摘要:

Epidemiological studies have demonstrated a significant positive correlation between attention deficit hyperactivity disorder (ADHD), a common childhood behavioural disorder, and the development of alcoholism or drug abuse in adulthood. Recent investigations have suggested that these disorders may be genetically determined.Dysfunction of the dopamine D2receptor gene (DRD2) has been identified as a possible genetic variation responsible for alterations in behaviour. Ongoing studies have indicated that variants of other dopamine receptor subtypes, such as D3, and serotonin (5-hydroxytryptamine; 5-HT) metabolism may also be implicated in impulsive, compulsive and addictive behaviours. Such alterations in the genetic make-up result in functional deficiency of mesolimbic and frontal lobe dopamine metabolism.These findings provide a sound pharmacological basis for the treatment of ADHD with stimulants, such as methylphenidate and dexamphetamine (dextroamphetamine), and indicate that dopamine agonists may prove to be useful in the treatment of other impulsive, compulsive and addictive behaviours.

ISSN:1172-7047    

出版商:ADIS    

年代:1994

数据来源: ADIS

摘要:

Serotonin 5-HT4receptors were first described in mouse colliculi neurons. They are positively coupled to adenylyl cyclase, and possess unique pharmacological properties. Indeed, they are not blocked by classical 5-HT1, 5-HT2or 5-HT3antagonists. Several classes of specific 5-HT4receptor agonists (benzamides and benzimidazoles) and antagonists have now been described. The most specific and potent 5-HT4antagonist is an indole derivative, GR-113808, which has been used to prepare a radioligand for 5-HT4receptors.Both functional and radioligand binding studies indicate that 5-HT4receptors are expressed in the brain of several species, including human brain. The restricted brain distribution of 5-HT4receptors indicates that specific neurological and psychiatric functions are affected by these receptors. Thus, specific central nervous system disorders may benefit from the development of 5-HT4ligands.The similarities between the molecular mechanisms of action of 5-HT4receptors and those inAplysia(sea hare) neurons may suggest a role for the receptors in synaptic plasticity events and memory processes. The localisation of 5-HT4receptors in the limbic structures suggests a role for the receptors in emotional and reward processes, and expression of the receptors in the basal ganglia and substantia nigra indicates a role in the control of visuo-motor activity.

ISSN:1172-7047    

出版商:ADIS    

年代:1994

数据来源: ADIS

摘要:

The assessment and management of suicidal patients are important issues that may be faced by any physician. A series of risk factors for suicide has been identified, which includes psychiatric diagnosis, psychosocial and environmental factors, personality disorders and traits, genetic and family variables, and biochemical factors. Knowledge of these risk factors can assist clinicians in determining those patients who are most likely to attempt to harm themselves. This in turn enables pharmacological intervention to prevent suicide attempts. Psychopharmacological agents such as antidepressants, antipsychotics (in patients with personality disorders) and lithium (in patients with bipolar disorders) have been shown to be effective in preventing suicidal behaviour. The efficacy of electroconvulsive therapy (ECT) is more controversial. Other equally important aspects of the optimal clinical management of suicidal patients are the quality of the doctor-patient relationship and the issues involved in deciding whether hospital admission of the patient is necessary.

ISSN:1172-7047    

出版商:ADIS    

年代:1994

数据来源: ADIS

摘要:

Status epilepticus can assume as many forms as there are types of epileptic seizures. From a clinical point of view, 3 types of status epilepticus have been defined: generalised tonic-clonic status epilepticus, nonconvulsive status epilepticus (absence status epilepticus and status epilepticus of complex partial seizures) and status epilepticus with partial motor symptoms.A number of precipitating factors lead to the development of status epilepticus. These include fever, alcohol abuse, sleep deprivation, medication with proconvulsive drugs and noncompliance with antiepileptic medication. Most often, status epilepticus develops because of a combination of these factors.Status epilepticus may arise from a prolonged seizure or evolve from a series of seizures. The syndrome may occur in patients with chronic epilepsy, without brain damage or with acute brain damage.The clinical symptomatology varies during the course of status epilepticus, especially in nonconvulsive status epilepticus. In generalised convulsive status epilepticus, the intensity of seizures decreases during the course of the syndrome.The outcome of status epilepticus may be complicated by neuropsychiatric deficits. A lethal outcome is also possible and usually occurs in the post-status phase. The prognosis of status epilepticus strongly depends on the interval to the onset of therapy and the efficacy of the treatment. The aetiology of any underlying disease also affects the prognosis. Long term treatment with antiepileptic medication and prevention of precipitating factors are helpful in preventing a relapse of status epilepticus.First-line agents for the treatment of generalised tonic-clonic status epilepticus are benzodiazepines and phenytoin, with phenobarbital (phenobarbitone) being used if phenytoin is ineffective. However, a single study demonstrated that phenobarbital was superior to a combination of benzodiazepines and phenytoin as first-line therapy. Phenobarbital-induced respiratory depression may occur but is of consequence only at high dosages. If these drugs fail to prevent status epilepticus, anaesthesia with pentobarbital (pentobarbitone) or thiopental sodium (thiopentone) is recommended. There is limited experience with the use of other drugs in the treatment of status epilepticus. Lidocaine (lignocaine), isoflurane, propofol, chloral hydrate, paraldehyde and clomethiazole (chlormethiazole) have been used.Therapy of partial status epilepticus is similar to that of generalised tonic-clonic status epilepticus, with benzodiazepines and phenytoin being the drugs of choice. Anaesthesia is only used when focal seizures of status epilepticus with motor symptomology evolve to generalised tonic-clonic status epilepticus. Benzodiazepines are used in the treatment of absence status epilepticus.

