摘要:

Alzheimer's disease is characterised by the gradual but progressive loss of memory and other cognitive abilities. Pathological features include the accumulation of neurofibrillary tangles, neuritic plaques and &bgr;-amyloid protein within vulnerable regions of the brain. A number of actions of estrogen have the potential to affect brain function and influence the pathology of Alzheimer's disease.Early-onset Alzheimer's disease is a relatively infrequent disorder which is usually inherited in an autosomal dominant manner. However, for late-onset illness, it is likely that several genetic and environmental factors are pathogenetically important.A number of epidemiological studies link postmenopausal hormonal replacement therapy to a reduced risk of developing Alzheimer's disease. Estrogen can affect cognition and mood, and a number of generally small intervention trials suggest that estrogen improves cognitive skills among women with Alzheimer's disease. However, most treatment studies have not been conducted in a methodologically rigorous fashion. There are no firm data on different estrogen preparations and dosages or on the role of progestins in the prevention and treatment of Alzheimer's disease in women, and no data support the use of estrogen for this disorder in men.

ISSN:1172-7047    

出版商:ADIS    

年代:1997

数据来源: ADIS

摘要:

The use of antidepressants in patients with unipolar depression is associated with a negligible rate of switching into mania. In contrast, in patients with bipolar disorder, even those treated concomitantly with a mood stabiliser, such switching appears to represent a greater problem. Preliminary evidence from some controlled studies suggests that antidepressants may double the incidence of a switch, from some 25% in patients receiving placebo to 50% in those receiving tricyclic antidepressants. Other series in patients with rapid cycling bipolar disorder suggest an even higher switch rate; however, only about one-third of the observed switches are likely to be attributable to the antidepressant (i.e. unrelated to the natural course of illness).In addition to these phenomena, cycle acceleration has been observed consistently in a subgroup of patients with bipolar disorder who are receiving maintenance treatment with tricyclic antidepressants, and this has been verified by periods of discontinuation and reintroduction of the drug. Cycle acceleration appears to occur in approximately one-fifth of patients with refractory bipolar illness.Given these potential liabilities, it is unclear as to what is the most judicious treatment algorithm to follow for the bipolar patient with depression that is breaking through treatment with a mood stabiliser. In the absence of adequate studies, our own algorithm is to use antidepressants judiciously in nonrapid cycling patients, but to relatively avoid them in rapid and ultra-rapid cyclers. Instead, we prefer to use adjunctively a second mood stabiliser prior to the introduction of a unimodal antidepressant. Systematic controlled clinical trials are eagerly awaited, comparing not only the acute antidepressant efficacy of the newer antidepressants, but their liability in causing a switch or cycle induction when introduced into long term prophylaxis.With the advent of a series of new potential mood stabilising agents, direct comparison of the addition of a second mood stabiliser with that of a unimodal antidepressant will help establish the comparative risk : benefit ratios of these differential approaches. It is also hoped that clinical and biological markers of differential antidepressant responsivity will ultimately be identified and help to refine the process of choosing the best antidepressant modality for depression breaking through prophylaxis with mood stabilisers in patients with bipolar disorder.

ISSN:1172-7047    

出版商:ADIS    

年代:1997

数据来源: ADIS

摘要:

For almost 20 years, anticonvulsant monotherapy has been regarded as the ideal method of management of epilepsy. This line of thought, while true, has mutated into a general view of polypharmacy with anticonvulsants as a sign of therapeutic failure. However, even when the ‘right’ drug is given at the ‘right’ dose, studies have shown that in around 30% of patients, epilepsy will not fully respond to anticonvulsant monotherapy. For these patients, polypharmacy with anticonvulsants is an inevitability.There are good reasons why the established anticonvulsants should not be particularly well tolerated in combination. However, anticonvulsant polypharmacy has become so ‘undesirable’ that there has been a failure to search for firm treatment strategies for refractory epilepsy. Nevertheless, there are strong arguments to suggest that the newer anticonvulsants will prove to be better tolerated in combination than their established counterparts, particularly in view of their paucity of drug interactions, more predictable pharmacokinetics and narrower spectrum of action.This review calls for the development of a rational plan for the treatment of refractory epilepsy. Proper double-blind trials should be carried out to compare the efficacy and tolerability of anticonvulsant drug combinations. This is a huge task that could be rationalised by concentrating on combinations that have been reported to have particular benefit, or those with neurochemical properties that suggest an additive or even synergistic effect.

