摘要:

Brofaromine is a reversible and selective inhibitor of monoamine oxidase type A. Available preclinical and clinical data indicate that brofaromine is an effective and well tolerated treatment for major depression and anxiety disorders. Despite these encouraging findings, the manufacturer (CIBA) terminated the development of this compound in 1993. The main reason for this termination has been problems with resources associated with the necessity to perform further placebocontrolled trials. The brofaromine story illustrates the complex, and often frustrating, nature of drug development.

ISSN:1172-7047    

出版商:ADIS    

年代:1995

数据来源: ADIS

摘要:

Paraphilias are sexual impulse disorders characterised by intensely arousing, recurrent sexual fantasies, urges and activities that are considered ‘deviant’ with respect to cultural norms. Behaviours classified as paraphilias include exhibitionism, paedophilia, voyeurism, fetishism, transvestite fetishism, sexual sadism and masochism, and frotteurism. An accompanying set of sexual impulse disorders, the paraphilia-related disorders, have also been identified.Three major classes of psychopharmacological agents (antipsychotics, antiandrogens and serotonergic antidepressants) have been used as treatments for sexual impulsivity. For nonpsychotic individuals, antipsychotics should no longer be considered as primary agents for the control of sexual impulsivity due to the nonspecificity of their effect and the adverse effects associated with their use.Commonly used antiandrogens are medroxyprogesterone and cyproterone. Since data regarding their efficacy in sexually aggressive men are most extensive, antiandrogens remain the primary treatment for sexually dangerous offenders. While effective (presumably by reducing the physiological effects of circulating testosterone), these agents are associated with adverse effects such as body weight gain, fatigue, depression, feminisation and decreased spermatogenesis.Based on the available animal and clinical literature, diminished central serotonin (5-hydroxytryptamine; 5-HT) neurotransmission may be involved in the aetiology of human sexual impulse disorders. Indeed, recent and emerging data suggest that serotonergic antidepressants, especially serotonin reuptake inhibitors, may be useful for the amelioration of sexual impulse disorders.

ISSN:1172-7047    

出版商:ADIS    

年代:1995

数据来源: ADIS

摘要:

Several different types of myoclonus can be distinguished on physiological grounds. Cortical myoclonus arises from an abnormal discharge in the sensorimotor cortex and corticospinal pathways. Brainstem reticular reflex myoclonus and hyperekplexia are forms of generalised myoclonus arising in the brainstem, and palatal myoclonus is a segmental form of brainstem myoclonus. Ballistic overflow myoclonus occurs in hereditary essential myoclonus. Propriospinal myoclonus consists of axial jerks of spinal origin, while segmental spinal myoclonus is thought to arise as a result of the isolation of spinal motoneurons from inhibitory influences or from direct cellular injury.Treatments of first choice for cortical myoclonus are valproic acid (sodium valproate) and clonazepam. Primidone and phenobarbital (phenobarbitone) may also be useful. However, most patients require polypharmacy for adequate symptomatic improvement. Piracetam has advantages in these circumstances, as its addition to existing treatments is rarely accompanied by sedation. 5-Hydroxytryptophan in combination with carbidopa is now rarely used because of gastro-intestinal adverse effects.In patients with brainstem reticular reflex myoclonus, valproic acid and clonazepam are the most useful agents. In hyperekplexia, treatment is directed against the disabling tonic spasms, rather than jerks. Carbamazepine, phenytoin and clonazepam are useful agents in this respect. Ballistic overflow myoclonus may improve with anticholinergic drugs, such as benzatropine (benztropine) or trihexyphenidyl (benzhexol). Antiepileptic drugs are disappointingly ineffective in this condition.Treatment of palatal myoclonus is often unsuccessful, but phenytoin, carbamazepine, clonazepam, trihexyphenidyl and baclofen have been effective in some patients. Clonazepam is effective in over half of patients with propriospinal myoclonus, but other anticonvulsants are usually unhelpful. Segmental spinal myoclonus is often resistant to drug treatment, but diazepam, carbamazepine, tetrabenazine and, particularly, clonazepam are sometimes effective.

