摘要:

The Maillard reaction is a complex cascade of reactions initiated by glycation or the spontaneous reaction between the free amino groups of proteins and reducing sugars. The cascade reaction leads to the production of the so-called ‘advanced glycation end-products’ (AGEs), which include brown pigments, fluorescent compounds, free radicals and cross-linked protein products.While a role for protein glycation and AGEs in the complications associated with diabetes mellitus has been established, it is now becoming clear that the Maillard reaction may have a more widespread importance in human disease, especially those disorders typified by amyloidosis. Many of the properties of products of the Maillard reaction are also found in the brain lesions that characterise Alzheimer's disease, namely neuritic plaques and neurofibrillary tangles. AGE-modified tau and amyloid &bgr;-protein (A&bgr;) are both found in the brains of patients with Alzheimer's disease. Glycation of tau inhibits its normal microtubule-binding functions, while glycated A&bgr; serves to accelerate the nucleation of aggregated A&bgr;. Glycated tau can generate oxygen-free radicals in cell culture, and biomarkers of neuronal protein oxidation co-localise with the neuropathological hallmarks of Alzheimer's disease. These findings are consistent with the involvement of glycation and glyco-oxidation in the generation of these lesions from normal cellular proteins.Inhibitors of the Maillard reaction, such as pimagedine (aminoguanidine), are currently being assessed in clinical trials for the treatment of diabetic complications. In contrast, their potential for the treatment of Alzheimer's disease is only just being recognised, although the ability of these agents to cross the bloodbrain barrier may limit their therapeutic use. Tenilsetam, a compound shown to improve cognitive function in patients with Alzheimer's disease, has been found to inhibit glycation-induced protein cross-linking, as have the anti-inflammatory compounds indomethacin and aspirin (acetylsalicylic acid), drugs that have also shown therapeutic potential in Alzheimer's disease.These recent studies extend the therapeutic potential of inhibitors of the Maillard reaction to Alzheimer's disease. They also indicate possible neuroprotective approaches to the disease based on inhibition of the action of AGEs by the use of AGE-binding compounds and the modulation of AGE-cross-linked protein degradation. Finally, the pathological role of glycation in Alzheimer's disease implicates a disorder of metabolism as a primary defect in the disease, and offers the prospect of prophylaxis and improved diagnosis.

ISSN:1172-7047    

出版商:ADIS    

年代:1996

数据来源: ADIS

摘要:

Essential tremor is a very common movement disorder characterised by postural rhythmic oscillatory movements. The disorder may effect almost any body part, is gradually progressive and may be severely debilitating.First-line medical treatment usually involves propranolol or other nonselective &bgr;-adrenoceptor antagonists, or primidone. Both of these approaches reduce tremor severity in approximately 70% of patients, but tend to lose efficacy over time. Other promising medicines that have been less rigorously evaluated include benzodiazepines, calcium antagonists, carbonic anhydrase inhibitors, gabapentin, clozapine and low-dose theophylline. Botulinum toxin injected into the affected muscles helps some patients, and contralateral tremor can be dramatically reduced by surgical thalamotomy or deep brain thalamic stimulation.Recent advances in our understanding of tremor mechanisms should greatly facilitate rational therapy in the near future.

ISSN:1172-7047    

出版商:ADIS    

年代:1996

数据来源: ADIS

摘要:

Several specific epileptic syndromes begin during adolescence, including juvenile myoclonic epilepsy, juvenile absence epilepsy, epilepsy with tonic-clonic seizures on awakening, and some forms of partial epilepsies. These syndromes need careful attention in terms of drug treatment because adolescence is a complex period socially and behaviourally and the adverse effects of drugs during this period could prove problematic. Whether all epilepsies that begin during adolescence require treatment is a difficult issue. In 10% of adolescents, a seizure may remain isolated. Furthermore, the avoidance of precipitating factors could be a sufficient therapeutic strategy in some patients. Instructions should be given regarding the potentially seizure-triggering effect of certain behaviours, e.g. sleep deprivation and the consumption of alcohol (ethanol) and recreational drugs. If drug treatment is required, the choice of drug will depend on the identified epileptic syndrome and the efficacy and adverse effect profile of the drug.

