摘要:

The chemotherapy of tumours located in the brain is far from satisfactory, with very poor response rates even with tumour types known to be sensitive when they occur extracranially. The brain is protected by the blood-brain barrier, which consists of tight capillary endothelial cell junctions. As a result, many drugs cannot penetrate into the tumour to achieve cytotoxic concentrations. Although the vasculature of some tumours may allow greater uptake of drugs than into normal brain tissue, the poor uptake of drugs into CNS tumours is still seen as a barrier to effective chemotherapy.The permeability of the blood-brain barrier may be affected by osmotic agents or mediators of inflammation. Notable among the latter is bradykinin, which induces a transient, specific increase in permeability that is more pronounced in tumour than in normal brain.The nonapeptide RMP-7 [H-Arg-Pro-Hyp-Gly-Thi-Ser-Pro-Tyr(Me)-&PSgr;(CH2NH)-Arg-OH] was developed as a bradykinin analogue. This peptide displays greater stability in plasma than the parent compound. Preclinical investigations in animal tumour models showed that RMP-7 increased the uptake of a number of markers in RG2 gliomas implanted into rat brain. More importantly, RMP-7 also increased carboplatin uptake in the tumour and brain surrounding the tumour, without affecting uptake into normal brain. Animals treated with RMP-7 and carboplatin showed significantly prolonged survival compared with controls. The doses used in these animal studies were quite high, administered via the intracarotid artery.In studies in humans, lower doses of RMP-7 were used and the drug was usually administered intravenously. Adverse effects were mild and transient, mostly related to vasodilation. Phase I and II studies in patients with brain tumours confirmed the increased uptake of radiochemical markers into tumours that had been seen in animal models. Recently published data suggest that the combination of carboplatin with RMP-7 has activity in malignant brain tumours, both in terms of neurological improvement and overall survival, and was well tolerated. In particular, the neurotoxicity reported with other methods of increasing bloodbrain barrier permeability has not been reported. Using a reliable method of individualised carboplatin administration, based on renal function, any effect of RMP-7 on the elimination of carboplatin may be determined.Overall, the use of RMP-7 as an adjunct to the treatment of tumours within the CNS may potentially be effective in terms of increasing tumour drug concentrations.

ISSN:1172-7047    

出版商:ADIS    

年代:1997

数据来源: ADIS

摘要:

The use of CNS stimulants for the treatment of attention deficit hyperactivity disorder (ADHD) in children has steadily increased in most areas of the world over the last 30 years. In mid- 1995, at least 1.5 million US children were receiving methylphenidate or dexamphetamine (dextroamphetamine). However, in other countries these agents are not used as widely.Specific stimulant-induced benefits for children with ADHD include: improved school grades, more completed classroom work, fewer reprimands for disruptive behaviour, improved handwriting, and improved behaviour at home and in social situtions. Stimulants benefit at least 75% of children with ADHD and are remarkably well tolerated, having few (for the most part minor and temporary) adverse effects.However, the benefits of stimulants that are obvious in most patients with ADHD during a brief clinical trial are primarily symptomatic. Although the behavioural benefits of stimulants are generally present during each period of treatment for as long as the ADHD condition exists (and children with ADHD are now often staying on stimulant medication into their mid-teens), the treatment has not been shown to change the long term outcome of the disorder.Before prescribing stimulants, paediatric physicians need to perform a careful diagnostic assessment for ADHD using multiple sources of information, including detailed ratings of the child's behaviour from his/her teachers and from a parent. If at baseline, the child's academic and behavioural adjustment in the classroom is good, stimulant medication would be inappropriate. However, if the child's pattern of ADHD has consistently and seriously interfered with his/her classroom and home adjustment, stimulant treatment should be actively considered. Should stimulant therapy be initiated, knowledgeable medical follow-up is required.