ISSN:1172-7047    

出版商:ADIS    

年代:1995

数据来源: ADIS

摘要:

Body dysmorphic disorder (BDD) is defined as a preoccupation with an imagined or minimal defect in appearance. Virtually any body part can be the focus of concern, although preoccupations with the hair, nose and skin are particularly common. Associated features include repetitive and often ritualistic behaviours, such as mirror checking and requests for reassurance, as well as ideas or delusions of reference. The degree of impairment associated with the disorder is variable, but most patients experience significant functional impairment as a result of their concerns.While this often secret disorder has been described for more than a century and reported around the world, it has received little empirical investigation. Nonetheless, emerging data suggest that BDD is frequently a chronic disorder that usually begins during adolescence. Psychiatric hospitalisation and suicide attempts are common in patients with BDD. Disorders that are frequently comorbid include major depression, social phobia and obsessive-compulsive disorder. The prevalence of BDD among patients with other psychiatric disorders, such as atypical depression, obsessive-compulsive disorder and social phobia, appears to be relatively high.The majority of patients with BDD seek often costly nonpsychiatric therapies, such as surgical or dermatological interventions. These approaches are usually unsuccessful. In contrast, preliminary data from noncomparative studies suggest that serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors are often, and perhaps preferentially, effective in the treatment of BDD. Other preliminary data suggest that cognitive-behavioural strategies may also be useful. There are virtually no data on treatment-resistant BDD, but certain pharmacological approaches including augmentation, combination and switching strategies are sometimes effective.Further investigation of all aspects of this understudied disorder is greatly needed. Aspects that require particular attention are the epidemiology, clinical features, relationship to other psychiatric disorders, biology and, ultimately, aetiology and treatment response.

ISSN:1172-7047    

出版商:ADIS    

年代:1995

数据来源: ADIS

摘要:

An association exists between maternal use of antiepileptic drugs (AEDs) during pregnancy and birth defects in offspring. The overall malformation rate is 11.1% in offspring of AED-treated epileptic mothers, while it is 5.7% in the offspring of untreated epileptic mothers and 4.8% in those of the general population. Cardiovascular defects, facial cleftings and skeletal anomalies are the most frequently occurring AED-associated malformations. No firm patterns of specific AEDs inducing particular birth defects have been established. Nevertheless, neural tube defects may be specific malformations in infants exposed to both valproic acid (sodium valproate) and/or carbamazepine. Several minor anomalies are influenced by genetic factors.From prospective studies a number of primary risk factors for increased incidences of congenital malformations in the offspring of epileptic mothers receiving AEDs have been identified. These include high drug dosage, high serum drug concentration, the use of AEDs with high teratogenicity potency [primidone > valproic acid > phenytoin > carbamazepine > phenobarbital (phenobarbitone)] and AED polypharmacy (especially combinations of valproic acid and carbamazepine, and phenytoin and/or carbamazepine with or without barbiturates).The mechanism of teratogenicity of AEDs is still being investigated, but it is postulated that epoxide intermediates and other toxic metabolites of AEDs might be involved. In addition, the folate deficiency and impaired folate metabolism caused by AEDs may contribute to the teratogenicity of these drugs.To prevent birth defects, the use of the lowest effective AED dosage and a change from polypharmacy to monotherapy are recommended before conception. A decrease in serum AED concentrations during pregnancy does not in itself justify an increase in drug dosage. The high risk of neural tube defects in offspring exposed to valproic acid (or carbamazepine) warrants prenatal examination in pregnant women receiving this drug, such as ultrasound and amniotic fluid &agr;-fetoprotein investigations. To reduce the risk of this malformation, replacement of conventional formulations of valproic acid with controlled release formulations and the use of folate supplementation are recommended.

ISSN:1172-7047    

出版商:ADIS    

年代:1995

数据来源: ADIS

摘要:

Immunological therapy with cytokines can cause acute, subacute, delayed and, occasionally, irreversible toxicity to the CNS. Neurotoxic adverse effects are manifested by changes in cognitive, motor and emotional functioning. Although these changes are sometimes global in nature, most subacute neurotoxic symptoms attributable to interferon-&agr;, interleukin-2 and tumour necrosis factor are specific to frontal-subcortical dysfunction and involve specific neuroanatomical and neurochemical systems.The symptoms observed typically include memory deficits, difficulties with motivation and flexible thinking (frontal lobe executive function) and motor coordination. Reasoning, language functions and visual perception are generally not affected. Depression and other psychiatric presentations are common and appear to be due to the biochemical changes induced by cytokines rather than psychological reactions to the illness for which the agents are administered.The mechanism of action of cytokines on brain function may include alterations in neurotransmitter function (mostly involving opioid and dopaminergic systems), induction of the release of neuroendocrine hormones and of other cytokines. Improved understanding of the mechanism of cytokine action in the brain is guiding the development of treatment interventions to reduce or eliminate CNS toxicity without sacrificing therapeutic efficacy. In addition, studies of cytokine neurotoxicity have advanced our knowledge of the normal role of these agents in the CNS.