ISSN:1172-7047    

出版商:ADIS    

年代:1994

数据来源: ADIS

摘要:

The approach to the treatment of Parkinson's disease is slowly but steadily moving away from symptomatic treatment to neuroprotective therapy. To understand the concept of neuroprotection, it is imperative to understand the mechanism of neuronal death in Parkinson's disease.Biochemical abnormalities presumed to play a role in degeneration of nigral neurons include loss of mitochondrial complex I, accumulation of iron in the substantia nigra, and possible increase in oxygen free radical formation. In addition, the existence of a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-type neurotoxin cannot be excluded.Neuroprotective agents which may be potentially useful in Parkinson's disease include monoamine oxidase B inhibitors, iron chelators, dopamine transporter blockers, antioxidants,N-methyl-D-aspartate (NMDA) receptor antagonists, and neurotrophic factors. Although most of these agents are still in the experimental stage, there is initial evidence that some may be of use as future neuroprotective therapies.

ISSN:1172-7047    

出版商:ADIS    

年代:1994

数据来源: ADIS

摘要:

SynopsisFluvoxamine is a selective serotonin reuptake inhibitor which was initially developed as an antidepressant. Additional clinical research has identified several other disorders of the central nervous system in which fluvoxamine has potential benefits, and which are the focus of this review.At present, the largest volume of data concerns the use of fluvoxamine in obsessive-compulsive disorder. Oral fluvoxamine at dosages of up to 300 mg/day is effective in alleviating, although not preventing, the symptoms of obsessivecompulsive disorder in 40 to 50% of patients, and limited data indicate that it is as effective as clomipramine. Encouraging initial data are also available regarding the efficacy of fluvoxamine in panic disorder. Further data are required to fully establish the efficacy of fluvoxamine in preventing panic attacks, and to investigate possible beneficial effects in the treatment of anxiety symptoms, bulimia nervosa, alcohol (ethanol)-induced amnesia, schizophrenia and several other psychiatric disorders, and pain states. Comparative and long term data in all disorders in which fluvoxamine shows potential are also required.Fluvoxamine is well tolerated by the majority of patients. Nausea is the most frequent adverse effect and can lead to withdrawal from treatment. However, nausea and most other adverse effects are generally mild to moderate in nature. Fluvoxamine induces less anticholinergic and sedative effects than tricyclic antidepressants, and does not appear to have cardiotoxic effects. In addition, as with many other antidepressants there is no evidence that fluvoxamine induces suicidal behaviour. Compared with tricyclic antidepressants, fluvoxamine is relatively safe in overdose.Thus, studies available to date have demonstrated the efficacy of fluvoxamine in obsessive-compulsive disorder. Efficacy in other central nervous system disorders has been indicated but further confirmatory data are required, as are comparative data in all disorders. The improved tolerability profile of fluvoxamine compared with many other agents used in these conditions will help to establish the agent as a useful alternative in obsessive-compulsive disorder, and in other conditions if preliminary efficacy findings are confirmed.Pharmacological PropertiesFluvoxamine is a potent and selective inhibitor of serotonin reuptake. In addition to its lack of effects on other monoamine reuptake mechanisms, fluvoxamine has little or no effect on the neuronal function of other monoamines and has a low affinity for the receptors of a variety of neurotransmitters. While acute inhibition of serotonin reuptake by fluvoxamine is well documented, clinical response is slower and therefore is not readily explained by this acute effect.Studies in animals and humans have shown that fluvoxamine, unlike the tricyclic antidepressants, has relatively few cardiovascular or anticholinergic effects. In addition, fluvoxamine does not appear to have pro-convulsive or sedative effects, and does not impair cognition. Fluvoxamine has anxiolytic and antinociceptive activity in some animal models, and reduces alcohol (ethanol) intake in alcohol-preferring rats. Pain thresholds in healthy volunteers are increased by fluvoxamine.The pharmacokinetic properties of fluvoxamine are well established. The drug is almost completely absorbed