ISSN:1172-7047    

出版商:ADIS    

年代:1997

数据来源: ADIS

摘要:

Recognition of the role of active metabolites in mediating therapeutic and/or adverse effects of many antidepressants is an important part of understanding the mechanisms of action of these medications. While virtually all antidepressants except lithium undergo extensive hepatic metabolism, the profile of activity of the resulting breakdown products varies considerably.The metabolites of some antidepressants share the primary biochemical actions of their parent compounds and appear to contribute to the therapeutic efficacy of those medications. Examples of this are the tricyclic antidepressant (TCA) nortriptyline, the selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor (SSRI) fluoxetine and the serotonin-noradrenaline (norepinephrine) reuptake inhibitor venlafaxine. Less commonly, the activity of the primary metabolite may differ from that of the parent drug. An example is clomipramine. This drug is a potent serotonin reuptake blocking TCA, but its demethyl-metabolites are noradrenaline reuptake inhibitors. On the other hand, a number of effective antidepressants, including most of the SSRIs other than fluoxetine, lack active metabolites.On the negative side, antidepressant metabolites may add to the adverse effect burden presented by their drugs of origin. At sufficiently high doses, the amphetamines resulting from the metabolism of some monoamine oxidase inhibitors, e.g. selegiline (deprenyl), may directly produce toxicity from the pharmacodynamic interaction with the parent antidepressant. While hydroxy-nortriptyline produces lesser anticholinergic effects than its parent compound, this metabolite may block the therapeutic action of nortriptyline when present in high concentrations. Excessive plasma concentrations of the major metabolite of amfebutamone (bupropion) have been associated with nonresponse and clinical worsening in some patients.Amfebutamone also illustrates the importance of pharmacokinetic factors in determining the magnitude of the influence of metabolites on antidepressant action. Active metabolites that have long elimination half-lives may predominate over the parent compound in plasma and CSF, exerting considerable clinical impact. With several of the newer drugs, notably amfebutamone, venlafaxine and nefazodone, the presence of active metabolites with half-lives approaching 1 day suggests that once-daily administration may be sufficient.The formation of most antidepressant metabolites is under strong genetic control and the metabolites themselves often exert effects on hepatic enzyme systems. This can lead to the possibility of drug-drug interactions. A key example is norfluoxetine, which is associated with potent inhibition of the cytochrome P450 isozyme 2D6 (and, consequently, reduced metabolism of drugs such as TCAs). This effect lasts for weeks even after fluoxetine discontinuation, due to the fact that norfluoxetine has a half-life of up to 2 weeks.The clearance of most antidepressant metabolites is ultimately dependent on elimination by the kidneys. Therefore, these substances tend to accumulate in states of reduced renal function, including normal aging. The relative increase in TCA hydroxy-metabolite concentrations in the elderly may contribute to the cardiovascular and other toxicities of these antidepressants in this vulnerable patient population.Attention to the existence and implications of active metabolites from the earliest stages of antidepressant drug development may help optimise the benefit: risk ratio of this valuable class of psychotropic medications.

ISSN:1172-7047    

出版商:ADIS    

年代:1997

数据来源: ADIS

摘要:

Most psychotropic drugs, such as antipsychotics, lithium and tricyclic antidepressants, do not improve alcohol (ethanol) abstinence rates, at least in alcohol-dependent patients who do not have a comorbid psychiatric disorder. In recent years, numerous studies have been published that have focused on the effect of alcohol on various neurotransmitters. The glutamatergic, opioid-endorphin, mesolimbic dopamine, and serotonergic systems are believed to be of special relevance to the positive reinforcing effects of alcohol and clinical phenomena such as craving. Based on these neurobiological and molecular-biological findings, and some preclinical findings, a number of pharmacological agents have been tested to assess their potential in reducing relapse in alcoholism.To date, the glutamatergic modulator acamprosate and opioid antagonists naltrexone and possibly nalmefene show the most promise as anti-craving drugs. Both acamprosate (in most European countries) and naltrexone (in the US. Canada and Austria) have been introduced into clinical practice and can be considered drugs of first choice.Some studies indicate that buspirone is effective in reducing symptoms of anxiety in alcohol-dependent individuals, although a significant effect on alcohol intake has not been reported in all studies. Most studies of the selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors have found that these drugs have no effect on abstinence rates, but that they may have their place in the treatment of alcohol-dependent patients who have comorbid depression (fluoxetine) and cognitive deficits (possibly fluvoxamine). The therapeutic potential of other possible anti-craving drugs such as serotonin receptor agonists (e.g. buspirone) and antagonists (e.g. ondansetron) and dopaminergic drugs (e.g. bromocriptine, flupenthixol) needs to be examined in more detail.

