摘要:

Cyclooxygenase (COX; prostaglandin H synthase, prostaglandin endoperoxidase) is the key enzyme in the synthesis of the prostaglandin and thromboxane families of eicosanoid mediators, and is the target for the nonsteroidal anti-inflammatory drugs (NSAIDs). The identification of an inducible COX isoform, COX-2, and the demonstration of its specific expression at sites of inflammation suggested that it may provide a useful therapeutic target for novel anti-inflammatory drugs. Inhibition of an enzyme that is not expressed in most healthy tissues would potentially avoid most of the adverse effects associated with NSAIDs, which target a constitutively expressed isoform, COX-1. The development of novel ‘super aspirins’ with high selectivity towards the inhibition of COX-2 showed that this hypothesis was well-founded and that high levels of these drugs could be tolerated without these serious adverse effects. The first two of these new generation NSAIDs, celecoxib and rofecoxib, are now in clinical use.More recently, however, concern has been expressed that COX-2 inhibition may in fact have a number of potential, previously hidden, pitfalls. These have arisen from the demonstration that COX-2 induction is not exclusively associated with the onset of an inflammatory reaction, with expression limited to inflammatory sites. In fact, COX-2 is expressed more chronically, and is also seen during the resolution of inflammation and in areas of wound-healing. The application of COX-2-selective inhibitors during these periods has been shown to be deleterious in that resolution of inflammation is delayed, gastric ulcer healing is delayed and, in some patients, ulcers have been shown to progress further to perforation. The suggestion has now been made that, in these situations, COX-2 may help resolve the pathology, perhaps by generating alternative series of prostaglandins such as the cyclopentenone prostaglandins. The finding that these prostaglandins can affect proteins by direct chemical modifications as well as having their own receptor families has rekindled debate on the deleterious and beneficial effects of prostanoids, and the implications of inhibiting the production of these mediators, in the body.Therefore, in this review we discuss the role of COX-2 in inflammation and the potential adverse effects of its inhibition.

ISSN:1173-8804    

出版商:ADIS    

年代:2001

数据来源: ADIS

摘要:

International guidelines recommend that long-acting β-agonists should be considered in patients who are symptomatic despite moderate doses of inhaled corticosteroids. When combined with inhaled corticosteroids they improve asthma symptoms and lung function and reduce exacerbations. The evidence suggests that they are well tolerated. However, they are less effective than inhaled corticosteroids as monotherapy and should not be used alone, although the addition of a long-acting β-agonist may permit a small reduction in the corticosteroid dose. Both salmeterol and formoterol appear equally effective in improving asthma control. Formoterol, however, has a rapid onset of action and is now being promoted for the relief of acute asthma symptoms. Both drugs provide prolonged protection against exercise-induced bronchospasm. However, this effect rapidly diminishes with continuous therapy and if this is the main aim of treatment, intermittent use may be preferable.When compared with alternative treatments, inhaled long-acting β-agonists are more effective in controlling asthma symptoms than either theophylline or antileukotriene agents. Bambuterol, an oral prodrug of terbutaline, appears to be as effective as the inhaled long-acting β-agonists and has the advantage of once daily oral administration. However, the inhaled long-acting β-agonists are less likely to have systemic adverse effects.There are theoretical concerns that regular β-agonist treatment may lead to tolerance and a failure to respond to emergency asthma treatment. While there is no doubt that tolerance occurs, there is currently little evidence that this is a clinical problem.Insights into pharmacological as well as therapeutic interactions between inhaled corticosteroids and β-agonists are providing justification for their use in combination. Guidelines for the management of patients with chronic persistent asthma are likely to require modification to reflect these developments.

ISSN:1173-8804    

出版商:ADIS    

年代:2001

数据来源: ADIS

摘要:

Behçet's syndrome is a multisystem disorder that causes orogenital ulceration, skin lesions and intraocular inflammation with uveitis and retinal vasculitis. A proportion of affected individuals also develop vascular and central nervous system manifestations, with significant morbidity and mortality. Although the aetiopathogenesis of Behçet's syndrome is poorly understood, the condition is considered to be driven, at least in part, by autoimmune mechanisms. Conventional therapy relies on available anti-inflammatory and immunomodulatory agents, and, in view of the paucity of controlled clinical trials, it is to a large extent empirical. Oral ulcers can often be treated by topical application of corticosteroids. In addition to corticosteroids, agents used to treat ocular inflammation and significant systemic manifestations include colchicine, thalidomide, azathioprine, mycophenolate mofetil, cyclosporin, tacrolimus, cyclophosphamide and chlorambucil. The response to these agents is variable and there is a distinct need for more effective rational treatment. Over the last decade, a number of open studies have produced promising results using recombinant interferon-α preparations. Evaluating, in a methodical manner, the other new biological agents that are becoming available for the treatment of inflammatory diseases offers great promise, not only for effective management but also for providing insights into aetiopathogenesis.

ISSN:1173-8804    

出版商:ADIS    

年代:2001

数据来源: ADIS

摘要:

Mycophenolate mofetil (MMF) is an immunosuppressive drug designed to inhibit inosine monophosphate dehydrogenase (IMPDH). IMPDH is a key enzyme in thede novopurine synthesis of lymphocytes. It is crucially important for proliferative responses of human T and B lymphocytes. The inhibition of IMPDH thus leads to selective lymphocyte suppression. After successful use in variousin vitroand animal models, MMF was brought to clinical trial in patients undergoing transplantation. The drug is rapidly and completely absorbed following oral administration. Pilot studies of administration with cyclosporin and corticosteroids suggested a significant reduction in the incidence of organ rejection at dosages of 1 to 3 g/day. As a result of these studies, 3 pivotal randomised double-blind multicentre trials, involving nearly 1500 patients, were designed to investigate the effects of addition of MMF to different standard immunosuppressive protocols on the prevention of acute renal allograft rejection. After 6 months, the rates of biopsy-proven rejection were significantly reduced in patients receiving MMF. In combination with cyclosporin and corticosteroids, the adverse effect profile resembled that of azathioprine. Most adverse effects were associated with the gastrointestinal tract, the blood system and opportunistic infections. MMF offers improved immunosuppressive therapy following renal and probably other solid organ transplantation. MMF has been licensed since 1995 for the prevention of acute renal allograft rejection in most countries. It has been used in different combinations of immunosuppressive drugs and in various dosages and regimens.

ISSN:1173-8804    

出版商:ADIS    

年代:2001

数据来源: ADIS

摘要:

Patients with chemotherapy-resistant acute myeloid leukaemia are rarely cured by non-allogeneic transplant therapies. Multiple new investigational agents have become available for treatment of these patients and there are few tools to permit rational drug and clinical trial selection. In this review, we describe the chemical and biological properties of some of these agents and some of their initial clinical activity to date. The selected agents react with either cell surface molecules or signal pathway intermediates and include antibody and antibody conjugates to CD33 and CD45, a fusion protein directed to the granulocyte-macrophage colony-stimulating factor receptor, an anti-sense oligonucleotide to Bcl2, a farnesyl transferase inhibitor, and a protein kinase C agonist/inhibitor. The challenge for the next decade will be how to select patients for particular molecularly targeted therapeutics and how to combine these agents.

ISSN:1173-8804    

出版商:ADIS    

年代:2001

数据来源: ADIS