following oral administration and the extent of absorption is not affected by the presence of food in the gastrointestinal tract. Maximum plasma concentrations are reached within 2 to 8 hours of administration and steady-state concentrations are achieved after 10 days. There is no drug accumulation after repeated administration. Fluvoxamine is extensively metabolised in the liver, with 11 pharmacologically inactive metabolites identified. Most of a dose of fluvoxamine is excreted in the urine, with only about 3% as unchanged parent compound. Mean elimination half-life is 14 to 22 hours.Limited data suggest that the pharmacokinetic parameters of fluvoxamine are not affected by increased age, renal impairment or genetic polymorphism. However, elimination half-life is increased in patients with hepatic disease.Therapeutic PotentialFluvoxamine at oral dosages of 50 to 300 mg/day has been investigated in a number of non-depressive disorders. Positive results in 6 placebo-controlled trials support the efficacy of fluvoxamine in obsessive-compulsive disorder. At present, comparative data are limited but promising, with 2 trials showing that fluvoxamine is as effective as clomipramine. As with clomipramine, fluvoxamine reduces but does not eliminate obsessions and compulsions, is effective in only 40 to 50% of patients and has a delay in onset of action of approximately 4 weeks.Limited data indicate that fluvoxamine may also be effective in preventing panic attacks, although further placebo-controlled comparisons with standard agents are required. Encouraging preliminary results suggest that fluvoxamine may have potential in the treatment of anxiety symptoms, bulimia nervosa, alcohol-induced amnesia, schizophrenia and several other psychiatric disorders, and pain syndromes. Fluvoxamine does not appear to be effective in patients with dementia, post-traumatic stress disorder or menstrually related disorders, or in reducing bodyweight in obese patients.TolerabilityFluvoxamine is well tolerated in patients with depression or other central nervous system disorders at oral dosages of up to 300 mg/day for up to 12 weeks. Long term tolerability has not been fully established. A least 43% of patients experience at least 1 adverse effect, with the highest incidence of adverse effects being associated with the gastrointestinal tract (nausea, vomiting, abdominal pain) and central nervous system (somnolence, headache, insomnia). Asthenia is also a common adverse effect. The most common adverse effect is nausea, which can result in discontinuation of therapy. Most adverse effects are transient and of mild to moderate severity. No fluvoxamine-associated clinically significant changes in vital signs or laboratory parameters have been reported.Fluvoxamine produces fewer anticholinergic effects than tricyclic antidepressants, and is thought to have less epileptogenic potential than these agents. In addition, fluvoxamine does not appear to have any cardiotoxic effects. The adverse effects profile of fluvoxamine appears to be similar to that of other selective serotonin reuptake inhibitors. Fluvoxamine treatment has not been associated with an increase in suicidal behaviour, and the agent is considered less harmful than tricyclic antidepressants in overdose.Dosage and AdministrationFor the treatment of non-depressive disorders, fluvoxamine has been administered at oral dosages of 50 to 300 mg/day. Dosages over 100 mg/day were most commonly used. Titration of the dosage in 50mg increments is recommended for the treatment of depression and a similar procedure should probably be used for other disorders. A starting dosage of 50 mg/day may reduce nausea. Dosage should not exceed 100 mg/day in patients with hepatic or renal impairment. While it does not seem necessary to reduce the dosage in elderly patients, slow titration of the dosage should be employed in these patients.Caution is recommended when administering fluvoxamine with agents with which it is known to interact, such as lithium, theophylline, tricyclic antidepressants or warfarin. In addition, cautious use is recommended when fluvoxamine is administered to patients with epilepsy or a medical condition that may be exacerbated by vomiting. Fluvoxamine should not be administered with or within 2 weeks of withdrawing a monoamine oxidase inhibitor, and a monoamine oxidase inhibitor should not be started within 1 week of stopping fluvoxamine.

ISSN:1172-7047    

出版商:ADIS    

年代:1994

数据来源: ADIS