ISSN:1172-7047    

出版商:ADIS    

年代:1996

数据来源: ADIS

摘要:

Sexual function can be subdivided into phases of sexual desire, penile erection, ejaculation and orgasm. Dysfunction of these processes is manifest as disorders that include hypoactive sexual desire, male erectile dysfunction, premature and retarded ejaculation, and anorgasmia. These disorders can be primary in aetiology or can be caused by a number of psychoactive drugs including, commonly, antidepressants.At present, sexual dysfunction is rarely treated with pharmacological agents. The usual approach consists of psychotherapy. However, in recent years, more interest has arisen in treating disorders of sexual function with psychopharmacological drugs, particularly sexual dysfunction that is the adverse effect of antidepressants.Clinical reports suggest that primary premature ejaculation can be successfully treated with clomipramine and selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors. At present, only a few oral medications have been shown to be useful in the treatment of erectile dysfunction (including yohimbine and trazodone), although these have not been developed specifically for this indication. The pharmacological treatment of primary retarded ejaculation and female primary anorgasmia still offers no efficacy. There are, on the other hand, a number of drugs available for treating the sexual adverse effects of antidepressant therapy. These appear to act either on the central or peripheral nervous system and include cyproheptadine, bethanechol, yohimbine, buspirone and some dopamine receptor agonists [amantadine, amfebutamone (bupropion), dexamphetamine and pemoline].More methodologically correct clinical research is necessary to elucidate better treatments for sexual dysfunction.

ISSN:1172-7047    

出版商:ADIS    

年代:1996

数据来源: ADIS

摘要:

Specific inhibitors of monoamine oxidase type B (MAO-B) constitute a novel and expanding pharmacological class. At present, only one compound from this class is marketed, selegiline (deprenyl). Other MAO-B inhibitors that are in various stages of development include lazabemide and mofegiline, which are differentiated from selegiline by their greater specificity for MAO-B and the absence of active metabolites.The role of MAO-B in the catabolism of amines (essentially, dopamine and phenylethylamine) and the acceleration of the neurodegenerative process (i.e. oxidative stress) justifies the most common indications for these compounds - Parkinson's disease, Alzheimer's disease, pathological aging and, possibly, depression. The possibility that MAO-B inhibitors may antagonise the evolution of neurodegenerative disorders needs further scrutiny.Selegiline is the most extensively studied MAO-B inhibitor and is marketed for Parkinson's disease in most Western countries. A dosage of 10 mg/day improves motor symptoms and delays the need for levodopa inde novopatients. Adverse effects are rare and trivial, although some reports of changes in blood pressure have to be considered seriously. Long term clinical trials with new MAO-B inhibitors are not available. Current data suggest that these drugs are well tolerated and have a low potential for drug interactions.

ISSN:1172-7047    

出版商:ADIS    

年代:1996

数据来源: ADIS

摘要:

