摘要:

Current treatment modalities available for hepatitis B virus (HBV) or hepatitis C virus (HCV) infections are not efficient. The enormous disease burden caused by these two infections makes the development of novel therapies critical. For HCV, the development of an effective vaccine is urgent in view of the escalating number of infected individuals. Molecular therapies for HBV and HCV infection can be directed at reducing viral load by interfering with the life cycle of the viruses or at generating immune response against viral epitopes. The antiviral approaches consist of the delivery or expression of antisense RNAs, ribozymes or dominant negative proteins. Viral biology can be interrupted by attacking various potential targets within the two viruses. DNA-based vaccination strategies are being explored for both prevention and treatment of these diseases. Both non-viral and recombinant viral vectors are being developed for safe, effective and long-term gene transfer to the liver. Although no ‘ideal’ vector is available at this time, the ingenuity of numerous investigators is leading to the improvement of the vector systems, promising successful application of gene therapy to the prevention and treatment of viral hepatitis in the foreseeable future.

ISSN:1173-8804    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

Although the insulinotropic actions of gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) have been known for almost 2 decades, the incretin hormones have not yet become available for clinical application. This can be explained by their unfavourable pharmacological properties. Both hormones are rapidly inactivated by the enzyme dipeptidyl peptidase IV (DPP IV), yielding biologically inactive fragments. There have been several attempts to make use of the antidiabetogenic potential of the incretin hormones. Various analogues of GLP-1 and GIP have been generated in order to achieve resistance to DPP IV degradation. The natural GLP-1 receptor agonist exendin-4, found in the saliva of the Gila monster, has a longer biological half-life after subcutaneous injection than GLP-1, and inhibition of DPP IV using, for example, pyrrolidine derivatives provides elevated concentrations of intact, biologically active GIP and GLP-1 endogenously released from the gut. A continuous intravenous infusion of native GLP-1 for a limited time may be suitable in certain clinical situations. Numerous clinical studies are currently underway to evaluate these approaches. Therefore, an antidiabetic treatment based on incretin hormones may become available within the next 5 years.

ISSN:1173-8804    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

Dendritic cells (DC), as potent antigen-presenting cells (APC), constitute a complex system of cells that initiate and regulate immune responses that result in two opposite outcomes: immunity or tolerance. The fine regulation of these two distinct functions is not completely understood. After loading with antigen, DC exhibit the properties of both antigen and adjuvant, the functional components of vaccines. For a long time, attention has focused on the exceptional ability of DC as professional APC capable of eliciting T and B cell-mediated responses, and on their potential as immunotherapy in cancer. DC exhibit both heterogeneity and plasticity. On the one hand, distinct DC subsets exhibit distinct functions. On the other hand, DC functions can be altered by the cytokine environment or other factors. There is increasing evidence that DC could be used as a tool to induce peripheral tolerance. Because DC-based immunotherapy in autoimmune diseases depends on tolerogenic DC, discerning markers for tolerogenic DC is of great importance. Immature DC, plasmacytoid DC and interleukin-10-modified DC can mediate immune tolerance by inducing T-cell anergy or T-helper type 2 responses. Several possibilities exist for rational modulation of DC to achieve therapeutic tolerance against autoimmune diseases. The final goal is to create optimal prerequisites to use autologous DC that are prepared from the individual patient with autoimmune disease, to render such DC tolerogenic by exposurein vitroto factors that promote tolerogenicity, and to re-infuse these pretreated DC to the patient in order to treat the ongoing autoimmune disease and prevent its future exacerbation.

ISSN:1173-8804    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

Asthma is an inflammatory disease of the airways, which in patients with mild to moderate symptoms is adequately controlled by either β2-adrenoceptor agonists or corticosteroids, or a combination of both. Despite this, there are classes of patients that fail to respond to these treatments. In addition, there is a general trend towards increasing morbidity and mortality due to asthma, which suggests that there is a need for new and improved treatments. The p38 mitogen-activated protein kinases (MAPKs) represent a point of convergence for multiple signalling processes that are activated in inflammation and that impact on a diverse range of events that are important in inflammation. Small molecule pyridinyl imidazole inhibitors of p38 MAPK have proved to be highly effective in reducing various parameters of inflammation, in particular cytokine expression. Like corticosteroids, inhibitors of p38 MAPK appear to be able to repress gene expression at multiple levels, for example, by transcriptional, posttranscriptional and translational repression, and this raises the possibility of a similarly broad spectrum of anti-inflammatory activities. Indeed these molecules have proved to be effective in numerousin vitroandin vivomodels of inflammation and septicaemia, which suggests that such compounds may be effective as therapeutic agents against inflammatory disorders. Despite these very promising indications of the possible therapeutic use of p38 MAPK inhibitors, a number of events that are p38-dependent are in fact also beneficial to the resolution or modulation of diseases such as asthma. We conclude that the overall effect of p38 MAPK inhibition would be beneficial in inflammatory diseases such as rheumatoid arthritis and asthma. However, these drugs may result in a complex phenotype that will require careful evaluation. Currently, a number of second or third generation inhibitors of p38 MAPK are being tested in phase I and phase II clinical trials.

