摘要:

Traditionally neural transplantation has had as its central tenet the replacement of missing neurons that have been lost because of neurodegenerative processes, as exemplified by diseases such as Parkinson disease (PD). However, the effectiveness and widespread application of this approach clinically has been limited, primarily because of the poor donor supply of human fetal neural tissue and the incomplete neurobiological understanding of the circuit reconstruction required to normalize function in these diseases. So, in PD the progress from promising neural transplantation in animal models to proof-of-principle, open-labeled clinical transplants, to randomized, placebo-controlled studies of neural transplantation has not been straightforward. The emergence of previously undescribed adverse effects and lack of significant functional advantage in recent clinical studies has been disappointing and has served to cast a new, and perhaps more realistic, perspective on this treatment approach. In fact, there have been calls by some involved in neural transplantation to return to the drawing board before pressing on with further clinical trials, and the return to basic experimentation. This therefore precipitates the question – is there a future for neural transplantation?It is important to remember that there are a number of possible explanations for the disappointing results from the recent clinical trials in PD, ranging from the mode of transplantation to patient selection. Nevertheless, almost irrespective of these reasons for the current trial results, there have always been significant practical and ethical problems with using human fetal tissue, and so a number of alternative cell sources have been investigated. These alternative sources include stem cells, which are attractive for cell-based therapies because of their potential ease of isolation, propagation and manipulation, and their ability in some cases to migrate to areas of pathology and differentiate into specific and appropriate cell types. Furthermore, the availability of stem cells derived from non-embryonic sources (e.g. adult stem cells derived from the sub-ventricular zone) has removed some of the ethical limitations associated with the use of embryonic human tissue. These potentially beneficial aspects of stem cells means that there is a future for neural transplantation as a means of treating patients with a range of neurological disorders, although whether this will ever translate into a truly effective, widely available therapy remains unknown.

ISSN:1173-8804    

出版商:ADIS    

年代:2004

数据来源: ADIS

摘要:

Naked plasmid DNA can be used to introduce genetic material into a variety of cell typesin vivo. However, such gene transfer and expression is generally very low compared with that achieved with viral vectors and so is unsuitable for clinical therapeutic application in most cases. This difference in efficiency has been substantially reduced by the introduction ofin vivoelectroporation to enhance plasmid delivery to a wide range of tissues including muscle, skin, liver, lung, artery, kidney, retina, cornea, spinal cord, brain, synovium, and tumors. The precise mechanism ofin vivoelectroporation is uncertain, but appears to involve both electropore formation and an electrophoretic movement of the plasmid DNA. Skeletal muscle is a favored target tissue for three reasons: there is a pressing need to develop effective therapies for muscular dystrophies; skeletal muscle can act as an effective platform for the long-term secretion of therapeutic proteins for systemic distribution; and introduction of DNA vaccines into skeletal muscle promotes strong humoral and cellular immune responses. All of these applications are significantly improved by the application ofin vivoelectroporation. Importantly, the increased efficiency of plasmid delivery following electroporation is seen in larger species as well as rodents, in contrast to the decreasing efficiencies with increasing body size for simple intramuscular injection of naked plasmid DNA. As this electroporation-enhanced non-viral gene delivery system works well in larger species and avoids the vector-specific immune responses associated with recombinant viruses, the prospects for clinical application are promising.

ISSN:1173-8804    

出版商:ADIS    

年代:2004

数据来源: ADIS

摘要:

Kinases are believed to play a crucial role in the expression and activation of inflammatory mediators in the airway, in T-cell function, and in airway remodeling. Important pro-inflammatory transcription factors such as activating protein-1 and nuclear factor κB, which are activated in airway disease, require kinase activation to switch on inflammatory genes, while other kinases can regulate mRNA half-life. Selective kinase inhibitors have been developed that reduce inflammatory gene expression and some characteristics of disease in animal models. Targeting specific kinases that are overexpressed or overactive in disease should allow for selective treatment of airway inflammatory diseases. Interest in this area has intensified due to the success of the specific Abelson murine leukemia viral oncogene homolog tyrosine kinase inhibitor, imatinib mesylate, in the treatment of chronic myelogenous leukemia. Encouraging data from animal models and primary cells and early phase I and II studies in other diseases suggest that inhibitors of p38 mitogen-activated protein kinase and inhibitor of κB kinase-2 may prove to be useful novel therapies in the treatment of severe asthma and chronic obstructive pulmonary disease.

ISSN:1173-8804    

出版商:ADIS    

年代:2004

数据来源: ADIS

摘要:

Rheumatoid arthritis is a chronic inflammatory disease where the synovial tissue is characterized by heavy infiltration of leukocytes. Chemokines and chemokine receptors play an important role in cell migration and positioning of leukocytes within the inflamed rheumatoid synovium. There is now much focus on the specific contribution and role of each chemokine and chemokine receptor in the chronic inflammatory process in the synovial tissue. Recent evidence indicates that interference with the chemokines released from the inflamed synovial cells or the chemokine receptors expressed on the cells infiltrating the synovial tissue may lead to discovery of new therapeutics for this disease.

