摘要:

Substantial evidence exists for the physiological role of adenosine in the modulation of primary afferent transmission. Since the first description of the antinociceptive effects of adenosine, there has been considerable interest in the development of adenosine analogues as potential analgesics for the treatment of various pain states. The direction of effect of adenosine in the periphery is complicated by the existence of multiple receptors and species differences. The analgesic actions of agents acting on adenosine receptor systems are largely attributed to actions at the spinal cord. Two subtypes of adenosine receptors (A1and A2) have been identified in the substantia gelatinosa of the spinal cord where they were shown to be localised primarily on intrinsic neurons. Although evidence exists for the involvement of A2receptors in spinally mediated antinociception, it appears to be predominantly the A1receptor subtype which plays a major role in inhibiting the nociceptive input in the dorsal spinal cord.The antinociceptive properties of adenosine and receptor-selective analogues have been demonstrated across a wide range of animal models, including acute nociceptive tests and in models of inflammation and neuropathy. These results, observed across several models of pain, strongly support the potential clinical use of these agents in various pain states. In humans, systemic or intrathecal administration of adenosine was shown to be effective against experimentally induced pain in healthy volunteers. Subsequently, there is evidence for the effectiveness of systemic and spinally administered adenosine in patients with neuropathic pain.A number of studies have demonstrated possible interactions between adenosine and glutamate in the spinal cord, and betweenN-methyl-D-aspartate receptor activation and adenosine release elsewhere in the brain. There is also some evidence that drugs acting to inhibit the metabolism of adenosine may have therapeutic potential in pain states. In this context, the release of adenosine appears to be elevated in hyperexcitable neuronal systems. This would allow therapies to selectively target active neurons in pain systems and therefore would be expected to have low adverse effect liability.

ISSN:1172-7047    

出版商:ADIS    

年代:2000

数据来源: ADIS

摘要:

Neuroanatomical, neurochemical and neuropharmacological studies support a role for histamine in the control of the waking state. In this respect, the histamine H1receptor plays a predominant role. Acute administration of first-generation H1receptor antagonists [chlorphenamine (chlorpheniramine), diphenhydramine, mepyramine (pyrilamine) and triprolidine] produces somnolence, an increased likelihood of falling asleep and reduced concentration. These effects led to the use of these drugs as over-the-counter medications to promote sleep. The widespread use of sedative antihistamines as sleep aids stems from inappropriate attempts by undiagnosed and untreated patients with insomnia to resolve their sleep disturbance.The limited number of studies directed at disclosing the effects of first-generation antihistamines on sleep in patients with insomnia tend to suggest that these compounds are effective for the treatment of chronic insomnia; however, methodological flaws limit the validity of their conclusions. In addition, the development of acute tolerance to the sedative effects of first-generation H1receptor antagonists further calls into question their effectiveness as sleep aids in transient, short or long term insomnia.Despite their widespread use, current evidence suggests that sedative antihistamines compare unfavourably with the benzodiazepine, cyclopyrrolone (zopiclone), imidazopyridine (zolpidem) and pyrazolopyrimidine (zaleplon) hypnotics, which consistently improve the difficulty falling asleep or maintaining sleep that is experienced by individuals with chronic insomnia.

ISSN:1172-7047    

出版商:ADIS    

年代:2000

数据来源: ADIS

摘要:

Migraine is the most frequent subtype of primary headache. It affects about 18% of females and 6% of males in the general population. Despite this high frequency the disease is substantially underdiagnosed and undertreated. Several hypotheses have been put forward to explain the pathogenesis of migraine; at present, a derangement of vascular tone is believed to be an essential component for the development of clinical attacks of the disease.Helicobacter pyloriinfection, the most common cause of gastritis and peptic ulcer, has been recently associated with various primary functional vascular disorders such as primary Raynaud's phenomenon and recurrent spontaneous abortion. The infection causes a persistent activation of the immune system, which results in local and systemic release of a variety of vasoactive substances. Recent evidence suggest that infection withH. pylorimay also be associated with migraine. In patients with migraine who are infected withH. pylori, eradication of the bacterium resulted in the complete disappearance of migraine attacks in 20% of individuals and a significant decrease in intensity, duration and frequency of symptoms in the vast majority of the others. Further studies, however, remain necessary to better determine the pathogenetic mechanisms underlying this association. If confirmed, this could represent a novel diagnostic and therapeutical approach for at least a subgroup of migraineurs.

