摘要:

Oral contraceptive (OC) use is associated with an increased risk of cerebral thrombosis. However, the risk decreases with decreasing estrogen and progestogen dosage, and is not demonstrable for progestogen-only OCs. The risk estimates found in newer studies are substantially lower than those demonstrated for the OC brands used in the 1960s and 1970s.The relative risk of thrombotic stroke among users of OCs compared with non-users (i.e. never users plus ex-users) is about 1.5 and does not change with increasing age. The absolute risk, on the other hand, increases nearly exponentially with increasing age. For a 20-year-old healthy woman, the absolute risk of a cerebral thrombosis is about 2 per 100 000 individuals per year. The attributable risk from using OCs containing 30 to 40μg of estrogen is about 1 per 100 000 per year, corresponding to a total risk of 3 per 100 000 per year - still a very low risk. The type of progestogen in OCs has no influence on the risk of thrombotic stroke. OC use does not confer an increased risk of intracerebral haemorrhage.

ISSN:1172-7047    

出版商:ADIS    

年代:1997

数据来源: ADIS

摘要:

Myo-inositol is a ubiquitous carbohydrate that is present in large amounts in brain tissue and is involved in neuronal signalling and osmoregulation. This sugar is an essential component of the inositol signalling system, which is a post-receptor second messenger signalling system found in many cells.Myo-inositol is the precursor of membrane inositol phospholipids, which are critically linked to a number of CNS receptor signalling systems, including muscarinic, serotonergic, adrenergic, metabotropic and histaminergic systems, and those linked to cholecystokinin, tachykinins, neurotensin, platelet activating factor and other transmitters.Upon stimulation of these receptors, a signal is transmitted through a guanosine triphosphate (GTP)-binding protein (Gq), which then activates the enzyme phospholipase C. This results in the release of a second messenger, inositol 1,4,5-trisphosphate (InsP3), from membrane inositol phospholipids. InsP3then causes the release of free intracellular calcium into the cytosol, activating a number of enzymes or receptors.Myo-inositol in the brain is derived from 3 sources: (i) receptor stimulation (a salvage pathway); (ii)de novosynthesis from glucose; and (iii) uptake of dietarymyo-inositol through plasma membranemyo-inositol transporters. Mostmyo-inositol is probably derived from the first 2 sources, which are controlled through the lithium-sensitive enzymemyo-inositol monophosphatase (IMPase). This enzyme acts uponmyo-inositol monophosphates, hydrolysing them to release freemyo-inositol. Recent biochemical, molecular and crystallographic studies have demonstrated that the overall metabolism of brain inositol is closely modulated by this enzyme. Lithium salts, which are commonly used in various psychiatric conditions, inhibit this enzyme, and this action has been implicated as a therapeutic mechanism of action of lithium.A change in the availability of CNS inositol may lead to altered brain cell signalling pathways and, eventually, to the development of a neuropsychiatric disorder. Recent evidence indicates thatmyo-inositol has psychoactive effects, with initial studies demonstrating effectiveness in the treatment of depression, panic disorder and obsessive-compulsive disorder. At present, the exact mechanism of these clinical effects is uncertain. The development of various inositol system-based drugs may lead to future psychoactive drugs designed to modulate a second messenger cascade of events rather than a receptor system, and will lead to further understanding of CNS disease from a post-receptor second messenger perspective.

ISSN:1172-7047    

出版商:ADIS    

年代:1997

数据来源: ADIS

摘要:

Neurocysticercosis is, worldwide, the most frequently occurring parasitic disease of the brain. Its clinical picture is complex and so the disorder may present in various forms that range from a benign self-limited disorder to a severe life-threatening condition.Therapeutic approaches must be selected for each patient according to the number, location and stage of cysticerci. and the degree of the inflammatory response raised by the host against the parasites. Cysticercosis of brain parenchyma, including clumps and giant cysts, respond well to cestocidal drugs and have a good prognosis. In cases of ventricular cysticercosis, cestocidal drugs and surgery, alone or in combination, usually produce good results. Cysticercotic meningitis, accompanied by hydrocephalus, vasculitis and widespread chronic inflammation in the subarachnoid space, is a therapeutic challenge. These cases frequently have a poor prognosis due to secondary complications.Efforts to eradicate cysticercosis must emphasise public health measures of sanitation and extensive education about the mechanisms of transmission.