ISSN:1173-8804    

出版商:ADIS    

年代:2004

数据来源: ADIS

摘要:

ObjectiveThe binding and encapsulation of [3H] pGL3 luciferase reporter plasmid DNA by red blood cell (RBC) ghosts, intended as a vehicle for transfection and ultimately for gene therapy, were studied using two methods for DNA compaction.An alternative approach using polyethylene glycol6000at a final concentration of 15% (weight/volume) was used to collapse [3H] pGL3 DNA in the presence of 0.025M MgCl2. Addition of the reagents, premixed with DNA, to a pelleted suspension of RBC ghosts followed by a short incubation and then addition of 1.5M NaCl to restore tonicity, resulted in resealing of the ghosts. Uptake of [3H] pGL3 DNA by the ghosts was approximately 20% of the input amount of DNA. Further work showed that 60–70% of the DNA was inside the resealed ghosts and largely present in the supercoiled form. At no stage was any freezing and thawing used.Methods and ResultsIn the first approach, DNA was compacted through binding electrostatically to poly-L-lysine. Complexes were constructed to have a slight negative charge. Experimentally, it was found that a high percentage of binding was to the outside of the resealed RBC ghosts.An alternative approach using polyethylene glycol6000at a final concentration of 15% (weight/volume) was used to collapse [3H] pGL3 DNA in the presence of 0.025M MgCl2. Addition of the reagents, premixed with DNA, to a pelleted suspension of RBC ghosts followed by a short incubation and then addition of 1.5M NaCl to restore tonicity, resulted in resealing of the ghosts. Uptake of [3H] pGL3 DNA by the ghosts was approximately 20% of the input amount of DNA. Further work showed that 60–70% of the DNA was inside the resealed ghosts and largely present in the supercoiled form. At no stage was any freezing and thawing used.ConclusionTransfection studies have demonstrated that pGL3 DNA carrying the luciferase gene is successfully transferred from RBC ghosts to recipient HeLa cells in culture under mild fusion conditions.

ISSN:1173-8804    

出版商:ADIS    

年代:2004

数据来源: ADIS

摘要:

▴ Etanercept is a dimeric fusion protein based on the p75 tumor necrosis factor (TNF) receptor. It binds to TNFα and blocks its biological activity.▴ Subcutaneous etanercept is effective in the treatment of rheumatoid arthritis, psoriatic arthritis, and polyarticular-course juvenile rheumatoid arthritis. More recently, etanercept has shown efficacy in the treatment of adults with ankylosing spondylitis.▴ In randomized, double-blind, placebo-controlled trials, subcutaneous etanercept 25mg twice weekly for 6–24 weeks significantly reduced disease activity in patients with active ankylosing spondylitis. In the largest trial, etanercept produced a response rate of 57% compared with 22% for placebo after 24 weeks (response was determined via the validated ASAS 20 response criteria developed by the Assessments in Ankylosing Spondylitis [ASAS] Working Group).▴ Etanercept therapy significantly improved health-related quality of life in patients with ankylosing spondylitis compared with placebo. The greatest improvements in a 16-week study were seen in the domains of physical functioning, physical role, bodily pain, vitality, and social functioning.▴ Etanercept was generally well tolerated, with few serious adverse events or treatment withdrawals. The most common adverse events were injection-site reactions and minor upper respiratory tract infections.Table. Features and properties of etanercept (Enbrel®) in active ankylosing spondylitis

ISSN:1173-8804    

出版商:ADIS    

年代:2004

数据来源: ADIS

ISSN:1173-8804    

出版商:ADIS    

年代:2004

数据来源: ADIS

摘要:

Imatinib mesylate (Gleevec®, Glivec®) is an orally administered competitive inhibitor of the BCR-ABL tyrosine kinase created by the Philadelphia chromosome (Ph+) in chronic myeloid leukemia (CML).In patients with newly diagnosed and previously untreated (apart from hydroxyurea and/or anagrelide) CML in the chronic phase, imatinib mesylate 400 mg/day, compared with interferon-α (IFNα) plus cytarabine, resulted in higher hematologic response (HR) and cytogenetic response (CR) rates and fewer patients progressing to the accelerated phase or blast crisis in a large comparative trial. Preliminary results indicate that, compared with IFNα plus cytarabine, imatinib mesylate treatment was associated with similar total costs, but resulted in a higher health-related quality of life (HR-QOL).Imatinib mesylate was also effective in patients with chronic-phase CML refractory to or intolerant of treatment with IFNα (as 400 mg/day) and in those with blast-crisis or accelerated-phase CML (600 mg/day). In the latter groups, HR and CR rates were lower than those in patients with chronic-phase CML.Imatinib mesylate-associated adverse events were common in clinical trials, but were mostly mild to moderate in severity. The most frequently reported adverse events were superficial edema, nausea, muscle cramps, diarrhea, vomiting, and skin rash. Myelosuppression (thrombocytopenia and neutropenia) was also reported, especially in patients with advanced disease. In patients with previously untreated chronic-phase CML, serious adverse events (both hematologic and nonhematologic) were less common with imatinib mesylate than with IFNα plus cytarabine treatment.ConclusionImatinib mesylate is a valuable therapy for patients with newly diagnosed Ph+ chronic-phase CML. It is better tolerated and produces higher HR, CR and freedom from progressive disease rates than conventional therapy with IFNα plus cytarabine. Preliminary results indicate that, compared with IFNα plus cytarabine, imatinib mesylate treatment was associated with similar total costs, but resulted in a higher HR-QOL. Imatinib mesylate is also effective in patients with accelerated-phase and blast-crisis CML, and patients with chronic-phase CML who have failed IFNα therapy. Given its efficacy and generally manageable adverse event profile, imatinib mesylate offers an important early treatment option for patients with CML.

ISSN:1173-8804    

出版商:ADIS    

年代:2004

数据来源: ADIS