study reported here was to investigate whether times of commencement of drug liberation and absorption could be controlled by varying the amount of citric acid in granule cores or in the tablet matrix in enteric-coated multiple-unit tablets. One of the most important aims was to determine the optimal amounts and locations of citric acid in formulations intended as drugs targeted at the colon. Ibuprofen was used as the model drug. Drug release rates were studied in phosphate buffer at pH 6.8 and 7.4. A gradient dissolution study at pH 1.2, 6.8 and 7.4 was undertaken with two formulations. Drug absorption was studied by means of bioavailability tests. We concluded that the drug release rate could be controlled in vitro by changing the amount of citric acid in granule cores or the tablet matrix. In vivo tests confirmed that between 10 and 15% citric acid in the tablet matrix delayed the commencement of drug absorption most. This kind of formulations could be suitable for preparation of colon-specific dosage forms. It is probably unnecessary to include citric acid in granule cores. No logical correlation between in vitro and in vivo results was obtained.
Pharmazie 05/2004; 59(4):268-73. · 1.01 Impact Factor
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ABSTRACT: Delivery of drugs to the large bowel has been extensively investigated during the last decade. The aim of this study was to investigate whether enteric-coated tablets could be made from enteric-coated matrix granules and drug release targeted to the colon. Whether in vitro drug release rate and in vivo absorption could be delayed by adding citric acid to the granules and/or to the tablet matrix was also studied. Ibuprofen was used as model drug because it is absorbed throughout the gastrointestinal tract. Eudragit S and Aqoat AS-HF were used as enteric polymers. Drug release rates were studied at different pH levels and drug absorption was studied in bioavailability tests. The conclusion was that citric acid retarded in vitro drug release when used in multiple-unit tablets. In vivo absorption of ibuprofen was markedly delayed when citric acid was included in both granules and tablet matrix. Further studies are needed to determine the optimal amount of citric acid in formulations.
International Journal of Pharmaceutics 11/2001; 229(1-2):155-62. · 3.35 Impact Factor
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ABSTRACT: Interest exists in developing site-specific systems for release of a drug in the lower part of the small intestine or in the colon. The aim of this study was to investigate whether drug release rates from enteric matrix granules could be influenced by using organic acids as excipients. Ibuprofen was used as a model drug and Eudragit S and Aqoat AS-HF as enteric polymers. The dissolution rates of the drug were investigated at different levels of pH (5.8, 6.8 and 7. 4). Drug absorption was studied in bioavailability tests in healthy volunteers. In vitro/in vivo correlation was also investigated. It was concluded that although inclusion of an organic acid in a formulation retarded in vitro release of the model drug, no corresponding effect was evident in in vivo studies. Bioavailability tests are therefore important early on during development of new dosage forms or formulations. Although no correlation between in vitro and in vivo results was generally evident correlation could be demonstrated for individual formulations following mathematical transformation of data.
International Journal of Pharmaceutics 08/1999; 184(2):251-61. · 3.35 Impact Factor
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ABSTRACT: The aim of this study was to develop a multiple-unit, site-specific drug formulation allowing targeting of drug release in the colon. Initially, characteristics of matrix pellets containing various enteric polymers as binders were tested. An enteric coating was then added to the formulations. Ibuprofen and furosemide were used as model drugs. The former is absorbed throughout the gastrointestinal tract, the latter only from upper parts. Methacrylate copolymers, hydroxypropyl methylcellulose acetate succinates and cellulose acetate phthalate were used as enteric polymers. The properties of the products were initially tested via dissolution studies at different pHs, then via bioavailability studies in healthy volunteers. The main conclusion was that drug release can be targeted on the distal part of the small intestine and the colon by preparing film-coated matrix pellets in which enteric polymers dissolving at pH approximately 7 have been used both as binders in the pellets and as coating material. This conclusion is based on the finding that absorption of ibuprofen from the formulations developed was adequate, with a lag-time of about 2 h and tmax values at 4-5 h, where as absorption of furosemide from the analogous products was negligible. It was also found that uncoated pellets as such could represent a slow-release formulation for furosemide, a problem drug as far as modified-release products are concerned.