ISSN:1173-8804    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

The absence of curative therapies for advanced or recurrent forms of prostate cancer has prompted a vigorous search for novel treatment strategies. Immunotherapy encompasses one particularly promising systemic approach to the treatment of prostate cancer. Immune-based strategies for treating prostate cancer have recently been facilitated by the identification of a number of prostate tissue/tumour antigens that can be targeted, either by antibody or T cells, to promote prostate tumour cell injury or death. These same prostate antigens can also be used for the construction of vaccines to induce prostate-specific T cell-mediated immunity. Greater insight into specific mechanisms that govern antigen-specific T cell activation has brought with it a number of innovative methods to induce and enhance T cell-mediated responses against prostate tumours. For instance, autologous dendritic cells loaded with prostate antigens have proved useful to induce prostate-specific T cell activation. Similarly,in vivomanipulations of T cell costimulatory pathway receptors can greatly facilitate tumour-specific T cell activation and potentiate T cell-mediated responses against a number of malignancies, including prostate cancer. For example, blocking T cell cytotoxic lymphocyte-associated antigen 4 (CTLA-4) receptor binding to its ligand prevents the down-regulation of T cell responses and can even potentiate T cell antitumoural immunity in mouse models of prostate cancer. Androgen ablation (AA) may induce prostate tumour/tissue-specific T cell mediated inflammation and, as such, a phase II trial is currently in progress to ascertain whether CTLA-4 blockade can enhance AA-induced treatment responses in patients with advanced prostate cancer. Nevertheless, further basic and clinical investigation is still required to establish immunotherapy as a true prostate cancer treatment option.

ISSN:1173-8804    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

Etanercept (Enbrel®2) is a subcutaneously administered biological response modifier that binds and inactivates tumour necrosis factor-α, a proinflammatory cytokine.In patients with early active rheumatoid arthritis, etanercept 25mg twice weekly was associated with a more rapid improvement in disease activity and a significantly greater cumulative response than methotrexate over 12 months of treatment in a randomised, double-blind trial. In addition, etanercept recipients showed a slower rate of radiographic progression and a more rapid improvement in quality of life than methotrexate recipients. The efficacy of etanercept was maintained at 3 years' follow-up.Etanercept was also significantly better than placebo at reducing disease activity in patients who had an inadequate response to previous treatment with disease-modifying antirheumatic drugs (DMARDs) in several well controlled trials. At study end (after 3 or 6 months' treatment), the percentage of patients achieving an American College of Rheumatology 20% (ACR20) response with etanercept (25mg or 16 mg/m2twice weekly) was 59−75% as monotherapy and 71% in combination with methotrexate; corresponding placebo response rates were 11−14% and 27%, respectively. Response has been maintained in patients who continued treatment for up to 5 years.In patients with psoriatic arthritis, etanercept 25mg twice weekly significantly reduced disease activity and improved skin lesions in two double-blind, placebo-controlled, 12- to 24-week trials. In the 24-week study, ACR20 response rates (50 vs 13%), psoriatic arthritis response rates (70 vs 23%) and the median improvement in skin lesions (33 vs 0%) were significantly greater in etanercept than in placebo recipients.In patients with polyarticular-course juvenile rheumatoid arthritis, etanercept resulted in improvements in all measures of disease activity and was significantly more effective than placebo at reducing disease flare. Eighty percent of patients receiving etanercept achieved a ≥30% reduction in disease activity over 7 months of treatment, and this was maintained for up to 2 years in a trial extension.Etanercept was generally well tolerated in children and adults in clinical trials; the most commonly occurring adverse effects included injection site reactions, infection, headache, rhinitis and dizziness.In conclusion,etanercept has emerged as an important new treatment option in inflammatory arthritis. Etanercept provides rapid and sustained improvements in disease activity in patients with early and DMARD-refractory rheumatoid arthritis and has been shown to inhibit radiographic progression in those with early disease. Well controlled studies have also demonstrated the efficacy of etanercept in patients with psoriatic arthritis or polyarticular-course juvenile rheumatoid arthritis.

ISSN:1173-8804    

出版商:ADIS    

年代:2003

数据来源: ADIS