ISSN:1172-7047    

出版商:ADIS    

年代:1997

数据来源: ADIS

摘要:

Febrile seizures are common events, affecting at least 2 to 5% of children. They occur more often in boys. Most are ‘simple’, i.e. are generalised, shorter than 15 minutes in duration, and do not recur within 24 hours. When the seizures are focal or prolonged, or recur within a day, they are called ‘complex’. One-third of febrile seizures recur, with recurrences more frequent when febrile seizures begin in the first year of life, the initial febrile seizure is complex, the fever triggering the first febrile seizure has been brief and of low grade, there is a family history of febrile seizures or epilepsy, and the child is developmentally or neurologically abnormal. Children with febrile seizures are at an increased risk for later epilepsy, particularly when febrile seizures recur and especially when they are complex.Although a clinician may elect not to treat children to prevent recurrences of febrile seizures, there are stronger arguments in favour of treatment, including the prevention of major parental anxiety and family disruption, reduction of medical costs, and reduction in the risk of neurological morbidity. Daily medication with oral phenobarbital (phenobarbitone), primidone or valproic acid (sodium valproate) is often effective as prophylaxis against febrile seizures. Intermittent medication, however, taken only at the times of fever, is preferable since efficacy is higher and adverse effects lower. Antipyretics alone do not prevent febrile seizures from recurring, but intermittent therapy with benzodiazepines (rectal or oral diazepam and possibly oral nitrazepam or clobazam) is highly effective in lowering the recurrence risk. Whether this lessens the risk of later epilepsy is unknown.

ISSN:1172-7047    

出版商:ADIS    

年代:1997

数据来源: ADIS

摘要:

Intranasally administered medications for the treatment of headache have recently received increased attention because they offer a rapid onset of activity, even in patients with nausea and vomiting. In addition, patients are likely to use intranasal agents earlier in the course of a headache attack because the intranasal route overcomes potential patient objections to administration of agents by injection and suppository.Although not yet widely available, intranasally administered headache medications are likely to enjoy widespread acceptance once introduced to markets worldwide. At present, butorphanol nasal spray is available for use in severe headache and other pain syndromes only in the US. This drug is a synthetic opioid agonist-antagonist and thus is useful for pain control when an opioid is required. Dihydroergotamine nasal spray has recently become available in Canada, and should be available in the US and other countries in the near future. Sumatriptan nasal spray has recently been approved in The Netherlands and should soon be available throughout Europe. Other abortive migraine agents may become available in tablet or capsule form and later for nasal administration. Capsaicin, lidocaine (lignocaine) and calcitonin have been used for relief of migraine and cluster headache, but have not yet been widely accepted.

ISSN:1172-7047    

出版商:ADIS    

年代:1997

数据来源: ADIS

摘要:

The glutamate hypothesis of schizophrenia has been developed based on the observation that psychotic symptoms induced by phencyclidine and related agents, which are antagonists at theN-methyl-D-aspartate (NMDA) glutamate receptor, closely resemble both the positive and negative symptoms of schizophrenia. In contrast to the dopamine hypothesis, which explains primarily with positive schizophrenic symptoms, the glutamate hypothesis may provide a more comprehensive view of the illness.Postmortem brain assays also support the glutamate hypothesis by demonstrating alterations in glutamate receptors in several brain areas in patients with schizophrenia, especially remarkable increases in the receptors in frontal and parieto-temporal association fields. This increase in glutamate receptors may reflect postsynaptic up-regulation in response to a deficiency in glutamatergic neuronal activity. Thus, the glutamate hypothesis implies that schizophrenic symptoms might be ameliorated by augmenting glutamatergic neural transmission.Recent clinical studies have been conducted using glycine, milacemide or D-cycloserine as adjuncts to or as a replacement for antipsychotics, in an attempt to augment NMDA receptor-mediated glutamatergic functions by activating the glycine modulatory site. Glycine adjuvant treatment was moderately effective in some patients in all studies and significantly improved negative symptoms in a placebo-controlled study. Replacement of antipsychotics by milacemide, a supposed glycine prodrug that crosses the blood-brain barrier, did not ameliorate schizophrenic symptoms. This lack of effect may be due to the fact that milacemide is predominantly an inhibitor of monoamine oxidases rather than a glycine agonist. Adjuvant administration of D-cycloserine, a partial agonist of the glycine site, was inconclusive, with improvement in negative symptoms occurring in one study and overall exacerbation in most patients in another study.Well designed placebo-controlled studies using orally active full agonists of the glycine regulatory site should be pursued in the future. Also, intervention at other sites within the NMDA receptor complex should be considered.

