摘要:

The lysosomal storage disorder (LSD) mucopolysaccharidosis type I (MPS I, McKusick 25280, Hurler syndrome, Hurler-Scheie syndrome, Scheie syndrome) is caused by a deficiency in the lysosomal enzyme, α-l-iduronidase (EC 3.2.1.76). MPS I patients can present within a diverse clinical spectrum, ranging from classical Hurler syndrome to attenuated Scheie syndrome. Laronidase (Aldurazyme®) enzyme replacement therapy has been developed as a treatment strategy for MPS I patients and has been approved for clinical practice. Here we review the pre-clinical studies and clinical trials that have been used to demonstrate that intravenous laronidase therapy is well tolerated and effective for treating MPS I patients who do not have neuronal pathology. Current challenges for a viable treatment strategy for all MPS I patients include development of an early screening protocol that identifies patients before the onset of irreversible pathology, methods to predict disease severity, appropriate treatment for neuropathology, and an effective patient monitoring regimen.

ISSN:1173-8804    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Alemtuzumab is a humanized therapeutic monoclonal antibody (MAb) that recognizes the CD52 antigen, expressed on normal and neoplastic lymphocytes, monocytes, and natural killer cells. In 2001, alemtuzumab was approved in the US and Europe to treat B-cell chronic lymphocytic leukemia (CLL) that had been treated previously with alkylating agents and was refractory to fludarabine. In heavily pretreated patients this MAb is able to produce response rates of about 40%, and in symptomatic, previously untreated patients response rates of more than 80% can be achieved. Alemtuzumab can also be used in patients with CLL as a preparative regimen for stem cell transplantation (SCT) and to prevent graft versus host disease. Moreover itsin vivouse before or after SCT may also potentially result in depletion of residual leukemia cells, especially in the autologous setting. Adverse events associated with alemtuzumab include acute first-dose reaction, hematologic toxicity, and infectious complications. Usually they are predictable, manageable, and acceptable in the context of CLL. However, in a significant percentage of patients, cytomegalovirus reactivation occurs during alemtuzumab therapy, and routine weekly monitoring with the polymerase chain reaction methodology is indicated. Moreover, antiviral and antibacterial prophylaxis is mandatory.

ISSN:1173-8804    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Hyaluronic acid (HA) is a major component of human synovial fluid, providing the rheologic properties (elasticity and viscosity) that enable the synovial fluid to perform lubricating and shock-absorbing functions within the healthy joint. Over the last 2 decades, HA preparations have become established in intra-articular therapy of osteoarthritis (OA), particularly OA of the knee.Existing HA preparations, both cross-linked and non-cross-linked, are all administered by courses of multiple injections, and all have been associated with variable success rates. The clinical profile of an HA preparation is inextricably linked to the product’s physicochemical properties. For example, the molecular structure of the HA affects the intra-articular residence time, which should in turn influence the duration of action post-injection. Non-animal stabilized hyaluronic acid (NASHA) is a new-generation HA preparation, produced wholly from non-animal sources. NASHA is stabilized using a carefully controlled cross-linking process, which increases the intra-articular residence time from hours to weeks. This facilitates single-injection treatment for OA without affecting the biocompatibility of HA.This review evaluates the properties of NASHA, including the available clinical data, in the context of previously developed HA preparations.

ISSN:1173-8804    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease for which no cure or effective treatment presently exists. Many different types of drugs have been tested; most are based on various hypotheses of mechanisms for neuronal death, including oxidative damage, loss of trophic factor support, glutamate-mediated excitotoxicity, and chronic inflammation. The discovery that a small percentage of ALS cases are familial and involve mutation in a superoxide dismutase gene (SOD1) led to the development of transgenic mouse models presently widely used for testing possible drugs. Mutations in the vascular endothelial growth factor gene (VEGF) also appear to be involved. Riluzole, an inhibitor of glutamate release and the only agent presently approved for clinical use, only extends survival by a few months. A number of trophic factors, anti-inflammatory agents, and inhibitors of oxidative stress have been reported to prolong survival in mouse models and some are now in clinical trials. Gene transfer ofVEGFor glial cell-line derived neurotrophic factor, anti-inflammatory COX-2 inhibitors, and minocycline have had particularly promising results in mice. No breakthrough has yet occurred and present thinking is that combinations of drugs may be required to slow the multifactorial neurodegeneration process effectively.

ISSN:1173-8804    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Acute rejection during the first year post-transplant is a key predictor of graft survival after renal transplantation. Use of induction therapy with a lymphocyte-depleting agent or an interleukin-2 receptor (IL-2R) antagonist can provide effective protection against rejection in the first critical weeks and months post-transplant. Polyclonal lymphocyte-depleting antibodies are associated with a low incidence of rejection but evidence of their benefit in terms of graft survival is lacking. Thymoglobulin®appears to offer superior graft outcomes compared with generic antithymocyte globulin (ATG). The most frequent adverse events are symptoms of cytokine release syndrome, leukopenia, thrombocytopenia, and tachycardia; data on whether polyclonal antibody use increases the risk of lymphoma are conflicting. Muromonab CD3 (OKT3), a monoclonal lymphocyte-depleting antibody, is efficacious but a high incidence of cytokine release syndrome and increased risk of post-transplant lymphoproliferative disease have limited its use. Following their recent introduction, the IL-2R antagonists basiliximab and daclizumab are now used widely, after randomized trials demonstrated that addition to calcineurin inhibitor-based therapy significantly reduced acute rejection by approximately 30–40%. Meta-analyses and registry analysis suggest that addition of an IL-2R antagonist may improve graft survival. The safety profile of IL-2R antagonists is indistinguishable from placebo, with no apparent difference in incidence of infection or post-transplant lymphoproliferative disease. IL-2R antagonists and polyclonal lymphocyte-depleting antibodies (with delayed cyclosporine) offer equivalent efficacy in standard-risk populations; in a trial of high-risk patients, acute rejection rate and graft outcomes were improved with Thymoglobulin®. Tolerability is superior with IL-2R antagonists: cytokine release syndrome and hematologic disturbances (notably leukopenia) are significantly more frequent with polyclonal antibodies. Cytomegalovirus infection may also be more common with lymphocyte-depleting antibodies. Thus, in patients at high risk of graft loss, Thymoglobulin®may be the preferred choice for induction therapy, while for all other patients, IL-2R antagonists should be considered first-line choice for induction therapy.

