摘要:

Molecular therapy is emerging as a potential strategy for the treatment of cardiovascular disease such as restenosis after angioplasty, vascular bypass graft occlusion and transplant coronary vasculopathy, for which no known effective therapy exists. One strategy for combating disease has been to target the transcriptional and translational processes. Three approaches have been used to accomplish this. One approach is the use of antisense oligodeoxynucleotides (ODN) that are complimentary to the messenger RNA (mRNA) of interest. The second approach is the use of ribozymes, a unique class of RNA molecules that not only store information but also possess catalytic activity. Ribozymes are known to catalytically cleave specific target RNA species, leading to their degradation, whereas antisense molecules inhibit translation by binding to mRNA sequences on a stoichiometric basis. Thus, theoretically, ribozymes are more effective in inhibiting target-gene expression. A third approach is the transfection of cis-element double-stranded decoy ODN. Transfection of decoy ODN will result in attenuation of authentic cis-trans interaction, leading to the removal of trans-factors from the endogenous cis-elements, with subsequent modulation of gene expression. This novel decoy ODN strategy not only promises therapeutic potential but also represents a powerful tool for the study of endogenous gene regulationin vivoas well asin vitro. In particular, early work relating to graft restenosis appears promising. The application of DNA-based therapies to regulate the transcription of disease-related genesin vivohas important therapeutic potential.

ISSN:1173-8804    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

Bone grafting to achieve fusion is frequently performed in spinal surgery. Autograft is the gold standard bone graft material. However, due to limitations of supply and morbidity associated with the harvest of autograft, alternatives are being considered. Osteoconductive matrices, such as allograft, calcium or ceramic preparations are one such class of potential bone graft alternatives, but generally they lack osteoinductive properties. Recent attention has focused on osteoinductive materials such as demineralised bone matrix, recombinant bone morphogenetic proteins and bone marrow aspirates or blood product concentrates. These products may be combined with osteoconductive carriers and are clearly finding a place in the clinical arena.

ISSN:1173-8804    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

Crohn’s disease and ulcerative colitis are inflammatory bowel diseases (IBD) of unknown pathogenesis, for which no curative treatment is currently available. Although the recent introduction of agents designed to neutralise tumour necrosis factor has been an important achievement towards the control of Crohn’s disease, further development of more fundamental and non-toxic therapies is still required. One potential approach is the targeting of costimulatory membrane interactions between cells of the immune system. Costimulatory transmembrane ligands interact with receptors on target cells to enhance activation of the latter. Costimulatory interactions between antigen-presenting cells and T lymphocytes and between T lymphocytes and effector macrophages are of utmost importance for the activation of these cell types, which are all thought to be pivotal players in the immunopathology of IBD. Targeting these interactions with humanised monoclonal antibodies or soluble receptor fusion proteins is proposed as a potential new treatment modality of these often devastating pathologies. On the basis of experimental data, and in view of their essential role in the activation of antigen-presenting cells and T lymphocytes, the CD40/CD40 ligand and CD28/B7 interactions are likely to be the best targets for successful therapy.

ISSN:1173-8804    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

Due to the pivotal role of membrane proteins in many cellular processes, their direct link to human disease and their often extracellular accessibility towards drugs, an understanding of membrane protein function is desirable. However, the hydrophobic nature of membrane proteins often results in insoluble proteins which makes protein isolation difficult and therefore hinders the determination of protein complex composition and protein function. Recently, several yeast genetic techniques have made the characterisation of interactions among membrane proteins more feasible. Techniques such as the guanine-nucleotide binding protein fusion assay, the reverse Ras recruitment system and the split-ubiquitin system have been fruitful in monitoring known protein interactions and uncovering novel interactions. Since many disease states have altered membrane protein function, one can use these systems to recreate interactions involving disease causing membrane proteins. Once established, screens for small molecules, peptides and/or single chain antibodies which disrupt such interactions can provide insight into the biology of the interaction and thus help guide therapeutical research. In this review, we speculate on the feasibility of using inhibitors of protein interactions as drugs and the adaptation of these techniques to select for inhibitors of defined protein interactions.

ISSN:1173-8804    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

Tumour necrosis factor (TNF)-α is a potent cytokine involved in the inflammatory reactions of many acute and chronic diseases. Recently, agents that block TNFα either directly or indirectly have been successful in the treatment of a variety of immune-mediated inflammatory disorders including rheumatoid arthritis and Crohn's disease. Sarcoidosis is an immune-mediated inflammatory disorder characterised by the formation of granulomas. TNFα is important in the initiation and perpetuation of inflammation in sarcoidosis, contributing to the initiation of granulomas and the progression of fibrosis, as well as to nongranulomatous inflammation. Various agents used to treat sarcoidosis affect TNF, including the most widely used drug class, corticosteroids, which are usually effective in blocking TNFα release from cells. Other agents that nonspecifically inhibit TNFα release include methotrexate, azathioprine and pentoxifylline. Specific TNF-antagonising biological agents such as infliximab and etanercept are being tested in patients with sarcoidosis, with mixed success. Infliximab has been shown to produce clinical improvement and reduce the requirement for corticosteroids in a small number of patients with sarcoidosis. However, as infliximab can be associated with reactivation of tuberculosis, which could be mistaken as worsening sarcoidosis, it should be used with caution in this patient group.

ISSN:1173-8804    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

BackgroundThe differential tolerability profile of various interferon (IFN)-α preparations used in combination with ribavirin for the treatment of chronic hepatitis C needs to be elucidated. Approximately 8% of patients receiving recombinant IFNα-2b plus ribavirin discontinue treatment because of adverse events. Human leucocyte IFNα is deemed to have a better safety profile than recombinant IFNα. We therefore compared the safety profile and efficacy of ribavirin combined with leucocyte IFNα or with recombinant IFNα-2b in treatment-naive patients with chronic hepatitis C.Study designWe randomised 423 patients to either leucocyte IFNα 3MU three times weekly plus ribavirin (210 patients) or the same dose of recombinant IFNα-2b plus ribavirin (213 patients). Patients were treated for 24 weeks and followed-up for a further 48 weeks. The primary endpoint was the safety profile of the two therapies; the secondary endpoint was the rate of sustained response.ResultsIn patients receiving leucocyte IFNα, the total number of adverse events was lower than in the group receiving recombinant IFNα (259 vs 441 patients), and the percentage of patients discontinuing treatment because of adverse events or laboratory abnormalities was significantly reduced (4% vs 11%; p = 0.013). Sustained response was observed in 47% of patients receiving leucocyte IFNα plus ribavirin and in 44% of patients receiving IFNα-2b plus ribavirin.ConclusionsBoth therapeutic regimens were effective in inducing a sustained response in naive patients. However, the safety profile of leucocyte IFNα plus ribavirin was more favourable than that observed with the administration of recombinant IFNα-2b plus ribavirin, suggesting that leucocyte IFNα may be an alternative option in patients with reduced tolerability to other IFNs.

ISSN:1173-8804    

出版商:ADIS    

年代:2003

数据来源: ADIS