摘要:

Alzheimer’s disease is a neurodegenerative disorder characterised by a progressive loss of cognitive function. Despite the considerable progress being made, a complete description of the molecular pathology of this disease has yet to be elucidated. The evidence indicates that abnormal processing and extracellular deposition of the longer form of the β-amyloid (Aβ) peptide (Aβ1–42, a proteolytic derivative of the amyloid precursor protein [APP]) is implicated in the pathogenesis of Alzheimer’s disease.In this respect, recent use of experimental mouse models, in which the mice develop some aspects of Alzheimer’s disease in a reproducible fashion, has provided a new opportunity for a multidisciplinary and invasive analysis of mechanisms behind the amyloid pathology and its role in Alzheimer’s disease. It has been demonstrated, using a single transgenic mouse model system that overexpresses the human mutated APP gene, that an immunisation against Aβ1−42causes a marked reduction in the amyloid burden in the brain. The follow-up research provided more evidence that both active and passive Aβ immunisation also reduces cognitive dysfunction in transgenic mouse models of Alzheimer’s disease. Other studies using different approaches – such as secretase, cholesterol and Aβ metalloprotein inhibitors or NSAIDs – but all targeting the abnormal metabolism of Aβ have confirmed in each case that a significant reduction of amyloid plaque burden can be achieved in transgenic mouse models of Alzheimer’s disease.This research strongly supports the notion that abnormal Aβ processing is essential to the pathogenesis of Alzheimer’s disease and provides a crucial platform for the development and detailed testing of potential treatments in experimental models before each of these approaches can be proposed as a therapy for Alzheimer’s disease. Although the first clinical trial of active immunisation with a pre-aggregated synthetic Aβ42preparation (AN-1792 vaccine) met with some setbacks and was discontinued after several patients experienced meningoencephalitis, the follow-up analysis of the effect of immunisation against Aβ in humans revealed a powerful effect of vaccination in the clearance of amyloid plaques from the cerebral cortex.

ISSN:1172-7047    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

Fluctuations in response to levodopa in patients in the advanced stages of idiopathic Parkinson’s disease occur frequently and are a difficult problem to treat. Patients who are treated with levodopa have an additional 10% risk of experiencing response fluctuations with each year of treatment: 50% of patients have this problem after 5 years of receiving levodopa therapy and almost 100% of patients after 10 years.The mechanisms by which response fluctuations occur are only partially understood and can be divided into three main types:presynaptic neuronal degeneration leading to a lack of buffering of released levodopa, which is mainly related to wearing-off phenomena;postsynaptic changes in dopamine receptor sensitivity and number, partially caused by the presynaptic changes, which are clinically related to at-random response fluctuations; andpharmacokinetic and pharmacodynamic influences of exogenously administered dopaminergic agents.Several oral and parenteral treatment strategies are recommended to manage response fluctuations, such as optimisation of dopamine receptor agonist therapy in combination with a reduction of the levodopa load; use of slow-release levodopa formulations; use of catechol-O-methyltransferase inhibitors; an increase of levodopa dose frequency; use of high-dose amantadine; and intermittent or continuous use of apomorphine and/or levodopa. Continuous stimulation of dopamine receptors with dopaminergic agents is one of the crucial basic steps in the treatment of patients at an advanced stage of Parkinson’s disease, and the preferential use of dopamine receptor agonists has proven to be successful in the prevention and treatment of response fluctuations.

ISSN:1172-7047    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

Bipolar (manic-depressive) disorder is a common and severe illness. It is also potentially fatal as a result of accidents and increased mortality associated with comorbid substance use and medical illnesses, but its highest lethality results from suicide. Suicide rates, averaging 0.4% per year in men and women diagnosed with bipolar disorder, are >20-fold higher than in the general population. Suicidal acts often occur early in the illness course and in association with severe depressive and dysphoric-agitated mixed phases of illness, especially following repeated, severe depressions.Systematic consideration of risk and protective factors enhances assessment of potentially suicidal patients. Short-term interventions employed empirically to manage acute suicidality include close clinical supervision, rapid hospitalisation and use of electroconvulsive treatment. Several plausible therapeutic interventions have limited evidence of long-term effectiveness against mortality risks associated with any psychiatric disorder, including antidepressant, antimanic, antipsychotic and electroconvulsive, as well as psychosocial, treatments. However, in bipolar disorder and other major affective disorders, lithium maintenance treatment is a notable exception, with strong and consistent evidence that it reduces suicidal risk.The growing range of drugs being introduced to treat acute and long-term phases of bipolar disorder, including antiepileptic drugs, atypical antipsychotics and relatively safe, modern antidepressants, require research assessment for their ability to limit premature mortality from suicide and other causes. For now, however, more can be done to improve treatment in major affective illnesses by application of current knowledge in a systematic fashion, with close and sustained clinical follow-up of patients at risk, hopefully with a resulting reduction of mortality rates.

ISSN:1172-7047    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

Insomnia, an inability to initiate or maintain sleep, affects approximately one-third of the American population. Conventional benzodiazepines, such as triazolam and midazolam, were the treatment of choice for short-term insomnia for many years but are associated with adverse effects such as rebound insomnia, withdrawal and dependency. The newer hypnosedatives include zolpidem, zaleplon and zopiclone. These agents may be preferred over conventional benzodiazepines to treat short-term insomnia because they may be less likely to cause significant rebound insomnia or tolerance and are as efficacious as the conventional benzodiazepines. This review aims to summarise the published clinical drug interaction studies involving zolpidem, zaleplon and zopiclone. The pharmacokinetic and pharmacodynamic interactions that may be clinically important are highlighted.Clinical trials have studied potential interactions of zaleplon, zolpidem and zopiclone with the following types of drugs: cytochrome P450 (CYP) inducers (rifampicin), CYP inhibitors (azoles, ritonavir and erythromycin), histamine H2receptor antagonists (cimetidine and ranitidine), antidepressants, antipsychotics, antagonists of benzodiazepines and drugs causing sedation. Rifampicin significantly induced the metabolism of the newer hypnosedatives and decreased their sedative effects, indicating that a dose increase of these agents may be necessary when they are administered with rifampicin. Ketoconazole, erythromycin and cimetidine inhibited the metabolism of the newer hypnosedatives and enhanced their sedative effects, suggesting that a dose reduction may be required. Addition of ethanol to treatment with the newer hypnosedatives resulted in additive sedative effects without altering the pharmacokinetic parameters of the drugs.Compared with some of the conventional benzodiazepines, fewer clinically important interactions appear to have been reported in the literature with zaleplon, zolpidem and zopiclone. The fact that these drugs are newer to the market and have not been as extensively studied as the conventional benzodiazepines may be the reason for this. Another explanation may be a difference in CYP metabolism. While triazolam and midazolam are biotransformed almost entirely via CYP3A4, the newer hypnosedatives are biotransformed by several CYP isozymes in addition to CYP3A4, resulting in CYP3A4 inhibitors and inducers having a lesser effect on their biotransformation.

ISSN:1172-7047    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

The management of neurological and psychiatric disorders is a vast and evolving area for researchers, primary care physicians and specialists. To help you keep up to date with the latest advances worldwide on all aspects of drug therapy for neurological and psychiatric disorders, this section of the journal brings you information selected from the drug therapy reporting serviceInpharma Weekly1. The following reports are selected from the latest issues, summarising the most important research and development news, clinical studies, treatment guidelines, pharmacological, pharmacoeconomic and adverse drug reactions/interactions news, and expert opinion pieces published across a broad range of literature sources.

ISSN:1172-7047    

出版商:ADIS    

年代:2003

数据来源: ADIS