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1.
Effects of leflunomide on immune responses and models of inflammation 总被引:11,自引:0,他引:11
Robert R. Bartlett Hristo Anagnostopulos Thomas Zielinski Thomas Mattar Rudolph Schleyerbach 《Springer Seminars in Immunopathology》1993,14(4):381-394
Conclusions Leflunomide is an antiphlogistic and immunomodulating agent that has been shown to be effective in preventing and healing autoimmune disorders and reactions leading to organ graft rejection. From our preliminary clinical data [4], we now have hopes that these effects, observed in experimental animals, can truly be transferred to humans.Although we are far from understanding the mode of action of leflunomide, we are slowly gathering some insight. A good many of the immunosuppressive effects of leflunomide can be attributed to the antagonistic effects it has on responses to many cytokines, most likely through receptor expression and signal transduction (tyrosine kinase inhibition). The inhibition of transplant rejection could be explained by interference with the activity of IL-2 and IL-4, i.e. the interference of cytotoxic T cell formation. Considering, further, that increased IL-3-like activity has been reported in autoimmune MRL/lpr mice [23], and that it is felt that this amplified activity may contribute to the pathology of their illness [23], then the interference of leflunomide with IL-3 may, together with the antagonistic activity of TRF and specifically IL-4, explain some of the disease modifying properties of this drug in animals with SLE-like and other autoimmune diseases. Also, interference with responses to IL-6 (Germann, personal communication) could be responsible for the suppression of acute-phase proteins observed in adjuvant-diseased rats [24].Our data concerning tyrosine kinase inhibition as a hypothetical mechanism for the non-cytotoxic and reversible antiproliferative activity of A77 1726 are in many ways, intriguing. First of all, many known receptors for growth factors are associated with tyrosine kinase, i.e. EGF [35], IL-2 (the high binding, 75 kDa chain) [21], IL-3 [26], G-CSF, GM-CSF and TNF- [9]. Leflunomide antagonizes all of these mediators. On the other hand, IL-1, which is not antagonized by leflunomide, is not associated with tyrosine kinase, but with threonine and serine kinase [11]. Much more work must be conducted before we can be sure that tyrosine kinase inhibition is important for the mode of action of leflunomide.Another important aspect of this drug is its inhibitory effect on the release of histamine from basophils and mast cells, because of its role in inflammatory reactions. Relating to our findings on the activity of leflunomide on murine SLE-like disorders, it has been reported recently that SLE patients often exhibit abnormal production of antibodies to IgE, and that these autoantibodies may, by activating mast cells and basophils, play a consequential part in the release of vasoactive amines, thus leading to generalized tissue injury [15].We are confident that leflunomide will prove to be an effective drug in combating human autoimmune disorders. Indeed, we already have preliminary evidence for this, from studies of its effects on humans suffering from autoimmune diseases. Moreover, this drug provides a tool for gaining new insights into both the mechanisms leading to such ailments and their therapeutic control, and as such may facilitate the discovery of even more proficient drugs or other means to modulate these malfunctioning immune reactions. 相似文献
2.
The increased glycation of elastin is an important factor in vascular changes in diabetes. Using the ELISA method, we determined serum levels of IgM and IgG autoantibodies to advanced glycation end products of vascular elastin (anti-AGE EL IgM and anti-AGE EL IgG) in 59 hypertensive patients with type 2 diabetes (T2D) and 20 healthy controls. Serum levels of matrix metalloproteinases-2 and -9 (MMP-2 and MMP-9) and the C-reactive protein (CRP) were also determined. The levels of anti-AGE EL IgM antibodies in the T2D group were similar to those in the control group, while those of anti-AGE EL IgG antibodies were significantly higher (p = 0.017). Significant positive correlations were found between the levels of anti-AGE EL IgM antibodies and MMP-2 (r = 0.322; p = 0.013) and between the levels of anti-AGE EL IgG antibodies and CRP (r = 0.265; p = 0.042). Our study showed that elevated anti-AGE EL IgG antibody levels may be an indicator of the enhanced AGE-modification and inflammatory-mediated destruction of vascular elastin in hypertensive patients with T2D. Anti-AGE EL IgM antibodies may reflect changes in vascular MMP-2 activity, and their elevated levels may be a sign of early vascular damage. 相似文献
3.