ISSN:1172-7047    

出版商:ADIS    

年代:1997

数据来源: ADIS

摘要:

SynopsisThe semisynthetic ergoline dopamine agonist pergolide has demonstrated activity at pre- and postsynaptic dopamine D2receptors inin vitroandin vivoanimal studies. However, unlike other dopamine agonists such as bromocriptine, pergolide also has agonist activity at dopamine D1receptors. Certain other pharmacological effects of pergolide, such as reduction of dopamine turnover and effects on free radical scavenging enzymes, may be relevant in the early treatment of Parkinson's disease but this has not been conclusively determined.Short and long term noncomparative studies show that pergolide is an effective adjunct to levodopa therapy in patients with advancing Parkinson's disease, reducing the adverse effects of long term levodopa monotherapy and often enabling a reduction in levodopa dosage. In placebo comparisons pergolide was generally more effective than placebo and was associated with benefits similar to those seen in noncomparative studies.Longitudinal comparisons in individual patients indicate that the anti-parkinsonian efficacy of pergolide is similar to that of mesulergine, lergotrile and lisuride, and may be superior to that of bromocriptine. Controlled comparisons with bromocriptine tend to support this latter finding.Studies evaluating the efficacy of pergolide as monotherapy early in the course of Parkinson's disease have shown the drug to be effective, but opinion is divided as to the value of early treatment with dopamine agonists (as opposed to levodopa monotherapy).Thus, pergolide is an effective adjunct to levodopa therapy in patients with advanced Parkinson's disease and may have a role in the treatment of early disease if its postulated beneficial effects on disease progression are proven.Pharmacodynamic PropertiesPergolide is a semisynthetic ergoline dopamine agonist used in the treatment of Parkinson's disease. It has potent activity at presynaptic dopamine D2 receptors but is also active at postsynaptic D2 and dopamine D1 receptors.In vitro,pergolide suppressed D2-mediated prolactin release from rat anterior pituitary fragments and inhibited potassium-mediated dopamine or acetylcholine release from rat caudate slices. Pergolide-induced activation of rat striatal D1receptors has been shown to stimulate adenylate cyclase activity which, in turn, increased production of cyclic AMP.The majority of receptor binding studies indicate that pergolide is considerably more selective for D2than for D1receptors.In vivo,pergolide has been shown to induce contralateral turning in rats with right-side nigrostriatal lesions: it also induced climbing in rats selected on the basis of a climbing response to apomorphine.Pergolide had similar actions to those of selective D2agonists in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced hemiparkinsonian monkeys but was more potent than selective D1agonists. Pergolide improved parkinsonian symptoms in another study in this model. Its effects were more marked, but of shorter duration, than those of bromocriptine or cabergoline.One theory regarding the cause of Parkinson's disease is that metabolism of dopamine produces free radicals which damage nigral neurons. Its effects on oxygen radical scavenging enzymes are unclear: the drug induced superoxide dismutase in onein vivoanimal study but had no effect in another (but did induce catalase and glutathione peroxidase).Pharmacokinetic PropertiesSingle 1, 2, 5 and 10mg doses of pergolide produced mean peak plasma concentrations (Cmax) of 2.09, 4.57, 20.3 and 26 μg/L. respectively, in rhesus monkeys (administration of therapeutic doses to volunteers was considered unethical). The time to Cmaxranged between 2.4 and 2.7 hours at all dose levels.Mean steady-state pergolide plasma concentrations of 0.0275 to 1.167 μg/L were recorded during treatment with pergolide 2.25 to 9 mg/day in patients with Parkinson's disease; extensive interpatient variability was noted.55% of a 0.138mg radiolabelled oral dose of pergolide was excreted in the urine of volunteers; a further 40 to 50% of radioactivity appeared in the faeces and approximately 3% appeared in expired air.Analysis of urine and faecal extracts indicated the formation of 10 or more metabolites.Therapeutic UseA large noncomparative Japanese study has evaluated the short term efficacy of pergolide in combination with levodopa ± carbidopa (n = 314) or as monotherapy (n = 86). Addition of pergolide allowed a significant reduction in levodopa dosage and about 65% of patients experienced at least a mild improvement in wearing off and on-off phenomena. 