ISSN:1172-7047    

出版商:ADIS    

年代:1997

数据来源: ADIS

摘要:

An ever growing literature is providing evidence that levodopa, the major therapeutic agent for Parkinson's disease, and its metabolites (dopamine and quinone derivatives) are toxic to neurons, particularly in tissue culture. Neurons do not survive well in the presence of levodopa and undergo apoptosis. Toxicity has also been seen in somein vivomodels. The most commonly suggested mechanism by which levodopa and dopamine induce toxicity is by promoting oxidative stress. In support of this theory are findings that certain anti-oxidants, including sulphydryl compounds and ascorbic acid, decrease the neurotoxic effect. On the other hand, there are also a few studies that have failed to show that levodopa and dopamine are neurotoxic in animal models.There is no evidence that levodopa is toxic in humans, but the findings of neurotoxicityin vitroand in somein vivomodels raise concern about the safety of levodopa in humans. There is a need for clinical research to clarify this issue. A clinical trial that evaluates whether there is hastening of Parkinson's disease in patients treated with levodopa might be able to answer this question, and, fortunately, such a clinical trial is planned. The results should provide clinicians with information on how best to proceed in treating patients who have Parkinson's disease. In the meantime, until this information is available, the use of levodopasparing strategies, particularly for young patients who would be taking levodopa for a great many years, may be appropriate. Such a strategy calls for utilising non-levodopa medications that have symptomatic effects in the place of levodopa or as adjuvants to keep the dosage of levodopa as low as possible. Another approach is to develop agents that block the neurotoxicity of levodopa and dopamine, and which can be given in combination with levodopa.

ISSN:1172-7047    

出版商:ADIS    

年代:1997

数据来源: ADIS

摘要:

Nausea and vomiting are common adverse effects of therapeutic drugs. Such symptoms are more often due to CNS effects than to direct toxic effects on the gastrointestinal tract (GIT). Drugs may cross the blood-brain barrier and activate the chemoreceptor trigger zone in the brainstem, which contains cells that are responsive to cholinergic, dopaminergic and serotonergic stimulation.Selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs) are effective and well tolerated in the treatment of major affective disorders, but their usefulness is sometimes limited by adverse effects, particularly gastrointestinal effects. SSRIs exert their beneficial effects in depressive syndromes by increasing brain serotonin levels. They also increase serotonin levels in other tissues, particularly the GIT, which contains 90% of the body's store of serotonin and large numbers of serotonin-responsive cells. Increased serotonergic neurotransmission causes anorexia, nausea, vomiting and diarrhoea in other settings, such as carcinoid syndrome, so gastrointestinal adverse effects are not unexpected with drugs that increase tissue serotonin levels. SSRI-induced nausea and vomiting are probably due to effects on the GIT as well as on the CNS.There are complex interactions between serotonin receptor subtypes. Drugs antagonising one receptor subtype may act as agonists at another receptor. The pharmacotherapy of SSRI-induced nausea and vomiting requires an understanding of the actions and interactions of these receptors and their agonists/antagonists. The most effective drug for the treatment of SSRI-related adverse effects on the GIT is ondansetron, a serotonin 5-HT3receptor antagonist that blocks the effects of serotonin in the brain and GIT. However, this drug has a high acquisition cost. Thus, the drug of choice may be cisapride which, although a weak 5-HT3receptor antagonist, has the potential to reduce or abolish SSRI-induced nausea. Many patients with mild adverse effects will not require specific pharmacotherapy, as the nausea tends to abate with prolonged treatment with SSRIs because of gradual desensitisation of 5-HT3receptors.