Hristo Svilenov Lorenzo Gentiluomo Wolfgang Friess Dierk Roessner Gerhard Winter 《Journal of pharmaceutical sciences》2018,107(12):3007-3013
The early-stage assessment of the physical stability of new monoclonal antibodies in different formulations is often based on high-throughput techniques that suffer from various drawbacks. Accordingly, new approaches that facilitate the protein formulation development can be of high value to the industry. In this study, a dynamic light scattering plate reader is used to measure the aggregation (by means of the increase in the hydrodynamic radius [Rh]) of monoclonal antibody samples that were subject to incubation and subsequent dilution from different concentrations of a denaturing agent, that is, guanidine hydrochloride. The increase in the Rh of the protein samples is dependent not only on the denaturant concentration used but also on the buffer in which the incubation/dilution was performed. We also compare the aggregation after dilution from a denaturant with other high-throughput stability-indicating methods and find good agreement between the techniques. The proposed approach to probe the physical stability of monoclonal antibodies in different formulation conditions offers a unique combination of features—it is isothermal, probes both the resistance to denaturant-induced unfolding and the colloidal protein stability, it is entirely label-free, does not rely on complex data evaluation, and requires very short instrument measurement time on standard equipment. 相似文献
4.
Matteo Brucoli Paolo Boffano Irene Romeo Chiara Corio Arnaldo Benech Muhammad Ruslin Tymour Forouzanfar Thomas Starch‐Jensen Tanía Rodríguez‐Santamarta Juan Carlos de Vicente Johanna Snll Hanna Thorn Marko Tarle Emil Dediol Petia Pechalova Nikolai Pavlov Hristo Daskalov Iva Doykova Kadri Kelemith Tiia Tamme Andrey Kopchak Ievgen Shumynskyi Pierre Corre Helios Bertin Quentin Goguet Marine Anquetil Aurlien Louvrier Christophe Meyer Tadej Dovak David Vozli
Ane Birk Boban Ani
i Vitomir S. Konstantinovic 《Dental traumatology》2020,36(3):241-246
5.
Kajetan Klos Christoph H. Wilde Antje Lange Andreas Wagner Florian Gras Hristo Kostov Skulev Thomas Mückley Paul Simons 《Foot and Ankle Surgery》2013,19(4):239-244
BackgroundTMT-1 arthrodesis is an established method in hallux valgus surgery, but it is technically demanding and typically calls for a period of postoperative immobilization.MethodsIn this cohort study, initial experience with a plantar plate is described. 58 patients (59 arthrodesis) were included.ResultsThe mean duration of protected full weight bearing was 7 weeks. 94.12% patients were satisfied with the results, bony union was achieved in 98.31%. The Foot Function Index improved by 33 to a mean of 8 (p < .001). The postoperative Mayo Clinic Forefoot Score was excellent in 47.04 and good in 47.04%. The mean hallux valgus angle improved by 24.4–13.2° (p < .001). The mean first intermetatarsal angle improved by 11.2–5.2° (p < .001).ConclusionInitial experience with this form of fixation appears to provide suitable stability, allow early-protected weight bearing, with an acceptable level of complications. 相似文献
6.
Martina Hujslová Alena Kubátová Martin Kostovčík Miroslav Kolařík 《Fungal Diversity》2013,58(1):33-45
Extremely acidic soils (pH?<?3) harbour mycobiota that are different from less acidic habitats and are dominated by a small number of fungal species. During investigation of the mycobiota of highly acidic soils in the Czech Republic and Iceland, a group of melanised fungal isolates was obtained. Based on phenotype and nuclear ribosomal DNA sequences (ITS region, SSU, LSU), the isolates were accommodated by three phylogenetic lineages within the family Teratosphaeriaceae (Capnodiales, Dothideomycetes). The first lineage is here described as a new acidotolerant genus and species Acidiella bohemica gen. nov. et sp. nov. The most closely related species to this new clade are other extremotolerant fungi isolated from rocks and lichens collected in the Alps and Antarctica as well as leaf-spotting species and opportunistic human pathogens. The isolates belonging to the second and the third lineages were identified as the recently described acidophilic fungi Acidomyces acidophilus and Teratosphaeria acidotherma, respectively. The taxonomic status of both sister species is discussed and the latter species is ascribed here to the genus Acidomyces. 相似文献
7.
