摘要:

Leptin burst onto the scene in 1994 and transformed research into obesity and energy balance. Immediately, hopes were raised that this peptide, secreted by adipose tissue, might be causally related to human obesity, and that the regulatory mechanisms underlying its action might be manipulated for therapeutic benefit.In the last 6 years, the concentrated effort of the research community, both academic and commercial, has made enormous strides towards understanding the full range of physiological effects of leptin. In the mouse, leptin deficiency (ob/ob) induces hyperphagia, massive obesity and diabetes. Administration of leptin protein reverses this phenotype and results in rapid bodyweight loss, mainly in the form of fat. Leptin also modestly reduces food intake and bodyweight in normal lean rodents on systemic administration.Leptin is much more potent when administered directly into the cerebroventricular system of the brain. This observation, and the identification of leptin receptor expression in hypothalamic nuclei with an established regulatory function in energy homeostasis, confirms the CNS as a primary site of action of leptin. A number of leptin-sensitive, receptor-expressing hypothalamic neurons of different neurochemical phenotype have been identified, and leptin receptor mRNA and protein are widespread elsewhere in the mammalian brain. Leptin provides two forms of feedback to regulatory systems in the brain, a dynamic reflection of diurnal feeding pattern (where it may interact with satiety signals), and a basal level of secretion encoding body fat storage (a plausible lipostat). The absence of leptin is a potent signal of starvation, and in this state reduced leptin feedback regulates the activity of compensatory neuropeptide systems in the hypothalamus to drive the voluntary hyperphagia displayed by rodents when released back toad libitumfeeding.Despite the initial excitement over the therapeutic potential of leptin, these expectations have now begun to wane. Assessments of the value of leptin, and of potential therapies based on its activities, are now more realistic and may involve targeting of specific subpopulations of individuals, or particular weight loss strategies. This review focuses deliberately upon the possible exploitation strategies that are still patent.

ISSN:1172-7047    

出版商:ADIS    

年代:2000

数据来源: ADIS

摘要:

Cerebral venous thrombosis (CVT) is a relatively rare pathological condition. The clinical presentations can be nonspecific and quite variable, frequently resulting in delayed or missed diagnosis. The symptoms include headache, nausea, vomiting, visual disturbance, altered consciousness and seizures. These symptoms are believed to be caused by increased intracranial pressure secondary to impeded venous drainage.The diagnosis can be made with computed tomography (CT), magnetic resonant imaging (MRI) and cerebral angiography. CT is usually the initial diagnostic test that may show dense clot in the cerebral veins along with hemorrhagic venous infarctions. Empty delta sign can be seen on contrast-enhanced CT. MRI has become the preferred modality for detecting CVT; magnetic resonance angiography (MRA) and venography (MRV) are the best methods for detecting the condition. Angiography, once the standard, is now only indicated when MRI has resulted in an uncertain diagnosis or when endovascular intervention is desired.Therapy should be directed at treating the underlying causative process and symptoms secondary to elevated intracranial pressure. Although there is no consensus regarding antithrombotic treatment, the current trend is to use intravenous heparin initially, followed by warfarin. A newer approach has been developed using interventional endovascular modalities. Local infusion of thrombolytics can be achieved by transvenous catheterisation and catheter navigation. This may offer potential advantages over the established systemic antithrombotic therapy.

ISSN:1172-7047    

出版商:ADIS    

年代:2000

数据来源: ADIS

摘要:

Dopamine receptor agonists were originally developed as adjunctive therapies to ‘smooth out’ motor response fluctuations to levodopa in patients with advanced Parkinson's disease. However, they are now used in the early stages of the disease, in monotherapy or combination with low doses of levodopa, to delay the onset of levodopa therapy and its complications.Oral dopamine agonists currently available worldwide for Parkinson's disease include the older ergot derivatives bromocriptine and pergolide and the second generation non-ergoline compounds ropinirole and pramipexole. Other dopamine agonists that are used less frequently include cabergoline (a new ergoline drug, only recently released in some European countries as an antiparkinsonian drug), lisuride (an ergot derivative) and piribedil (an older non-ergot compound).Data on the pharmacokinetics of oral dopamine agonists, especially the older ergot derivatives, are scarce and mostly refer to small groups of healthy young individuals. All these agents, with the exception of pramipexole, are subject to extensive enterohepatic first-pass metabolism. Their bioavailability is low and shows high intra- and interindividual variability.The pharmacodynamic properties of dopamine agonists relevant to their antiparkinsonian effect have not been clearly defined. As a result, an optimal dosage schedule for the treatment of Parkinson's disease is generally identified using highly individualised empirical assessment. This involves considerable time expenditure and creates difficulty for patients, who have to follow complex titration schedules.Dopamine agonists appear to have a low potential for pharmacokinetic interaction with levodopa. Few data have been reported on the effect of coadministration on the pharmacodynamics of levodopa. The available data indicate that pergolide and bromocriptine significantly increase the duration of the motor response to levodopa, while baseline motor effects and the magnitude of motor response are substantially unchanged. Cabergoline also significantly prolongs the motor response to a dose of levodopa in patients experiencing motor fluctuations, but baseline motor scores are also significantly improved, suggesting a long-lasting effect.Subcutaneous apomorphine is currently the only non-oral formulation of a dopamine agonist available; it is used as add-on rescue therapy for patients who have advanced Parkinson's disease and a wide spectrum of complex motor, sensory, autonomic and cognitive ‘wearing-off’ phenomena not controlled by optimal oral dopaminergic therapy. Attempts to deliver apomorphine and other soluble dopamine agonists by more practical non-oral routes, such as intranasally or transdermally, have so far been of limited clinical utility or are currently still under investigation.