European Journal of Pharmaceutical Sciences 03/1999; 7(3):259-67. · 3.21 Impact Factor
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ABSTRACT: DNA synthesis in prolyl 4-hydroxylase (PH; EC 1.14.11.2) positive fibroblasts in situ in synovial tissue was studied using an autoradiography-avidin-biotin-peroxidase complex (ABC) double labeling. Fibroblasts in monolayer culture and in situ in synovial tissue were PH positive, whereas freshly isolated peripheral blood lymphocytes, monocytes, dendritic cells and granulocytes were PH negative. In rheumatoid arthritis (RA) 37 +/- 3 (22-56)% of all DNA synthesizing cells in situ were PH containing fibroblasts, whereas all DNA synthesizing cells in patients with meniscus lesion were PH positive. In both conditions, more than half of the self-replicating fibroblasts were located in the lining cell layer. This is probably not an artifact caused by insufficient penetration of 3H-thymidine because most of the DNA synthesizing lymphocytes were deep down in the synovial stroma. In RA 51 +/- 8 (17-88) PH positive fibroblasts in the S phase of the cell cycle were observed/3 mm2 synovial tissue, whereas the corresponding figure in meniscus patients was only 1 +/- 1 (0-5) (p less than 0.01). This suggests that the local fibroblasts in RA are activated, probably as a result of various fibroblast growth factors produced locally as a result of the inflammatory synovitis. In RA however, less than 1% of all local fibroblasts were self-replicating in situ, whereas labeling indices over 5% were not uncommon in RA synovial fibroblast cultures. This finding suggests that uncontrolled fibroblast proliferation is regulated in vivo by negative feedback mechanisms.
The Journal of Rheumatology 04/1989; 16(3):339-45. · 3.69 Impact Factor
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ABSTRACT: Chronic synovitis refers to fibrin deposits on the surface of proliferating superficial synovial lining cells leading to villous hyperthrophy, and associated with foci of cell necrosis and infiltration of chronic inflammatory cells. The superficial synovial lining cells include fibroblast-like type B cells and macrophage-like type A cells. Fibroblast- and macrophage-like cells in the early or leading edge of pannus may represent an extension of these cells, which themselves may be nothing else than stromal fibroblasts and macrophages adapted to the particular micro-milieu prevailing at the interface of hyaluronate (HA) containing synovial fluid and richly vascularized loose connective tissue in the sublining stroma. In all three locations fibroblasts are exposed to various humoral substances, extracellular matrix (ECM) and cell-cell contacts, which may modify their phenotype and function. Therefore, one would expect differences in the fibroblasts in inflammatory and non-inflammatory synovial tissue. These changes can be best understood by considering some of the basic fibroblast properties, namely migration, substrate adherence, proliferation and synthesis and degradation of ECM.
Scandinavian journal of rheumatology. Supplement 02/1988; 76:95-103.
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ABSTRACT: Tritiated-thymidine incorporating cells in synovial tissue samples from ten patients with definite or classic rheumatoid arthritis (RA) were studied by combining two techniques. Tritiated-thymidine-labelled cells were seen in autoradiography and simultaneously the subtype of them was determined with immunoperoxidase staining using monoclonal antibodies. Tritiated-thymidine-labelled cells comprised 0.8 +/- 0.4% of all the inflammatory cells in RA synovial membrane. Of all 3H-thymidine-labelled cells 34 +/- 17% were positive for OKT8 and 19 +/- 8% for OKT4 monoclonal antibodies. OKM1-positive cells comprised 7 +/- 3% of all 3H-thymidine labelled cells, whereas only a few (3 +/- 4%) of them were positive for pan-B monoclonal antibody. This study emphasizes the importance of activated OKT8 lymphocytes in RA synovial membrane.