45.3% of monotherapy recipients experienced at least moderate improvement according to a final global rating scale (vs52.9% of combination therapy recipients).Additional noncomparative studies in Australian, Thai, Chinese and Italian patients also reported adjunctive pergolide therapy to be effective.Early noncomparative long term studies reported an initial response to pergolide but the rate of clinical improvement tended to peak after 2 to 12 months, then decline. However, it does appear that the efficacy of pergolide, despite waning, can be maintained at a satisfactory level for several years.A long term continuation of the Japanese study discussed above reported a final global improvement rate that was at least moderate in 51.4% of adjunctive pergolide therapy recipients treated for at least 1 year, although the drug tended to become less effective after this time. 62 monotherapy recipients were included in this long term continuation; final global improvement rates were similar (moderate or greater in 61.3% of monotherapy recipientsvs51.4% in the combination therapy group).Results from a large 6-month multicentre double-blind placebo comparison have confirmed the result of earlier, smaller placebo comparisons. Pergolide recipients (n = 189) experienced a significantly greater improvement in many subjective measures of disease severity than placebo recipients. Pergolide allowed a 24.7% reduction in levodopa dosage compared with an approximate 5% reduction with placebo.On the basis of longitudinal sequential comparisons in individual patients, pergolide was considered to have similar utility to mesulergine, lergotrile and lisuride and appeared to be more effective than bromocriptine. In addition, a number of controlled studies reported that although both drugs were useful, pergolide tended to allow a greater reduction in levodopa dosage than bromocriptine. The sole available comparison of pergolide and bromocriptine as monotherapy reported the 2 drugs to be similarly effective.TolerabilityPostural hypotension occurs quite frequently in patients starting pergolide therapy but usually diminishes over time.In a recent placebo comparison, adverse events occurring significantly more frequently in pergolide recipients included dyskinesia (62% in the pergolide groupvs25% in placebo recipients), nausea (24vs13%), hallucinations (14vs3%), drowsiness (10vs3%), insomnia (8vs3%), nasal congestion (7vs1%), dyspepsia (6vs2%) and dyspnoea (5vs1%).ECG changes and palpitations have been noted in some patients receiving pergolide during clinical trials and close observation may be needed in patients with concomitant heart disease; limited data indicate that addition of domperidone attenuates these cardiac adverse events.Rarely, abrupt withdrawal of pergolide therapy can cause confusion or hallucinations; thus, when required, cessation of pergolide therapy should be gradual.Dosage and AdministrationTo avoid first dose hypotension and other adverse effects such as nausea and vomiting, pergolide therapy must be initiated at a low dosage (often 0.05 mg/day for 2 days). The dose should be slowly increased until maximum clinical benefit is achieved with no or minimal adverse effects.The drug is administered in divided doses, usually 3 or 4 times per day, and the most frequent effective total daily dose is 3 to 4mg; however, mean effective dosages were somewhat lower in Japanese studies.

ISSN:1172-7047    

出版商:ADIS    

年代:1997

数据来源: ADIS