摘要:

The feasibility of using adenoviruses for gene therapy has been under close scrutiny recently, as it has become clear that significant toxicity can result from the strong immune response created by intravenous administration of large doses of first generation adenovirus vectors. This suggests that other vectors could be more useful for treatment of metabolic and hereditary disease, where widespread transduction is often necessary for effective gene replacement, and the viability of target cells is important. However, promising recent results in human cancer trials have confirmed that adenoviruses can be very useful in oncology. For cancer treatment, the unparalleled transduction efficacy of adenovirus in dividing and dormant cells is a major benefit. As the goal in cancer gene therapy is to kill infected tumour cells, long-term transgene expression is not necessary. In addition, the immune response generated against infected cells could be useful for eradicating uninfected tumour. Importantly, more than 670 cancer patients have been treated with adenovirus intratumorally, intra-arterially, intraperitoneally and intravenously with very manageable adverse effects and no unexpected severe or lethal toxicity. Currently, the most promising approaches are based on replication-competent agents that allow efficient tumour penetration because of their capacity for tissue-specific replication. In addition to transcriptional control, it is becoming clear that targeting is necessary for efficient tumour transduction and less infection of normal tissues. Exciting results are anticipated when the first selectively replicating targeted adenoviruses go to clinical trials. In conclusion, intense gene therapy and virological research have suggested that while other vectors could be more useful for treatment of hereditary disease, adenoviruses are highly promising and safe agents for oncology, as suggested in a number of early phase clinical trials.

ISSN:1173-8804    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Cytomegalovirus (CMV) causes high morbidity and mortality in immunocompromised patients. The host immune response to CMV comprises specific and nonspecific cellular and humoral responses, but current knowledge supports a protective role only for cell-mediated immune responses. Although complete CMV eradication is unusual even in immunocompetent hosts, its morbidity can be limited by CMV-specific CD8+ cytotoxic lymphocytes supported by CD4+-mediated T lymphocyte helper activity. In patients with congenital or acquired deficiencies of cell-mediated immunity, recovery of CD4+ lymphocyte numbers and/or function coincides with cessation of CMV-associated morbidity. However, an immunological test that can predict protection against CMV disease across different types of high-risk patients is not yet available. In recent years, the introduction of antivirals active against CMV has improved the outcome of CMV disease. In addition, there is a continuous effort to develop CMV-specific immune-based therapies including vaccines and immune modulators such as cytokines, which may be of supplemental benefit in the control of CMV disease.

ISSN:1173-8804    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

The problems of why metastatic cancers develop pleiotropic resistance to all available therapies, and how this might be countered, are the most pressing in cancer chemotherapy. It is likely that such resistance involves a combination of mechanisms including changes in drug transport/drug targets, reduction in the degree of drug-induced apoptosis/cell loss, and increased rate of tumour repopulation following therapy. Current research must consider not only which mechanisms contribute, eventually relating this to individual patients with cancer, but also what strategies might be utilised to counter each of the important resistance mechanisms. A considerable amount of work has been devoted to the development of inhibitors of membrane-associated transport proteins such as P-glycoprotein, which mediate drug efflux. This work is now being complemented by approaches that target cell death pathways such as those mediated by release of mitochondrial proteins and by activation of surface receptors such as Fas. Rapid progress has been made in developing small-molecular-weight drugs that influence the rate of apoptosis, for instance by binding to the bcl-2 family of proteins regulating mitochondrial permeability. Antisense approaches aimed at reducingbcl-2expression, and thus increasing the rate of cell death, are also showing promise. Modification of repopulation kinetics provides a further approach but has not received as much attention as other aspects of tumour resistance. New therapeutic approaches will have to be complemented by improved diagnostic tests to evaluate the contributions of different resistance mechanisms in individual patients with cancer.

