摘要:

Inflammation in rheumatoid arthritis (RA) is associated with an imbalance between pro- and anti-inflammatory factors, which leads to a persistent chronic inflammatory state in the joint. Molecular studies of the physiology of the inflammatory response have identified a hierarchy of cytokine activities. The identification of this hierarchy has provided new potential therapeutic targets for the treatment of RA. At present the majority of new therapeutic agents have been developed to neutralise the activity of tumour necrosis factor-α (TNFα), a cytokine at the top of the inflammatory cascade. These agents consist of recombinant proteins that bind and neutralise TNFα, and they are effective in the treatment of inflammation in RA. In this review we discuss the rationale behind targeting TNFα, the various recombinant proteins that have been used, their clinical effectiveness, the possible adverse effects of these agents and the development of new chemical inhibitors of TNFα synthesis.

ISSN:1173-8804    

出版商:ADIS    

年代:2001

数据来源: ADIS

摘要:

Lymphomas are the fifth most common malignancy in the United States and are increasing in incidence. Despite being among the most responsive malignancies to radiation and chemotherapy, the majority of patients relapse or have progressive disease. Monoclonal antibodies (MAbs) directed at cell-specific surface antigens have been useful in the diagnosis of lymphomas and, more recently, the therapeutic mouse-human chimeric MAb rituximab has demonstrated effectiveness in B cell lymphomas. Conjugating MAbs to radionuclides is a strategy for improving the efficacy of MAb lymphoma therapy by delivering radiation in close proximity to the tumour (radioimmunotherapy or RIT). In addition, the low dose rate of the delivered radiation may exert a greater antitumour activity than an equivalent dose of conventional external beam radiation. The antigenic targets for MAb therapy have included CD20, CD22, HLA-DR, and B cell idiotype. Radionuclides that have been used include iodine-131, yttrium-90, and copper-67; there are relative merits and disadvantages to each source of radiation. Clinical studies to date have focused on relapsed and refractory patients with both indolent and aggressive lymphomas, although more recent studies have included previously untreated patients with indolent lymphoma. Radioimmunoconjugate has been delivered as either single or multiple doses. Response rates have varied widely, dependent on the patient population and the response criteria. Of note, complete responses can be achieved in this typically refractory patient group. Toxicities have generally consisted of mild infusion-related nausea, fever, chills, and asthenia. Neutropenia and thrombocytopenia are the dose-limiting toxicities and have prompted the incorporation of autologous stem cell support as a means of achieving dose escalation. To date, RIT has been delivered to highly selected patients in relatively few centres with requisite equipment and specialised personnel. In addition to these requirements, cost is likely to be a barrier to widespread use. The combination of RIT with chemotherapy at conventional or high dose, or with biological agents is a fertile area for investigation. The potential of RIT in the treatment for lymphomas will be defined only by well designed comparative prospective clinical studies.

ISSN:1173-8804    

出版商:ADIS    

年代:2001

数据来源: ADIS

摘要:

In addition to immunomodulatory and cytokine-modulatory properties, thalidomide has antiangiogenic activity. It has been investigated in a number of cancers including multiple myeloma, myelodysplastic syndromes, gliomas, Kaposi’s sarcoma, renal cell carcinoma, advanced breast cancer, and colon cancer. Its role has been best explored in myeloma, where, at daily doses of 100 to 800mg, it is remarkably active, causing clinically meaningful responses in one-third of extensively pretreated patients and in over half of patients treated early in the course of the disease. It also acts synergistically with corticosteroids and chemotherapy in myeloma. Thalidomide produces improvement of cytopenias characteristic of myelodysplastic syndrome, resulting in the reduction or elimination of transfusion dependence in some patients. Responses have also been seen in one-third of patients with Kaposi’s sarcoma, in a small proportion of patients with renal cell carcinoma and high grade glioma and, in combination with irinotecan, in some patients with colon cancer. Thalidomide is being investigated currently in a number of clinical trials for cancer. Drowsiness, constipation and fatigue are common adverse effects seen in 75% of patients. Symptoms of peripheral neuropathy and skin rash are seen in 30%. A minority of patients experience bradycardia and thrombotic phenomena. Despite the high frequency of adverse effects, those severe enough to necessitate cessation of therapy are seen in only 10 to 15% of patients. A therapeutic trial of thalidomide should be considered in all patients with myeloma who are unresponsive to or relapse after standard therapy. In other malignant diseases, the most appropriate way to use the drug is in the setting of well designed clinical trials. In the absence of access to such studies, thalidomide could be considered singly or in combination with standard therapy in patients with no meaningful therapeutic options.