SynopsisAmisulpride is a substituted benzamide. It is a dopamine antagonist with high selectivity for dopamine D2and D3receptors. In high doses, amisulpride exhibits dopaminergic blocking activity similar to that induced by classical antipsychotic agents, whereas in low doses it appears to facilitate dopaminergic transmission.In well controlled studies of patients with primary negative symptoms of schizophrenia who had high negative and low positive symptoms scores, amisulpride 50 to 300 mg/day was more effective than placebo. The drug was at least as effective as low-dose fluphenazine (2 to 12 mg/day) in less rigorous trials which included patients with negative symptoms of schizophrenia.At higher dosages (600 to 1200 mg/day), amisulpride exhibits efficacy similar to that of haloperidol 5 to 40 mg/day or flupenthixol 25 mg/day in patients with positive symptoms of schizophrenia.In low and high dosages, amisulpride is generally well tolerated. Extrapyramidal symptoms (EPS) induced by amisulpride can occur at both low and high dosages and are dose-dependent. Symptoms are generally mild or moderate. In comparative trials, amisulpride caused an incidence of EPS similar to that with placebo and lower than that caused by haloperidol, flupenthixol or fluphenazine. Neuroendocrine adverse events were reported rarely with low-dose amisulpride and at similar incidences with amisulpride ≥600 mg/day and haloperidol 16 mg/day. Insomnia and excitation occurred rarely.As classical antipsychotic drugs are not generally effective in reducing negative symptoms of schizophrenia, amisulpride should be considered a promising agent in the management of patients with schizophrenia who have predominantly negative symptoms. While amisulpride does not offer superior efficacy over classical antipsychotics in the management of patients with positive symptoms of schizophrenia, its lower potential for causing EPS justifies consideration of its use, especially in patients intolerant of classical antipsychotics.Pharmacodynamic PropertiesLike classical antipsychotic drugs, amisulpride is an antagonist of dopamine D2and D3receptors; however, the D3to D2receptor selectivity of amisulpride is greater than that of classical antipsychotic drugs. Amisulpride has little affinity for other neurotransmitter receptors or dopamine receptor subtypes. Low doses of amisulpride in animals facilitate presynaptic dopamine receptormediated behaviours, whereas higher doses decrease behaviours associated with postsynaptic receptor activation.No deleterious effects on psychometrics or memory performance were observed after single oral doses up to 200mg in healthy volunteers. Like classical antipsychotic drugs, amisulpride affects dopaminergic control of plasma hormone levels. Amisulpride produced a significant increase in daytime and nocturnal prolactin levels in healthy volunteers. Daytime, but not nocturnal, thyroidstimulating hormone levels were increased significantly and a significant decrease in the sleep-onset growth hormone peak was recorded. Other endocrine effects were minor.Pharmacokinetic PropertiesObserved peak plasma concentrations after single oral doses of amisulpride 50 and 200mg, respectively, are approximately 54 and 443 μg/L at 3 hours. An earlier, lower peak concentration is detectable 1 hour after drug administration. The drug distributes widely and rapidly to the tissues and is minimally bound to plasma protein. Clearance is principally through renal elimination of unchanged drug, although 10 to 15% of a dose is metabolised to inactive metabolites. Elimination is biphasic with a terminal elimination half-life of approximately 12 hours.Therapeutic EfficacyAmisulpride has demonstrated efficacy against both positive and negative symptoms of schizophrenia. At low dosages (≤300 mg/day) in randomised, doubleblind trials which included patients with high negative symptom scores and low positive symptom scores, amisulpride reduced negative symptoms as measured by the Scale for Assessment of Negative Symptoms (SANS). Scores were reduced by 32 to 46% from baseline compared with 8 to 23% in placebo-treated patients. In 2 double-blind trials with less rigorous inclusion and exclusion criteria, lowdose amisulpride (≤300 mg/day) and fluphenazine 2 to 12 mg/day reduced Brief Psychiatric Ratings Scale (BPRS) scores and SANS scores to a similar extent (BPRS 40 and 29% and SANS 18 and 22%, respectively).In patients with positive symptoms of schizophrenia, amisulpride 400 to 1200 mg/day reduced BPRS scores by approximately 50%, a response rate not significantly different from that produced by haloperidol or flupenthixol in doubleblind, randomised trials.TolerabilityIn low and high dosages, amisulpride is generally well tolerated. At low dosages (50 to 300 mg/day), amisulpride was as well tolerated as placebo. Adverse events reported in comparative trials included extrapyramidal symptoms (EPS), endocrine adverse events, insomnia, agitation and dryness of the mouth.EPS can occur at both low and high dosages of amisulpride, but the incidence is dose-related, with increases at dosages greater than 800 mg/day. Symptoms are usually mild or moderate and occur less frequently in amisulpride-treated patients than in comparable patients receiving haloperidol, flupenthixol or fluphenazine.The incidence of neuroendocrinological adverse events associated with low dosages of amisulpride is similar to that associated with placebo, and with high dosages the incidence is similar to that observed in haloperidol-treated patients.Dosage and AdministrationAmisulpride is administered orally twice daily. The recommended dosages of amisulpride are 50 to 300 mg/day for the treatment of patients with predominantly negative symptoms of schizophrenia and 400 to 800 mg/day for those with positive symptoms. Dosages as high as 1200 mg/day have been studied, but were not clearly superior to amisulpride 800 mg/day. Dosage reduction may be necessary in patients with creatinine clearance below 30 ml/min.

ISSN:1172-7047    

出版商:ADIS    

年代:1996

数据来源: ADIS