ISSN:1172-7047    

出版商:ADIS    

年代:2000

数据来源: ADIS

摘要:

Contemporary1H-magnetic resonance spectroscopy (MRS) techniques can estimate the levels of brain metabolites with a high reproducibility and add only 10 minutes to a routine or volumetric magnetic resonance imaging scan. In patients with Alzheimer's disease (AD),1H-MRS demonstrates decreases inN-acetylaspartate (NAA) and increases in myo-inositol (Ino) levels. Changes in NAA and Ino levels correlate with dementia severity and may predict future cognitive decline.1H-MRS could be a valuable outcome measure in clinical trials of individuals with AD for monitoring disease progression (using NAA and Ino levels) and evaluating therapeutic response to novel drugs (using NAA, choline and Ino levels). Further studies are warranted to evaluate the relative utility of1H-MRS compared with other imaging markers, such as cerebral blood flow and volumetric measures of atrophy. Protocols combining magnetic resonance perfusion, volumetry and spectroscopy in AD may prove to be powerful research tools.

ISSN:1172-7047    

出版商:ADIS    

年代:2000

数据来源: ADIS

摘要:

ObjectiveTo discern population-adjusted rates of office-based physician visits in the US documenting the use of antidepressant pharmacotherapy, a diagnosis of a depressive illness, or a diagnosis of a depressive disorder in concert with the use of antidepressant pharmacotherapy.Materials and MethodsData from the US National Ambulatory Medical Care Survey for the time-period of 1990 through 1998 were used to discern the population-adjusted rate of office-based physician visits documenting the use of antidepressant pharmacotherapy [tricyclic antidepressants (TCAs), selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs) or others], a diagnosis of depression (ICD-9-CM codes 296.2 to 296.36, 300.4 or 311) or both.ResultsOffice-based visits documenting the use of antidepressant pharmacotherapy for any purpose escalated from 16 534 268 in 1990 to 40 925 824 in 1998, a 147.5% increase. The number of office-based visits documenting a diagnosis of depression increased 59.1% during this period, while the proportion of office-based visits documenting a diagnosis of depression and use of antidepressant pharmacotherapy increased 31.3%. Among patients with a diagnosis of depression, use of a TCA declined from 42.1% in 1990 to 9.7% in 1998. In contrast, use of an SSRI increased from 37.1% in 1990 to 65.6% in 1998. The population-adjusted rate of office-based visits documenting the use of antidepressant pharmacotherapy for any purpose increased from 6.7 per 100 US population in 1990 to 15.1 per 100 US population in 1998, a 125.4% increase; documentation of a diagnosis of depression increased from 6.1 per 100 US population in 1990 to 8.9 per 100 US population in 1998, a 45.9% increase; and the recording of a diagnosis of depression in concert with the use of antidepressant pharmacotherapy increased from 3.2 per 100 US population in 1990 to 6.1 per 100 US population in 1998, a 90.6% increase.ConclusionOver the time-period 1990 to 1998, there was a significant increase in the rate of diagnosis of depressive illness in the US, and a sustained preference for use of an SSRI in the treatment of depression.

ISSN:1172-7047    

出版商:ADIS    

年代:2000

数据来源: ADIS

摘要:

Venlafaxine inhibits presynaptic reuptake of both serotonin (5-hydroxytryptamine; 5-HT) and noradrenaline (norepinephrine). Dysregulation of one or both of these neurotransmitters has been implicated in anxiety disorders, which often co-exist with depressive disorders.Venlafaxine extended release (XR) formulation has been evaluated in patients with generalised anxiety disorder (GAD) as defined in the DSM-IV without comorbid major depression. In randomised, double-blind, placebo-controlled, multicentre studies, venlafaxine XR 75 to 225 mg/day produced greater improvements in Hamilton Rating Scale for Anxiety (HAM-A) total scores than placebo. A therapeutic effect was evident within 1 week of the initiation of treatment with venlafaxine XR and improvements were sustained over ≤28 weeks. In 2 long term (6 month) studies all dosages of venlafaxine were significantly better than placebo. In an 8-week study venlafaxine XR 225 mg/day (but not lower dosages) was significantly better than placebo with respect to reductions in HAM-A total scores. Discontinuation because of an unsatisfactory clinical response was consistently less common among recipients of venlafaxine XR than placebo in the long term studies.Venlafaxine XR 75 and 150 mg/day was at least as effective as buspirone 30 mg/day and diazepam 15 mg/day in 2 randomised, double-blind, placebo-controlled multicentre trials. Reductions in HAM-A total scores in patients receiving active treatment exceeded those in placebo recipients, but were not statistically significant in either study.Adverse events pertaining to the digestive (nausea, dry mouth), nervous (insomnia, somnolence, dizziness) and urogenital systems (abnormal ejaculation) were the most frequently reported adverse events in venlafaxine recipients during 8 weeks of treatment in 2 randomised, double-blind, placebo-controlled, multicentre studies.In conclusionvenlafaxine XR is the only antidepressant presently approved for, and shown to be effective, in the long term management (i.e. ≤6 months) of GAD.

ISSN:1172-7047    

出版商:ADIS    

年代:2000

数据来源: ADIS