Rheumatology International 02/1986; 6(6):269-71. · 1.88 Impact Factor
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ABSTRACT: Monoclonal antibodies were used in avidin-biotin-peroxidase complex staining for activation marker analysis of rheumatoid synovial fluid cells. Although Ia expression indicates T cell activation, cells displaying receptors for interleukin 2 (Tac)-and transferrin receptor (T9)- positive proliferating cells were relatively few. Similarly, activated terminal effector cells of suppressor/cytotoxic nature were scarce in rheumatoid synovial fluid, as suggested by a low expression of Tac and 4F2 markers. The in vivo situation in the rheumatoid arthritic (RA) joint does not seem to be due to the inability of synovial fluid lymphocytes to become activated, because mitogen stimulation in vitro, in spite of a low proliferative response, induced expression of all the activation markers studied. The relevance of the present observations to the down-regulation of the active, inflammatory-immune response in situ is speculative, but the data show that in spite of T-cell activation and Ia expression, activated terminal effector cells of suppressor/cytotoxic nature are few in the RA joint in vivo.
Scandinavian Journal of Immunology 12/1985; 22(5):503-7. · 2.23 Impact Factor
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ABSTRACT: The subtype of the proliferating cells in the synovial fluid of patients with rheumatoid arthritis (RA), ankylopoietic spondylarthrosis (SPA), and osteoarthritis (OA) was studied with autoradiography-immunoperoxidase double staining. Of all spontaneously proliferating synovial fluid cells in chronic arthritis, 59 +/- 4% displayed T8 differentiation marker, whereas T4 (21 +/- 4%) and B (2 +/- 1%) cells were few. Of all T4+ and all T8+ lymphocytes, 0.55 +/- 0.1% and 0.90 +/- 0.1%, respectively, incorporated [3H]thymidine. The [3H]thymidine labelling index for B cells was 0.30 +/- 0.1%. This was in contrast to OA, in which no proliferating lymphocytes were observed in the synovial fluid. Our findings suggest that the predominance of proliferating T8+ cells in the synovial fluid reflects an underlying chronic inflammation. Because RA and SPA synovium is a site of intense immunoglobulin production, our finding of the predominance of activated, proliferating T8+ cells may also reflect a dissociation between phenotype and function as a reason for the chronicity of the joint inflammation.
Scandinavian Journal of Immunology 11/1985; 22(4):383-8. · 2.23 Impact Factor
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L M Virkki,
Y T Konttinen,
R Peltomaa,
K Suontama,
R Saario,
K Immonen,
J Jäntti,
T Tuomiranta, P Nykänen,
R Hämeenkorpi,
S Heikkilä,
P Isomäki,
D Nordström
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ABSTRACT: We evaluated the cost-effectiveness of infliximab therapy in Finnish RA patients in a real-life clinical setting and identified factors influencing it, using the national register of biological treatment (ROB-FIN).
A cost-utility analysis was performed, derived from EQ-5D, and related to HAQ score and disease activity using multiple regression. QALYs were calculated based on these utilities, using patient-level data up to the last control registered. Cost-effectiveness analyses included costs per ACR50 responder, and costs per low DAS28 score (<3.2) achieved, in combination with a clinically significant improvement (>1.2). The costs considered were direct medical costs of infliximab and cost of intravenous infusion. Patient-level costs were calculated based on dose and dosage frequency, and were related to the difference in QALYs resulting from infliximab therapy.
The 297 patients had been treated with infliximab for an average of 21 months. The HAQ score and patient's global assessment improved significantly on infliximab therapy. More than two-thirds of the patients achieved a clinically important improvement in HAQ. A QALY gain occurred in 76%. 35% of these had an incremental cost-effectiveness ratio of < or =40,000 Euro/QALY gained, the median cost being 51,884 Euro. The cost per QALY gained was significantly lower for patients achieving an ACR50 response at 3, 12 and 24 months.
Treatment with infliximab and aiming at ACR50 response appears cost-effective, remembering the restrictions of an observational study set up. Current Care guidelines, which require sufficient disease control when deciding on continuing biological therapy, get support from these findings.
Clinical and experimental rheumatology 26(6):1059-66. · 2.15 Impact Factor
