摘要:

This article reviews the role of various neuropeptides in controlling eating behaviour and the prospects for ligands of these signalling systems in the treatment of eating disorders, in particular overeating and obesity.Neuropeptide Y is the most well known appetite-stimulating peptide. It is believed to exert this action through either Y1or Y5receptor subtypes in the hypothalamus. Selected antagonists with high affinity for these subtypes reduce food intake in animals, and so suggest that the development of clinically useful analogues may be possible.Galanin, another appetite-stimulating peptide, has been less well studied and the development of antagonists for galanin receptors is less well advanced. Studies using combinations of neuropeptide Y and galanin receptor antagonists, that may target carbohydrate and fat intake, respectively, have not yet been reported.Several peptides are known to inhibit food intake. Agonists of receptors for these peptides that have a long duration of action could be useful appetite suppressants. These peptides include ‘gut’ peptides such as cholecystokinin and glucagon-like peptide, and ‘pancreatic’ peptides such as amylin and insulin. Recently, the obesity (ob/ob) gene-related peptide leptin has been proposed as an endogenous signalling system that regulates fat intake, and a novel analogue of leptin has been shown to reduce food intake in rats.These peptides are thought to act on feeding-related regions at various levels of the neuraxis, prominently including the nucleus of the solitary tract, the lateral parabrachial nucleus, the paraventricular hypothalamus and the amygdala.

ISSN:1172-7047    

出版商:ADIS    

年代:1997

数据来源: ADIS

摘要:

Antipsychotics include the ‘typical’ agents (phenothiazines, thioxanthines and butyrophenones) as well as the more recently introduced agents referred to as ‘atypical’ (dibenzodiazepines, diphenylbutylpiperidines and benzamides). There are significant differences between these drugs in their toxicity in overdose. For example, thioridazine has been observed to be more cardiotoxic in overdose than other antipsychotic drugs, whereas clozapine and loxapine are the most likely to cause seizures.Many antipsychotic overdoses will result in mild sedation and no other ill effect. Most patients can be safely discharged 6 hours after the poisoning, but it is critical to recognise the more seriously poisoned patient who will develop cardiotoxicity or seizures. These patients have ECG changes (QRS and/or QT prolongation) and decreased level of consciousness, and therefore require intensive care unit admission.Treatment of antipsychotic overdose includes supportive care of the comatose patient, effective gastrointestinal decontamination with activated charcoal, intravenous fluids and ECG monitoring. Cardiotoxicity in antipsychotic overdose may manifest as ventricular arrhythmia, various degrees of conduction delay, or hypotension. The primary treatment of cardiotoxicity is plasma alkalinisation with sodium bicarbonate and hyperventilation. Neurotoxicity is manifest as coma and seizures. Treatment consists of intubation, hyperventilation and plasma alkalinisation.

ISSN:1172-7047    

出版商:ADIS    

年代:1997

数据来源: ADIS

摘要:

The development of the passive transdermal therapeutic system (TTS) as an effective method of drug delivery has allowed the potent, lipid soluble opioid fentanyl to be administered transdermally as an analgesic agent to patients with postoperative and chronic pain.Due to the passive nature of the TTS, drug absorption is prolonged and the development of therapeutic plasma concentrations takes up to 16 to 24 hours. Steady-state plasma concentrations of fentanyl develop readily, but cannot be adjusted rapidly to compensate for acute increases or decreases in pain after surgery. This necessitates supplementation of TTS fentanyl with small quantities of systemic opioids. The difficulty in titrating TTS fentanyl for acute pain and the associated relatively high incidence of toxicity (respiratory depression) make the system unsuitable for pain after surgery.In patients with chronic pain (especially of a neoplastic origin), TTS fentanyl has proved reasonably effective. Several noncontrolled observational studies have shown that TTS fentanyl may be as effective as oral morphine as an analgesic for cancer pain, with claims of improved quality of life and increased acceptance by patients due to the ease of use. There are few data, however, from properly controlled clinical trials to substantiate these claims at the present time. In these opioid-tolerant patients, respiratory depression has not proved to be a problem if TTS fentanyl is used correctly.