ISSN:1172-7047    

出版商:ADIS    

年代:1997

数据来源: ADIS

摘要:

SynopsisBuspirone is an anxiolytic agent from the azapirone class of compounds. It differs structurally and pharmacologically from the benzodiazepines. Although the exact anxiolytic mechanism of action of buspirone is unknown, its primary pharmacological action is its binding to serotonin 5-HT1Areceptors in the brain. Unlike benzodiazepines, buspirone has no demonstrated sedative effect and has little effect on psychomotor performance or cognition. In addition, animal and human studies have found little evidence that buspirone has abuse potential or dependence liability.Recent large comparative trials have confirmed that buspirone is superior to placebo and has similar efficacy to benzodiazepines in the treatment of patients with anxiety. In comparative trials, patients receiving buspirone had reductions in Hamilton Anxiety Rating Scale (HAM-A) total scores ranging from 37 to 60%. By comparison, those receiving benzodiazepines had HAM-A total score reductions of 29 to 69%. Buspirone usually produced significant reductions in HAM-A total scores within 1 to 2 weeks of treatment initiation. Some studies have noted a faster onset of action with benzodiazepines than with buspirone, but larger, more recent trials have not confirmed this.Buspirone has also demonstrated efficacy in patients with anxiety and coexisting alcohol (ethanol) abuse/dependence or depression. Buspirone not only reduces symptoms of anxiety in these patients but produces improvements in the comorbid disorder. In most studies, alcohol-dependent patients were significantly more likely to remain on treatment than those receiving placebo. In patients with mixed anxiety-depression, treatment with buspirone produced significant reductions in both the HAM-A and Hamilton Depression Rating Scale total scores. Buspirone produced significant improvements in the cardinal symptoms of depression (depressed mood, guilt, work and interest, anergia and diurnal variation of mood) which indicates that it may have an antidepressant effect independent of its anxiolytic activity.In summary, recent clinical trials have verified the efficacy of buspirone in the treatment of anxiety disorders and confirmed its role as a well established alternative to benzodiazepines. Buspirone is particularly useful in patients wishing to avoid adverse effects associated with the benzodiazepines, such as sedation and performance and cognitive impairment, or those in whom abuse and dependence potential are a concern.Pharmacodynamic PropertiesAlthough the exact anxiolytic mechanism of action of buspirone is unknown, the drug is believed to act primarily through effects on central serotonergic systems. Buspirone binds both presynaptically and postsynaptically to serotonin 5-HT1Areceptors in the brain. At presynaptic receptors in the dorsal raphé, buspirone acts as a full agonist; postsynaptically, it acts as a partial agonist at 5-HT1Areceptors in the hippocampus. Buspirone also has a moderate affinity for presynaptic dopamine D2receptors. Unlike benzodiazepines, it has no effect on the &ggr;-aminobutyric acid (GABA)-benzodiazepine complex.Buspirone has a low potential for producing sedation or impairment of psychomotor performance and cognition. When compared with various benzodiazepines, buspirone produces significantly less daytime sedation and has less effect on tests designed to measure psychomotor performance, including driving ability. Benzodiazepines significantly impaired memory function, but buspirone had no effect.The abuse and dependence potential of buspirone appears to be minimal. In animal drug discrimination and drug self-administration studies, buspirone had no acute subjective intoxicating or reinforcing properties. In addition, benzodiazepines were significantly more likely to be preferred to buspirone in study participants with a history of substance abuse. The dependence liability of buspirone is lower than that of benzodiazepines as measured by significantly fewer withdrawal symptoms after drug discontinuation. Furthermore, buspirone is not cross-tolerant with benzodiazepines, as evidenced by the inability of buspirone to prevent benzodiazepine withdrawal symptoms after long term treatment with these drugs.Pharmacokinetic PropertiesBuspirone is well absorbed after oral administration; however, substantial firstpass metabolism reduces oral bioavailability to approximately 4%. At therapeutic dosages there is a linear relationship between dose and area under the plasma concentration-time curve (AUC). Administration of buspirone with food substantially increases the AUC.Buspirone undergoes extensive metabolism to at least 7 major and 5 minor metabolites. Less than 1% of an administered dose is excreted unchanged in the urine. The