ISSN:1172-7047    

出版商:ADIS    

年代:2000

数据来源: ADIS

摘要:

The treatment of schizophrenia in older populations poses special challenges for patients, family members and clinicians. These include changes in manifestation of schizophrenic illness in later life, age-related changes in response to pharmacological treatments and psychosocial issues associated with older life status.As with younger individuals, antipsychotic medications constitute the mainstay of treatment for schizophrenia in the elderly. However, the drug treatment of schizophrenia is substantially affected by the aging process. Medication sensitivity is pronounced in the elderly, largely due to age-related changes in the body's capacity to metabolise psychotropic and other drugs. Other relevant factors include higher rates of physical comorbidity, drug-drug interactions and age-related adverse effects. Generally, the appropriate starting dose of antipsychotic medication in the elderly is 25% of the adult dose. Total daily maintenance doses may be 30 to 50% of the adult dose.The use of conventional antipsychotics in the elderly is limited because of their association with extrapyramidal symptoms and anticholinergic and cardiovascular adverse effects. The advent of atypical antipsychotics has revolutionised the treatment of psychosis in the elderly. Based on the general psychiatric literature, the atypical agents have been found to be as efficacious as conventional agents in reducing positive symptoms, more efficacious against negative symptoms, and to have a much more benign adverse effect profile.Nonpharmacological issues in the management of schizophrenia in the elderly are at least as important as in younger individuals. Older individuals may face additional challenges that affect health outcome, such as living alone or being unable to drive. All drug treatments should be partnered with supportive approaches and psychosocial interventions that maximise treatment compliance and improve outcome.

ISSN:1172-7047    

出版商:ADIS    

年代:2000

数据来源: ADIS

摘要:

Epilepsy affects approximately 14 to 24% of patients who are mentally retarded. The prevalence increases in those patients who have associated neurological disorders. The severity of mental retardation also influences prevalence. Approximately 7 to 15% of patients with mild to moderate mental retardation, 45 to 67% of those with severe retardation and about 50 to 82% of patients with profound retardation have a lifetime history of epilepsy. The prevalence of epilepsy also varies according to patients' age and the aetiology of mental retardation. Both false positive and false negative diagnoses of epilepsy remain possible in patients who are mentally retarded.Polytherapy with anticonvulsants is a commonly used approach to the treatment of epilepsy in patients with mental retardation. However, a reduction in polytherapy has been shown to improve both seizure frequency and the behavioural profile of these patients. Because of the cognitive and behavioural adverse effects of barbiturates and the effect of phenytoin on the CNS, they are not ideal as drugs of first choice in patients with epilepsy who are mentally retarded. Both valproic acid (sodium valproate) and lamotrigine are favoured for use in these patients because of their broad spectrums of anticonvulsant activity and thus efficacy in different seizure types, effects in Lennox-Gastaut syndrome, and minimal effects on cognition and behaviour. The use of carbamazepine is restricted in certain seizure types but can be chosen for some patients who are mentally retarded because of its mood stabilising properties. Oxcarbazepine has similar properties to those of carbamazepine but with a better tolerability profile. Vigabatrin, felbamate, gabapentin, topiramate, tiagabine and zonisamide are also useful, particularly as add-on therapy. Serious adverse events, such as visual field defects caused by vigabatrin, and fatal blood dyscrasias and hepatotoxicity associated with felbamate, will restrict the use of these drugs in this population. Neurosurgical treatment has been proven effective in a number of patients with epilepsy who are mentally retarded.