ISSN:1172-7047    

出版商:ADIS    

年代:1995

数据来源: ADIS

摘要:

Abecarnil is a &bgr;-carboline partial benzodiazepine agonist which may be selective for certain subpopulations of benzodiazepine receptors. It has greater affinity for central benzodiazepine receptor sites than diazepam, but low affinity for peripheral benzodiazepine, adrenergic, dopaminergic, opiate and serotonergic receptors.At present, virtually all published pharmacodynamic data for abecarnil are derived from animals studies. Abecarnil is active in a number of animal models of anxiety and is generally more effective than diazepam. It also attenuated some, but not all, chemically- or electrically-induced seizures in animals (diazepam antagonised most types of induced seizures) and was protective in genetic models of epilepsy. In most instances, its anticonvulsant activity did not appear to be attenuated during long term administration. Although some sedation occurs with abecarnil administration to animals, the drug is associated with less sedation, muscle relaxation, ataxia and impairment of memory than are several benzodiazepines. It also produces less potentiation of the effects of ethanol and hexobarbital than diazepam. In animals, the withdrawal syndrome after abecarnil discontinuation or administration of the benzodiazepine antagonist flumazenil is generally reduced or absent compared with benzodiazepines, suggesting that abecarnil has a low dependence potential. Abecarnil appears to have less propensity to induce tolerance than diazepam; it may also have a reduced abuse liability compared with benzodiazepines, as suggested by limited evidence in animals.The pharmacokinetic profile of abecarnil has yet to be investigated in patients with generalised anxiety disorder. Although pharmacokinetic parameters showed great intra- and interindividual variability in volunteers, the mean oral bioavailability of abecarnil 5 or 10mg was 39% in older volunteers and 55 to 65% in younger volunteers, and maximum plasma concentrations and AUC values after a single dose or at steady-state were dose-proportional. Abecarnil is predominantly metabolised, with less than about 10% of the drug being excreted unchanged. The main metabolite is the glucuronide conjugate of abecarnil, although 4 metabolites have been identified.Only one clinical trial assessing the efficacy of abecarnil in the treatment of generalised anxiety disorder has been published in full. Low dosages of the drug (3 to 9 mg/day) were significantly more effective than placebo and produced few serious adverse effects with no significant withdrawal syndrome upon discontinuation of 3 weeks of treatment. However, higher dosages of abecarnil (15 to 30 mg/day, and to a lesser extent 7.5 to 15 mg/day) produced a high incidence of adverse CNS effects [including drowsiness (71 and 51%), a loss of equilibrium (26 and 11%), confusion (24 and 3%), amnesia (15 and 3%), fatigue (15 and 17%), lethargy (18 and 3%), insomnia (15 and 6%) and dizziness (18 and 11%)] which caused discontinuation of treatment in 29% of patients receiving abecarnil 15 to 30 mg/day. Higher drug dosages were also associated with some withdrawal signs upon discontinuation of therapy. In addition, there appeared to be some loss of efficacy with all tested dosages of abecarnil in comparison with placebo during the third week of treatment. Other trials of abecarnil, published collectively in abstract form with little detail, have suggested that 4 to 6 weeks of treatment with the drug had efficacy similar to benzodiazepines and produced a similar number of adverse effects or withdrawal symptoms as placebo when discontinued in a tapered fashion.In conclusion, experimental evidence to date suggests that abecarnil may be a valuable alternative to currently used agents for the treatment of generalised anxiety disorder, particularly if efficacy is maintained at lower dosages. However, clinical trials, including comparisons with benzodiazepines, will first need to demonstrate the potential advantages (reduced adverse effects, dependence and abuse potential) observed with abecarnil in animal models.

ISSN:1172-7047    

出版商:ADIS    

年代:1995

数据来源: ADIS