ISSN:1173-8804    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Psoriasis is a chronic inflammatory skin disease that can lead to significant physical and psychologic distress for patients. Psoriatic arthritis (PsA), originally thought to be quite a mild disorder, is now recognized as a progressive and destructive arthritis. To date, therapies for both these conditions have been non-specific and unable to maintain long-lasting remission. In addition, many of the current therapies have significant adverse effects, limiting their usefulness. However, elucidation of the pathogenesis of psoriasis and PsA at a molecular level and the development of selective biologic agents have led to an enormous expansion of the armamentarium available to psoriasis patients.Two agents (infliximab and etanercept) selectively block the role of the cytokine tumor necrosis factor (TNF)-α and have proved effective in clinical trials in the treatment of both the skin and the joint manifestations of psoriasis. A third anti-TNFα agent (adalimumab Humira®) is licensed for the treatment of rheumatoid arthritis; however, no studies have been published to date on its use in PsA or psoriasis. It is known that TNFα is elevated in both the skin and synovium of psoriatic patients and the effectiveness of its blockade by these two agents in psoriasis and PsA confirms its role in their pathogenesis.Randomized, double-blind, placebo-controlled trials have been performed with both agents in the treatment of psoriasis and PsA; in the case of etanercept these have been to support US FDA approval for use in psoriatic arthropathy. These studies are supported by smaller cohorts in open-label studies and anecdotal reports in the literature. Anti-TNFα therapy has proved to have disease-reducing activity in PsA and psoriasis and appears to be well tolerated.These studies have generally featured small numbers of patients and, until a larger cohort of treated patients is available, vigilance must be exercised. A considerable body of post-marketing safety data exists on the use of infliximab in rheumatoid arthritis and Crohn disease and for etanercept in rheumatoid arthritis and PsA. Certain issues, particularly the risk of infection, have emerged as features of the use of these agents. It remains to be seen whether effects seen in other disease entities may be extrapolated to psoriatic patients.More long-term data and experience are needed to define the role of anti-TNFα agents in the management of psoriasis and PsA. In particular, more studies are required to elucidate the finer points of co-medication; in some studies both agents have been used with other medications but there have been no formal trials of various possible combinations.

ISSN:1173-8804    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

BackgroundIntravenous immunoglobulins (IVIG) have usually been administered for replacement therapy of humoral immunodeficiencies, but their use in treating other disorders with an immune pathogenesis is increasing. The exact mechanism of action by which IVIG are of benefit in such diseases is complex and only partly understood. One of the proposed mechanisms of action is the modulation of cytokine release.MethodsWe selected 29 patients with primary hypogammaglobulinemia (common variable immunodeficiency), receiving long-term substitutive therapy with IVIG, and 14 healthy blood donors as a control group. Blood samples were then taken before and 1 hour after finishing the IVIG infusion. Only one blood sample was obtained from the healthy controls. The cytokines studied were interleukin (IL)-1β, IL-1 receptor antagonist (IL-1Ra), IL-2, IL-6, IL-8, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ.ResultsPatients with primary hypogammaglobulinemia showed significantly higher serum levels of IL-6, IL-8, IL-1Ra, and TNFα than healthy controls. IVIG infusion significantly increased serum concentration levels of IL-6, IL-8, IL-1Ra, and TNFα. No significant variation was observed in serum levels of IL-β, IFNγ, or IL-2 after IVIG infusion. Age, IVIG commercial preparation, and IVIG dose did not influence cytokine serum levels. Moreover, a significant correlation was observed between serum level variations of IL-1Ra and TNFα, as well as an associative trend between maximum changes in IL-6 and IL-8 concentrations.ConclusionsIVIG administration significantly alters the serum pattern of selected cytokines, which might explain, at least in part, the mechanism of action of IVIG in autoimmune or inflammatory disorders.

ISSN:1173-8804    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Insulin detemir (Levemir®) is a soluble long-acting human insulin analog acylated with a 14-carbon fatty acid. The fatty acid modification allows insulin detemir to reversibly bind to albumin, thereby providing slow absorption and a prolonged and consistent metabolic effect of up to 24 hours in patients with type 1 or type 2 diabetes mellitus. Insulin detemir has a more predictable, protracted, and consistent effect on blood glucose than neutral protamine Hagedorn (NPH) insulin, with less intrapatient variability in glycemic control than NPH insulin or insulin glargine.Insulin detemir, administered once or twice daily, is at least as effective as NPH insulin in maintaining overall glycemic control, with a similar or lower risk of hypoglycemia, especially nocturnal hypoglycemia, compared with NPH insulin in patients with type 1 or type 2 diabetes. Insulin detemir also provides the added clinical benefit of no appreciable bodyweight gain in patients with type 1 diabetes and less bodyweight gain than NPH insulin in patients with type 2 diabetes. Insulin detemir is, therefore, a promising new option for basal insulin therapy in patients with type 1 or 2 diabetes.

ISSN:1173-8804    

出版商:ADIS    

年代:2005

数据来源: ADIS