ISSN:1172-7047    

出版商:ADIS    

年代:2000

数据来源: ADIS

摘要:

The occurrence of seizures in the first week after traumatic brain injury is a well known phenomenon and requires the physician to address several issues in the management of patients with such an injury. There is a wide range in the reported incidence of clinical seizures after brain injury. An incidence of 5 to 15% is often quoted, although the incidence can be higher (20 to 24%) if nonconvulsive electroencephalographic (EEG) criteria for seizures are used. The main clinical risk factors for seizures are younger age, greater severity of brain injury and subdural haematoma and penetrating wounds.The significance of seizures is highlighted by initially considering the pathophysiology of brain injury. Early after brain injury there is a selective increase in nonoxidative glucose metabolism, increased extracellular levels of glutamate and potassium, and a moderate reduction in cerebral blood flow. This state of cellular stress creates vulnerability in the cells to further injury. Seizures give rise to similar metabolic stress and serve to exaggerate hyperglycolysis and thereby may give rise to secondary injury.It is important to recognise and treat post-traumatic seizures that occur in the early postinjury period. These seizures may be nonconvulsive and require EEG monitoring. We have gained considerable experience with continuous EEG monitoring of traumatic brain−injured patients and find that over 20% of patients will have seizures, 50% of which are nonconvulsive. Ongoing repeated seizures or status epilepticus, require immediate treatment with benzodiazepines, followed by long-acting anticonvulsants (e.g. phenytoin). Recalcitrant status epilepticus requires treatment with continuous intravenous infusions of anticonvulsants (e.g. barbiturates, propofol, midazolam).

ISSN:1172-7047    

出版商:ADIS    

年代:2000

数据来源: ADIS

摘要:

Over the past decade many neuroprotective agents have been developed with the hope of being able to improve outcome in patients with acute cerebral disorders, such as stroke, head injury and subarachnoid haemorrhage. Unfortunately, in the field of head injury none of the phase III trials performed have convincingly demonstrated efficacy in the overall population. A common misconception is that consequently these agents are ineffective. Such has, however, not been proven, and some trials show evidence of efficacy in subgroups of the population studied. The negative results, as reported in the overall population, may in part be caused by specific aspects of the head injury population, as well as by aspects of clinical trial design and analysis. The present manuscript addresses these issues, and critically analyses the relevance of preclinical evidence and pharmacokinetic studies.It appears that decisions about initiating phase III trials in head injury were strongly influenced by experience in related disorders, such as subarachnoid haemorrhage and stroke. The available evidence from experimental studies in the field of head injury is limited and uncertainties exist about whether the pathophysiological mechanisms at which neuroprotective agents were targeted really occurred in all patients studied. Moreover, for many agents, aspects of pharmacokinetics and penetration into the brain were insufficiently investigated before proceeding into phase III trials.The heterogeneity of the head injury population may cause specific problems, such as a risk of imbalances between placebo and treated groups, but also causes problems when a possible treatment effect is evaluated in relation to the prognostic effect present. It is concluded that trials of neuroprotective agents should be targeted first of all to a population in which the mechanism at which the agent is directed is likely to be present, and secondly to a population in which the chances of demonstrating efficacy are realistic, i.e. patients with an intermediate prognosis. The aim in most trials of trying to demonstrate a 10% absolute improvement in favourable outcome in patients with head injury is over-optimistic and unrealistic in relation to the heterogenous patient population. Specific problems incurred by the use of the dichotomised Glasgow Outcome Scale as the primary outcome measure are discussed, and the risk highlighted that even a substantial change in outcome distribution may not be adequately detected.The complexity of problems occurring in clinical trial design and analysis in head injury is such that a strong and sustained input and effort is required from all experts involved in the field of neurotrauma.

ISSN:1172-7047    

出版商:ADIS    

年代:2000

数据来源: ADIS