摘要:

Profiling of absorption of cyclosporin microemulsion (Neoral®) is a concept in therapeutic drug monitoring (TDM) designed to further optimise the clinical benefits of this formulation in transplant recipients. A single blood concentration measurement 2 hours after Neoral®administration (C2) has been shown in both liver and kidney transplant recipients to be a significantly more accurate predictor of drug exposure than trough concentrations (C0), and its use results in a reduction in the incidence and severity of cellular rejection. In a prospective trial inde novorenal transplant recipients, patients who achieved target concentrations for area under the concentration-time curve over the first 4 hours postdose (AUC0-4h) of 4500 to 5500 ng · h/ml within 5 days of transplantation had a 7% incidence of histological acute rejection, compared with 37% rejection in those patients who did not achieve this target level. Of the single sampling points, C2correlates best with AUC0-4h(r2= 0.86); C0had the poorest correlation. In an international study in 21 centres examining the absorption profiling, C2samples were the most accurate predictors of AUC0-4hand freedom from rejection.In liver transplant recipients receiving Neoral®-based maintenance immunosuppression, adoption of Neoral®C2monitoring identifies patients who are both over- and under-dosed, which is not distinguished by C0measurements. Further adjustment of C2to recommended targets, even at 5 and 10 years after transplantation, results in reduction in nephrotoxicity without exposing the patient to the risk of rejection.In summary, despite a level of simplicity comparable to C0measurement, Neoral®absorption profiling, and specifically C2measurement, is a much more sensitive approach to assessing the pharmacokinetics and predicting the clinical effect of this formulation in the individual patient, with a consequent marked reduction in the incidence of acute cellular rejection and improved long term graft function.

ISSN:1173-8804    

出版商:ADIS    

年代:2001

数据来源: ADIS

摘要:

Type 1 diabetes mellitus is a chronic T cell-mediated disease resulting from autoimmune destruction of pancreatic β-cells. This process leads to progressive and irreversible failure of insulin secretion. Development of the disease involves both genetic and environmental factors. Genetic predisposition is mainly connected with the human leucocyte antigen (HLA) region, which encodes structures responsible for antigen presentation. A comprehensive molecular understanding of the pathogenesis of the disease is essential for the design of rational and well tolerated means of prevention.This paper describes recent experimental and clinical findings and elucidates the current possibilities for immunotherapy of type 1 diabetes. The nature of breakdown of self-tolerance and the mechanisms involved in its recovery are discussed.

ISSN:1173-8804    

出版商:ADIS    

年代:2001

数据来源: ADIS

摘要:

Influenza virus infections remain an important cause of morbidity and mortality. Furthermore, a recurrence of pandemic influenza remains a real possibility. There are now effective ways to both prevent and treat influenza. Prevention of infection is most effectively accomplished by vaccination. Vaccination with the inactivated, intramuscular influenza vaccine has been clearly demonstrated to reduce serious morbidity and mortality associated with influenza infection, especially in groups of patients at high risk (e.g. the elderly). However, the inactivated, intramuscular vaccine does not strongly induce cell-mediated or mucosal immune responses, and protection induced by the vaccine is highly strain specific. Live, attenuated influenza vaccines administered intranasally have been studied in clinical trials and shown to elicit stronger mucosal and cell-mediated immune responses. Live, attenuated vaccines appear to be more effective for inducing protective immunity in children or the elderly than inactivated, intramuscular vaccines. Additionally, novel vaccine methodologies employing conserved components of influenza virus or viral DNA are being developed. Preclinical studies suggest that these approaches may lead to methods of vaccination that could induce immunity against diverse strains or subtypes of influenza.Because of the limitations of vaccination, antiviral therapy continues to play an important role in the control of influenza. Two major classes of antivirals have demonstrated ability to prevent or treat influenza in clinical trials: the adamantanes and the neuraminidase inhibitors. The adamantanes (amantadine and rimantadine) have been in use for many years. They inhibit viral uncoating by blocking the proton channel activity of the influenza A viral M2 protein. Limitations of the adamantanes include lack of activity against influenza B, toxicity (especially in the elderly), and the rapid development of resistance. The neuraminidase inhibitors were designed to interfere with the conserved sialic acid binding site of the viral neuraminidase and act against both influenza A and B with a high degree of specificity when administered by the oral (oseltamivir) or inhaled (zanamivir) route. The neuraminidase inhibitors have relatively low toxicity, and viral resistance to these inhibitors appears to be uncommon. Additional novel antivirals that target other phases of the life cycle of influenza are in preclinical development. For example, recombinant collectins inhibit replication of influenza by binding to the viral haemagglutinin as well as altering phagocyte responses to the virus. Recombinant techniques have been used for generation of antiviral proteins (e.g. modified collectins) or oligonucleotides.Greater understanding of the biology of influenza viruses has already resulted in significant advances in the management of this important pathogen. Further advances in vaccination and antiviral therapy of influenza should remain a high priority.