elimination half-life of buspirone ranges from 2 to 11 hours.The elimination of buspirone is reduced in patients with cirrhosis; however, interpatient variation is considerable. Some studies have also reported decreases in buspirone clearance in patients with renal impairment. The pharmacokinetic properties of buspirone do not appear to be changed in the elderly.Therapeutic EfficacyData from several recent large comparative studies have confirmed that buspirone is superior to placebo and has equivalent efficacy to benzodiazepines in the treatment of patients with anxiety. After treatment periods of 3 to 6 weeks, buspirone 10 to 60 mg/day produced reductions in Hamilton Anxiety Rating Scale (HAM-A) total scores ranging from 37 to 60%. This compared with reductions in HAM-A total scores of 29 to 69% for patients receiving benzodiazepines. Buspirone also produced significant reductions in HAM-A total scores in a few trials in patients aged ≥ 65 years. HAM-A scores in patients receiving buspirone declined progressively over the treatment period and were usually significantly different from baseline or placebo within 1 to 2 weeks of treatment. Results of a few studies have shown that benzodiazepines have a faster onset of effect than buspirone, although this was not confirmed in recent, larger studies. Buspirone is effective in alleviating both the psychic and the somatic symptoms of anxiety; however, psychic symptoms generally declined first. Studies evaluating the long term efficacy of buspirone have confirmed that the drug is effective after treatment periods lasting up to 1 year.Patients with anxiety and co-existing alcohol (ethanol) use disorders receiving buspirone were significantly more likely to remain on treatment than those receiving placebo in 3 of 4 studies. In these studies, buspirone also produced significantly greater reductions in anxiety and alcohol consumption than placebo.The addition of buspirone to treatment with selective serotonin reuptake inhibitors (SSRIs) in patients with major depression who had failed to respond, or had partially responded, to an adequate trial with an SSRI improved depressive symptoms. Preliminary studies suggest that buspirone may be useful in the treatment of agitation in patients with dementia.In patients with mixed anxiety-depression, buspirone was significantly superior to placebo in reducing HAM-A total scores. It was also associated with significant reductions in Hamilton Depression Rating Scale (HAM-D) total scores. Significant reductions in the cardinal symptoms of depression (depressed mood, guilt, work and interest, anergia and diurnal variation of mood) in patients receiving buspirone indicated that the drug has intrinsic antidepressant properties.Preliminary studies of the use of buspirone in other indications such as smoking cessation and of buspirone alone or combined with an SSRI in obsessivecompulsive disorder have been conducted. Results of these studies were inconclusive, and further research is needed to establish whether buspirone has a role in these conditions.TolerabilityBuspirone is generally well tolerated. In pooled data from 17 clinical trials, the most commonly reported adverse events not seen at equivalent incidence in placebo recipients include dizziness, nausea, headache, nervousness, lightheadedness and dry mouth. However, the frequencies of drowsiness, insomnia and excitement were similar to those reported in patients receiving placebo. Neither age nor duration of treatment appears to affect the frequency of adverse events. There have been rare case reports of buspirone-induced psychological (psychosis, mania, panic attack) and neuromuscular (dystonia, dyskinesia) adverse events.Data concerning the effects of buspirone overdose are limited; however, the drug appears to produce relatively mild symptoms. There are no reported deaths after overdose when buspirone was the sole ingestant.Dosage and AdministrationBuspirone should be initiated at a dosage of 15 mg/day, administered in 2 divided doses. The target therapeutic dosage is 30mg daily, which can be achieved by the second week of treatment. Maximum dosage is 45mg daily in the UK and 60 mg/day in the US. Dosage adjustments may be necessary in patients with severe hepatic or renal dysfunction, as there is some decreased elimination of buspirone in such patients (although interpatient variation is considerable). Dosage adjustments in the elderly do not appear to be necessary.No pharmacokinetic or pharmacodynamic interactions have been found between buspirone and tricyclic antidepressants or benzodiazepines. Buspirone should not be coadministered with monoamine oxidase inhibitors because of reports of elevated blood pressure with combined use.

ISSN:1172-7047    

出版商:ADIS    

年代:1997

数据来源: ADIS