ISSN:1173-8804    

出版商:ADIS    

年代:2001

数据来源: ADIS

摘要:

The autoimmune pathogenesis of myasthenia gravis is relatively well understood. The current options for treatment of this disease are acute and long term immunotherapies, acetylcholinesterase inhibitors and thymectomy. Many factors influence the timing of initiation of immunomodulatory therapy in myasthenia gravis and both disease factors, such as stage and severity, and patient factors, such as age, pregnancy and intercurrent illness, must be considered. Decisions regarding the choice of therapy can be difficult because of the limited number of randomised controlled trials that have been performed in myasthenic patients. In general, acetylcholinesterase inhibitors alone are used only in mild ocular disease, and in the majority of other patients immunomodulatory therapy is begun early. Corticosteroids are the most commonly used initial therapy, followed by azathioprine. In refractory cases, the available options include immunosuppressants such as cyclosporin, mycophenolate mofetil and cyclophosphamide. Plasmapheresis and intravenous immunoglobulin are important in the treatment of acute exacerbations and myasthenic crisis and in the perioperative setting. Despite many years of experience, the role of thymectomy in improving long term outcome in nonthymomatous myasthenia gravis remains controversial.

ISSN:1173-8804    

出版商:ADIS    

年代:2001

数据来源: ADIS

摘要:

The Global Initiative for Asthma (GINA) guidelines stated the therapeutic goals for the management of asthma and, through a stepwise approach to treatment, defined the various grades of asthma severity and the therapeutic options available to the clinician at each step. This article considers the options at step 3; the management of a patient with poorly controlled asthma who is already taking low-dose inhaled corticosteroids.Before considering a change in therapy, the clinician should rule out alternative diagnoses, confirm compliance with treatment, explore potential exacerbants in the patient's environment and, where possible, remove them. If a change in medication is necessary, the choice of drug will depend on the therapeutic goal that needs to be achieved. If the most important goal is the control of symptoms and optimisation of lung function, most studies support the addition of a long-acting β2-agonist to low dose inhaled corticosteroids. If recurrent severe exacerbations are a major feature of the poor control, increasing the dosage of inhaled corticosteroids may be most effective. The addition of a leukotriene antagonist may be the best choice if exercise-induced symptoms are prominent or in the setting of aspirin-sensitive asthma.General recommendations supported by the findings of large therapeutic trials do not allow for significant variability in the individual response to a particular drug. Receptor polymorphisms have recently been discovered that may account for variability in the response to β2-agonists and leukotriene receptor antagonists. However, until more is known about the reasons behind this variability, a therapeutic trial may be the most effective way of determining the best drug for an individual patient.One of the key developments in asthma over the past decade has been the acceptance of the concept of asthma as a chronic inflammatory disorder of the airways. However, the long term significance of this inflammation is not clear and the importance of control of inflammation beyond the suppression of symptoms, reduction of exacerbation frequency and the optimisation of lung function has not been established.

ISSN:1173-8804    

出版商:ADIS    

年代:2001

数据来源: ADIS

摘要:

The aetiology of multiple sclerosis (MS) remains unknown. Epidemiological, clinical and pathological data support the theory that MS is a complex disease/syndrome with many factors affecting its development and progression. It may be appropriate to regard MS as a syndrome with differing clinical and pathological features occurring along a spectrum. Patients with MS are more likely to have an affected relative than are individuals without MS, which suggests that there is a genetic component to this illness. Despite this genetic susceptibility, 85% of MS patients do not have an affected relative and only 1 in 3 monozygotic (identical) twins develops MS if the other twin already has it. These data strongly suggest that environmental factors influence the development of MS.Many putative infectious agents have been proposed to be involved in the aetiology of MS. Although research into identifying MS-causative agents dates back for more than 5 decades, no agent has yet emerged with any consensus as the cause of MS. This controversy is due to a number of factors, including lack of specificity of an agent to MS, lack of reproducibility in other laboratories, inappropriate controls, laboratory contamination and lack of a standard and easily reproducible assay system.Chlamydia pneumoniaeis a recently described pathogen that may have a role in the pathogenesis of MS.C. pneumoniaeis an intracellular bacterial organism that is infectious to humans. It has recently been detected in the cerebrospinal fluid (CSF) of MS patients but not in that of patients with other neurological diseases. There is also a case report of a patient with CNSC. pneumoniaeinfection and rapidly progressive MS responding to antimicrobial therapy directed against this pathogen. An association betweenC. pneumoniaein the CSF and MS is now apparent, but its role in the development of MS remains unknown.Further work exploring the role ofC. pneumoniaein inflammatory demyelination is required. This may be accomplished either by developing an animal model or in a therapeutic trial in patients with MS.

ISSN:1173-8804    

出版商:ADIS    

年代:2001

数据来源: ADIS