ISSN:1172-7047    

出版商:ADIS    

年代:1997

数据来源: ADIS

摘要:

▴ Naratriptan is a new serotonin 5-HT1B/1Dreceptor agonist that is indicated for the acute treatment of migraine.▴In vitroandin vivostudies indicate that naratriptan mediates vasoconstriction in the cerebral vasculature and inhibits responses mediated by the trigeminal nerve.▴ Studies in healthy volunteers demonstrate that naratriptan has good oral bioavailability.▴ Naratriptan is effective in alleviating migraine headache and associated symptoms such as photophobia, phonophobia and nausea. It is also effective in preventing the recurrence of headache symptoms.▴ In general the efficacy of naratriptan is similar to that of sumatriptan in treating migraine; however, naratriptan is associated with a lower incidence of headache recurrence than sumatriptan.▴ Studies have shown that the tolerability of naratriptan is good, with the overall incidence of adverse events during treatment with naratriptan at doses up to 2.5mg similar to that observed with placebo.▴ Naratriptan had no clinically significant effect on blood pressure or heart rate.

ISSN:1172-7047    

出版商:ADIS    

年代:1997

数据来源: ADIS

ISSN:1172-7047    

出版商:ADIS    

年代:1997

数据来源: ADIS

摘要:

SynopsisCitalopram is a selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor (SSRI) which has been evaluated primarily in the treatment of major depression. In well controlled short term studies, citalopram had efficacy similar to that of a number of, but not all, tricyclic or tetracyclic antidepressants and was as effective as fluoxetine and fluvoxamine. There is some evidence of a faster onset of action for citalopram compared with fluoxetine. Initial data suggest that citalopram is effective in the prevention of depressive relapse and in the treatment of post-stroke depression.The anticholinergic and cardiovascular adverse events often seen with tricyclic antidepressants generally occur less frequently or are infrequent with citalopram, as with other SSRIs. Citalopram has been well tolerated in the elderly and in patients with existing cardiovascular disease.In vitroandin vivopharmacodynamic studies suggest that citalopram is a weak inhibitor of cytochrome P450 (CYP) 2D6, and data from several interaction studies in patients and healthy volunteers are consistent with this finding.Thus, citalopram is an effective and well tolerated SSRI which, like the other members of its class, represents a suitable first-line therapy for major depression. Additional efficacy data would be beneficial in clarifying the potential of citalopram in the elderly and in patients with post-stroke depression or preexisting cardiovascular disorders, for whom anticholinergic or cardiovascular adverse events (caused by tricyclic antidepressants) are a serious concern. The main distinguishing feature of citalopram within its class is its apparent low propensity to cause problematic drug interactions with CYP2D6 substrates; these include a number of commonly prescribed drug classes, such as antipsychotics, tricyclic antidepressants, antiarrhythmics and&bgr;-blockers. Thus, citalopram may prove useful in the many patients with depression who require one or more such agents for treatment of additional psychiatric or general disorders.Pharmacodynamic PropertiesCitalopram is a potentin vitroinhibitor of serotonin (5-hydroxytryptamine; 5-HT) uptake. Its activity in this respect is more than 3000 times greater than that against noradrenaline (norepinephrine) uptake, making it the most serotonin-selective agent in its class. Citalopram has low affinityin vitrofor adrenergic, muscarinic, dopaminergic and serotonergic receptors. Evidence from behavioural studies in animals supports a selective facilitatory effect of citalopram on serotonergic neurotransmission.Citalopram is a weakerin vitroandin vivoinhibitor of the hepatic cytochrome P450 (CYP) 2D6 isozyme than paroxetine and fluoxetine and therefore has a lower potential for pharmacokinetic interactions with cytochrome CYP2D6 substrates such as tricyclic antidepressants and antipsychotic agents.Pharmacokinetic PropertiesPeak plasma concentrations of citalopram are observed 2 to 4 hours after single or multiple oral doses and steady-state plasma concentrations are reached after about 1 week of daily administration. The plasma concentration-dose relationship for citalopram is linear for doses of 10 to 60mg.Citalopram is converted by hepatic CYP isozymes to the metabolites demethyl- and didemethyl-citalopram which are less lipophilic than the parent molecule (and are weaker serotonin reuptake inhibitors).Preliminary indications suggest that citalopram may cause only moderate pharmacokinetic interactions