摘要:

Conjugation of the polymer polyethylene glycol (PEG) to proteins can significantly decrease their clearance from plasma, thus increasing their half-livesin vivo. The increased half-life of PEG-proteins is directly proportional to the total molecular weight of the construct. This approach has been used to design cytokine constructs that can be administered once a week, rather than on a daily or alternate-day schedule. Two cytokines for which this approach appears to be successful are PEG−interferon-α-2a (PEG−IFNα-2a) and PEG-granulocyte colony- stimulating factor (PEG−G-CSF). Both use high molecular weight PEG (20 to 40kD) to give sufficiently long durationin vivo. In the case of PEG−G-CSF conjugates, thein vivoefficacy is directly proportional to molecular weight, whereas thein vitroactivity is inversely proportional, suggesting that overall duration of contact is more important than the affinity of the interaction. Conjugates of a number of other cytokines have been prepared, but until recently, few have used the high molecular weight polymers. In the future, as this approach is taken to make new PEG-cytokine constructs, thorough pharmacokinetic studies will be essential for their development and clinical use.

ISSN:1173-8804    

出版商:ADIS    

年代:2001

数据来源: ADIS

摘要:

Melanoma is generally resistant to chemotherapy and radiation therapy. Its unique immunological properties lend support to developing innovative new therapies via manipulation of the patient's own immune system. The use of whole-cell−based tumour vaccines, including autologous, whole-cell allogeneic and cytokine gene-modified vaccines, as well as tumour lysate vaccines, for active specific immunotherapy of melanoma, is discussed in detail with regard to rationale and available clinical data. Although phase II data on the use of melanoma vaccine in the adjuvant setting show promise, there is no randomised phase III trial demonstrating the efficacy of active specific immunotherapy for melanoma. The coming years will bring the results of several pivotal multicentre phase III trials testing the clinical utility of active specific immunotherapy in the management of melanoma.

ISSN:1173-8804    

出版商:ADIS    

年代:2001

数据来源: ADIS

摘要:

Parathyroid hormone (PTH), especially intact human PTH [hPTH(1-84)] and its various fragments [hPTH(1-31), (1-34), (1-36), (1-38) and their modifications], has been used for the treatment of osteoporosis over the last 10 years. Although chronic continuous excess of PTH markedly increases bone resorption, as seen in the typical example of primary hyperparathyroidism and osteitis fibrosa generalisata, intermittent PTH administration has been found to stimulate bone formation in animals, providing a basis for the use of PTH as a therapeutic agent for osteoporosis.In addition to dramatically increasing trabecular bone density and also sustaining cortical bone density, PTH administration increases bone strength and reduces the fracture rate, despite occasional increases in cortical porosity. Administration of PTH in combination with antiresorptive agents such as estrogen, calcitonin, vitamin D and bisphosphonates augments its effect. Because of its bone anabolic action, PTH is expected to be effective for osteoporosis in those of advanced age with suppressed bone remodelling, which might not respond favourably to antiresorptive agents.

ISSN:1173-8804    

出版商:ADIS    

年代:2001

数据来源: ADIS

摘要:

In vitroandin vivodata have demonstrated that leukotrienes play a key role not only in allergic airway diseases but also in inflammatory reactions of the skin. Antileukotriene drugs, i.e. leukotriene receptor antagonists and synthesis inhibitors, are a new class of anti-inflammatory drugs that have shown clinical efficacy in the management of asthma, allergic rhinitis and inflammatory bowel disease. To address the question of the validity and applicability of published evidence of the use of antileukotriene drugs in dermatological diseases, we reviewed data concerning the pathophysiological effect of leukotrienes in the skin and in skin diseases, and the experience with antileukotriene treatment that has been published.In vivoandin vitrodata suggest that antileukotriene treatment may have efficacy in atopic dermatitis, different types of urticaria or psoriasis and other skin diseases such as bullous skin diseases, collagenoses, Sjogren-Larsson syndrome or Kawasaki disease. Nevertheless, published evidence is very limited and before any conclusions can be drawn, additional basic research needs to be performed with regard to the role of different leukotrienes and leukotriene receptors in skin diseases.On the basis of these data, randomised and placebo-controlled clinical trials with leukotriene antagonists and synthesis inhibitors should be performed. Moreover, future studies investigating the additive benefit of antileukotriene drugs are warranted, e.g. in combination with antihistamines, corticosteroids or other anti-inflammatory drugs.

ISSN:1173-8804    

出版商:ADIS    

年代:2001

数据来源: ADIS

摘要:

The humanised monoclonal antibody daclizumab is an immunosuppressive agent that reduces acute rejection in solid organ transplantation. It is specific for the α subunit (Tac/CD25) of the interleukin (IL)-2 receptor on activated T cells and achieves immunosuppression by competitive antagonism of IL-2−induced T cell proliferation.When added to standard triple immunosuppression regimens, daclizumab significantly reduces the rate of acute rejection at 1 year in renal transplantation by 36% and there are indications that it may be effective in other solid organ transplantations. Three-year outcomes of two phase III clinical trials in renal transplantation indicate similar values for graft and patient survival between daclizumab and placebo when given in addition to triple immunosuppression; however, these pivotal trials were not designed with sufficient power to demonstrate any statistical significance.The addition of daclizumab induction shows potential in allowing calcineurin inhibitor- and corticosteroid-sparing regimens without increasing the rate of acute graft rejection or adverse effects in renal and liver transplantation.Preliminary reports indicate that daclizumab may also be a useful agent in delayed graft function and graft versus host disease (GVHD). Further investigation of its efficacy in these groups and in children is needed.Data from clinical trials show daclizumab to be well tolerated in solid organ transplantation. It does not increase the incidence of infection, including cytomegalovirus infection, when compared with placebo or no induction groups. Preliminary comparative data with muromonab CD3 indicate that daclizumab may be associated with a lower rate of infectious complications and similar or better efficacy.ConclusionsIn conclusion, daclizumab has been proven to reduce acute rejection in renal transplant recipients when given in addition to traditional baseline immunosuppression. It has shown potential to reduce acute rejection in other solid organ transplants; however, well designed, randomised studies are required to confirm this.Clinical experience from trials to date indicate that daclizumab has a tolerability profile similar to placebo with no significant effect on the incidence of infection. The relative efficacy and tolerability of daclizumab compared with other induction agents has yet to be defined. Available data suggest that daclizumab may allow the use of calcineurin inhibitor-sparing and corticosteroid-sparing regimens and may have potential in the treatment of GVHD.

ISSN:1173-8804    

出版商:ADIS    

年代:2001

数据来源: ADIS