ISSN:1173-8804    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Background and aimsAddition of a 40kD polyethylene glycol moiety to interferon-α-2a [peginterferon-α-2a (40kD)] improves pharmacokinetic properties over those of standard interferon. We conducted a phase II study to assess the safety and initial efficacy of peginterferon-α-2a (40kD) plus ribavirin combination therapy in patients with chronic hepatitis C (CHC).MethodsTwenty patients received open-label 180μg peginterferon-α-2a (40kD) subcutaneously once weekly and oral ribavirin 1000 or 1200mg daily for patients weighing <75 or ≥75kg, respectively, for a period of 24 weeks. Patients with hepatitis C virus (HCV) genotype 1 and a virological response at week 24 received study drugs for an additional 24 weeks.ResultsA sustained virological response, defined as undetectable HCV RNA 24 (i.e. <100 copies/ml) weeks after completing the therapy, was achieved in 50% of patients in an intent-to-treat analysis (6/16 genotype 1 and 4/4 genotype non-1). Adverse events were similar to those reported with unmodified interferon plus ribavirin combination therapy. Anaemia led to ribavirin dose reduction in five patients. Neutropenia led to dose reduction in three patients treated with peginterferon-α-2a (40kD).ConclusionsThe addition of ribavirin to a once-weekly peginterferon-α-2a (40kD) regimen should be investigated in larger clinical trials.

ISSN:1173-8804    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Infliximab is a chimeric monoclonal antibody that binds to tumour necrosis factor-α (TNFα) and neutralises its effects. TNFα plays an important role in the development of both Crohn's disease and rheumatoid arthritis.In a large, double-blind, randomised study involving patients with active, refractory Crohn's disease, significantly more recipients of intravenous infliximab, compared with placebo, achieved a clinical response after 4 weeks' follow-up. Moreover, infliximab administration was associated with a rapid improvement in endoscopic and histological findings in clinical trials involving patients with active, refractory Crohn's disease. The results of the A Crohn's Disease Clinical Trial Evaluating Infliximab in a New Long-Term Treatment Regimen (ACCENT) I study showed that maintenance infliximab therapy prolonged response and remission in patients with moderate to severe Crohn's disease.In patients with enterocutaneous fistulae associated with Crohn's disease who were involved in a double-blind, randomised study, significantly more patients who received multiple infusions of infliximab, compared with placebo, experienced a ≥50% reduction from baseline in the number of draining fistulae at ≥2 consecutive study visits.In patients with active rheumatoid arthritis refractory to treatment with methotrexate who were enrolled in a large, double-blind, randomised study [the Anti-TNF Trial in Rheumatoid Arthritis with Concomitant Therapy (ATTRACT) study], American College of Rheumatology (ACR) 20, 50 and 70% response rates were seen in significantly more patients who received multiple infusions of infliximab plus methotrexate, compared with methotrexate plus placebo, after 30 and 54 weeks' treatment. Moreover, the ACR 20% response rate was maintained after 102 weeks' treatment. In addition, significantly less radiographic progression was seen in infliximab plus methotrexate, compared with methotrexate plus placebo, recipients after 54 weeks' treatment.Infliximab therapy was also associated with improvements in health-related quality of life in patients with Crohn's disease or rheumatoid arthritis.Infliximab was generally well tolerated in clinical trials with the most common adverse events including upper respiratory tract infection, headache, nausea, coughing, sinusitis and diarrhoea. Infliximab therapy may be associated with an increased risk of reactivation of tuberculosis in patients with latent disease.In conclusion,infliximab is an important treatment option in patients with active Crohn's disease who have not responded to conventional therapy and in patients with Crohn's disease who have fistulae. Moreover, infliximab plus methotrexate is effective in patients with active rheumatoid arthritis who have not responded adequately to traditional disease-modifying antirheumatic drugs, in terms of reducing symptoms and signs, improving physical function and delaying the progression of structural damage.

ISSN:1173-8804    

出版商:ADIS    

年代:2002

数据来源: ADIS