or have no effect when coadministered with tricyclic antidepressants which are metabolised by CYP2D6, although formal studies of such interactions are limited. Available data suggest that coadministration of citalopram and antipsychotic agents does not cause any significant pharmacokinetic interactions.The elimination half-life of citalopram following oral administration is about 30 hours, with an estimated clearance of 26 to 28 L/h. Approximately 12% of an oral dose of citalopram is excreted unchanged into the urine.Aging appears to be associated with increased plasma concentrations and decreased clearance of citalopram. Similar effects are seen in patients with renal or hepatic dysfunction.Clinical EfficacyIn well controlled clinical studies, score reductions for the Hamilton Depression Rating Scale (HDRS) or Montgomery-Åsberg Depression Rating Scale (MADRS) ranged from about 43 to 81% with citalopram and from about 56 to 71% with tricyclic or tetracyclic antidepressants. In the largest comparative study published to date, reductions in HDRS scores after 6 weeks were similar for citalopram and imipramine in more than 400 patients from general practice. Furthermore, the proportions of patients whose HDRS score was reduced by ≥50% were similar for citalopram and imipramine. In smaller studies, citalopram had end-point efficacy similar to that of amitriptyline or maprotiline (2 studies each), although comparisons with mianserin have produced somewhat contradictory findings. Citalopram was less effective than clomipramine in a single study. Results from meta-analyses indicate that citalopram is broadly similar to tricyclic agents (amitriptyline, clomipramine, nortriptyline and imipramine) in its antidepressant efficacy in clinical trials.Citalopram had overall efficacy similar to that of fluoxetine in general practice patients and in psychiatric inpatients and outpatients. However, analysis of 3 different clinical parameters after 2 weeks indicated that the effects of citalopram were achieved significantly faster than those of fluoxetine in the general practice study; no significant difference between the two treatment groups was apparent at subsequent timepoints. A comparison of citalopram with fluvoxamine in patients with major depression demonstrated equivalent efficacy for the 2 drugs.TolerabilityData from clinical trials and meta-analyses suggest that nausea and vomiting (20% incidence in a meta-analysis of 746 patients), increased sweating, dry mouth and headache were the most common adverse events experienced by citalopram recipients. The anticholinergic and cardiovascular adverse events often seen with tricyclic antidepressants (dry mouth, constipation, tachycardia, orthostatic hypotension) appear to occur less frequently or to be infrequent with citalopram in most large studies. Data from 2 comparative studies suggest that there are no major differences in tolerability between citalopram and fluoxetine, although vomiting during the first week of treatment was significantly more common in citalopram recipients (3.8%) than in fluoxetine recipients (0%) in one study (the citalopram dosage in this trial was twice that recommended for initial treatment). Nausea and diarrhoea were significantly more common in patients receiving fluvoxamine 100 to 200 mg/day than in those receiving citalopram 20 to 40 mg/day in a single study (the starting dosage of fluvoxamine was twice that normally recommended). This difference was apparent at all timepoints for nausea, but had disappeared by week 6 for diarrhoea.Clinical and postmarketing experience with citalopram suggests that it is not associated with serious cardiovascular toxicity, and is well tolerated in patients with existing cardiovascular conditions, in those who are receiving drugs that may cause ECG abnormalities and in the elderly. Like the other SSRIs, citalopram appears to be less toxic than tricyclic antidepressants when taken in overdose during suicide attempts.Dosage and AdministrationThe recommended oral treatment regimen for citalopram in depressed patients is 20 to 60mg once daily, titrated to therapeutic effect, with a minimum treatment period of 6 months to prevent relapse. Citalopram 20 to 30mg once daily is currently recommended for elderly patients. Dosage adjustments are not necessary in patients with mild or moderate renal impairment; information on the use of citalopram in patients with severe renal dysfunction is lacking. Citalopram 20 to 30mg is recommended as the maximum dose in patients with impaired hepatic function. Citalopram should not be given to patients who are taking monoamine oxidase inhibitors.

ISSN:1172-7047    

出版商:ADIS    

年代:1997

数据来源: ADIS