Ivan Lyutakov Radislav Nakov Hristo Valkov Rositsa Vatcheva-Dobrevska Borislav Vladimirov Plamen Penchev 《The Turkish journal of gastroenterology》2021,32(4):374
BackgroundIn chronic diarrhea patients, massive over-reporting symptom-based criteria for functional bowel disorders are pitfalls. There is currently no objective biomarker that may provide a correct correlation with the severity of chronic diarrhea. To clarify the role of fibroblast growth factor-19 (FGF-19) as a biomarker of objective measurements of the severity of diarrhea in comparison with a patient-reported outcome, based on the Bristol Stool Form (BSF) Scale.MethodsConsecutive 100 patients with chronic diarrhea underwent standard investigations with laboratory tests, fecal calprotectin (FC), endoscopy with biopsies, and serum FGF-19. All patients and 14 healthy controls completed a diary recording, BSF, and stool frequency. ResultsWe found that irritable bowel syndrome with diarrhea (IBS-D) n = 21/23 (91%) reported a high number on BSF ≥6, compared to patients with inflammatory bowel diseases (IBD) 56/77 (72%) with BSF ≥ 6 (P = .011). FGF-19 median serum levels were significantly lower in Microscopic colitis (0.010 pg/mL) and IBD patients (0.009 pg/mL) compare to IBS-D (266.9 pg/mL) and high levels in healthy subjects (463 pg/mL) (P < .001). Strong inverse correlation of FGF-19 with the stool frequency/day and stool index was found (r = −0.800, P < .001; r = −0.739, P < .001), independently from disease activity (r = −0.718, P = .001; r = −0.792, P = .001).ConclusionSerum FGF-19 can become a new biomarker for evaluating the severity of diarrhea with objectively and independently from intestinal inflammation. FC and FGF-19 are predictive biomarkers for the organic cause of diarrhea. 相似文献
8.
Stojanović M Jeremic M Stojanović P Stojiljković M Gmijović D Stanojković Z Savić V Djordjević V Cvetković Z Kostov M Colović R 《Acta chirurgica Iugoslavica》2002,49(1):39-45
The aim of this study was to test the protective effects of fibrin sealing on the pancreatico-jejunostomy (PJA), the high-risk anastomosis following pancreas head resection. Experimental study was performed on the mongrel dogs, divided in two groups (20 animals each): Experimental group-with end to end "dunking" PJA, protected by temporary occlusion of the pancreatic duct with fibrin sealant/Tissucol/Immuno Ag/, while control group was without any protective procedure. The animals were followed 5 months in order to study: protective effects of such procedure on the PJA quantified with the percent of anastomotic leakage, effects of the exocrine secretion and effects the endocrine function Results: PJA leakage occurred in 13.33% in control group. No leakage was registered in experimental group. Biochemical, histological and electron microscopic study showed slight transitory elevation of amylase levels. Fibrin glue plug was dissolved and pancreatic juice output was reestablished 12th days postoperatively. Long term follow-up showed no damages of the endocrine and exocrine pancreas. Pancreatic duct occlusion with fibrin glue appeared to be an useful method in the prevention of pancreatico-jejunostomy leakage, without negative effects on the exocrine and endocrine pancreas. 相似文献
9.
Training models are needed to perform accurate off-pump coronary artery bypass (OPCAB) surgery and to test evolving new technologies like minimally invasive devices and robotics. We describe a simple, effective and reproducible live animal training model to perform multiple arterial anastomoses on the beating heart that would maximize the use of available resources for training purposes. 相似文献
10.
Dextrocardia is a rare condition not spared by coronary artery disease. We report the case of a 72-year-old patient with dextrocardia associated with situs inversus totalis who presented to our Institution with acute myocardial infarction complicated by congestive heart failure. Due to the severe general conditions of the patient, an emergent off-pump complete myocardial revascularization was undertaken. The patient tolerated the procedure well and was asymptomatic at discharge. The technical aspects encountered in the setting of mirror-image anatomy and the advantages of off-pump myocardial revascularization in the critically ill patient are discussed. 相似文献