ISSN:1173-8804    

出版商:ADIS    

年代:2001

数据来源: ADIS

摘要:

Alzheimer's disease (AD) is a chronic neurodegenerative disease causing progressive impairment of memory and cognitive function. The amyloid cascade hypothesis suggests that mismetabolism of the β-amyloid (Aβ) precursor protein (APP) followed by subsequent formation of non-fibrillar and fibrillar Aβ deposits leads to glial activation and eventually to neurotoxicity, causing cognitive impairment. Several lines of evidence indicate that an inflammatory process contributes to the pathology of AD. First, inflammatory proteins have been identified as being associated with neuritic plaques and in glial cells surrounding these plaques. Second, certain polymorphisms of acute-phase proteins and cytokines associated with AD plaques increase the risk or predispose for earlier onset of developing AD. Third, epidemiological studies indicate that anti-inflammatory drugs can retard the development of AD. Several steps in the pathological cascade of AD have been identified as possible targets for actions of nonsteroidal anti-inflammatory drugs. For instance, microglia are considered a target because this cell type is closely involved in AD pathology through secretion of neurotoxic substances and by modulating a positive feedback loop of the inflammatory mechanism that may be involved in the pathological cascade in AD. On the basis of studies in APP transgenic mice, immunisation with Aβ was recently suggested as a novel immunological approach for the treatment of AD. Immunisation elicits Aβ-specific antibodies that could affect several early steps of the amyloid-driven cascade. Antibodies could prevent Aβ from aggregating into fibrils and accelerate clearance of Aβ by stimulating its removal by microglial cells. This review outlines the pathological and genetic evidence that an inflammatory mechanism is involved in AD and the therapeutic approaches based on inhibition or mediation of inflammation.

ISSN:1173-8804    

出版商:ADIS    

年代:2001

数据来源: ADIS

摘要:

Since its synthesis in the 1930s and subsequent introduction, sulfasalazine has been an effective treatment for inflammatory bowel disease. However, up to one-third of patients are unable to take the drug because of severe intolerance. The finding in 1977 that the anticolitic effect of sulfasalazine lay in its 5-aminosalicylic [(5-ASA); mesalazine] moiety led to the development of new generations of 5-ASA agents.These new agents include a slow continuous release formulation, pH-dependent release formulations, formulations using alternative carrier molecules and rectally administered formulations. Newer 5-ASA formulations are more effective than placebo in maintaining remission of ulcerative colitis. They have also been used for the treatment of active Crohn's disease as well as maintenance treatment of ileocolonic Crohn's disease, although their role in isolated small bowel disease is controversial. In general terms, all of the newer 5-ASA preparations are much better tolerated than sulfasalazine. The use of standard dosages of mesalazine in pregnancy appears to be tolerated; however, continuing surveillance of pregnancy outcome is recommended. While there is evidence that mesalazine can cause nephrotoxic reactions, these reactions can occur with all 5-ASA-containing preparations, particularly in individuals with existing renal disease. Blood dyscrasias can also occur with all aminosalicylates.

ISSN:1173-8804    

出版商:ADIS    

年代:2001

数据来源: ADIS