ISSN:1172-7047    

出版商:ADIS    

年代:1997

数据来源: ADIS

摘要:

In this article, we raise the following question regarding the treatment of depression with the selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs) citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline: are there clinically relevant differences between these SSRIs in terms of their (i) pharmacodynamic and pharmacokinetic and (ii) clinical (i.e. efficacy, tolerability, adverse events and safety) profiles?In order to answer the first part of the question, the large body of literature on the pharmacodynamics and pharmacokinetics of SSRIs were examined. It can be concluded that, except for a few special situations (such as breast feeding), the many differences that the SSRIs show in their pharmacodynamic and pharmacokinetic profile are probably of limited importance in clinical practice.In order to answer the second part of the question, the 16 head-to-head comparisons between SSRIs that were published before January 1997 were reviewed. These were double-blind randomised studies that directly compared the SSRIs using a parallel group design; however, they were limited, quantitatively as well as qualitatively. The data published do not reveal unequivocal, clinically relevant differences between the SSRIs in terms of general efficacy, profile of action (e.g. effect on anxiety, agitation, sleep, suicidal ideation or cognitive function), speed of onset of action, total severity or profile of adverse events, or safety.We conclude that the differences between the SSRIs may lead the clinician when making a choice inindividualcases. However, at present, neither pharmacodynamic/pharmacokinetic considerations nor direct clinical comparisons between SSRIs provide data that can assist clinicians in making a rationalgeneralchoice between these drugs.

ISSN:1172-7047    

出版商:ADIS    

年代:1997

数据来源: ADIS

摘要:

▴ Zolmitriptan is indicated for the acute treatment of migraine with and without aura.▴ The drug is a serotonin 5-HT1B/1Dreceptor agonist that has little or no affinity for other serotonin receptors or receptors of other neurotransmitters.▴ Preclinical studies indicate that zolmitriptan has a novel dual mechanism of action, having effects at both central (trigeminal nucleus caudalis) and peripheral (trigeminovascular system) targets.▴ Studies in volunteers demonstrate that zolmitriptan has relatively good oral bioavailability.▴ Zolmitriptan is effective in alleviating migraine headache and also nonheadache symptoms such as photophobia, phonophobia and nausea.▴ The tolerability of zolmitriptan is good, with the most common adverse experiences being paraesthesia, asthenia, nausea, somnolence and dizziness. Heaviness, tightness or pressure in the chest have been reported, but have not been associated with ECG abnormalities.

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:

SynopsisSertraline, a selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor (SSRI) which was initially developed as an antidepressant, has also been shown to be an effective treatment for patients with obsessive-compulsive disorder (OCD).Results of short and long term (≤ 2 years) clinical trials have shown that sertraline is an effective treatment for nondepressed adult and paediatric patients with OCD. In several placebo-controlled clinical trials conducted in patients with OCD, sertraline 50 to 200 mg/day produced significantly greater improvements than placebo on Yale-Brown Obsessive-Compulsive Scale and Clinical Global Impression Severity Scale and on various other OCD assessment scales. The efficacy of sertraline in OCD has not yet been directly compared with that of the SSRIs fluvoxamine, fluoxetine or paroxetine. However, findings of a single comparative trial indicate that sertraline is at least as effective as, and is better tolerated than, the tricyclic antidepressant (TCA) clomipramine in adults.Sertraline, like other SSRIs, is generally well tolerated. It is not associated with the anticholinergic, sedative and cardiovascular adverse effects that are characteristic of the TCAs. Headache, insomnia, nausea and diarrhoea were reported as the most common adverse events in sertraline recipients who participated in a 12-week placebo-controlled trial; the incidences of these events (except headache) decreased in patients who received sertraline treatment in a 40-week extension of this trial. Like other SSRIs, sertraline has been reported to cause sexual dysfunction in some patients.Because sertraline has a plasma elimination half-life of 25 to 26 hours, oncedaily administration is sufficient to ensure adequate plasma sertraline concentrations are achieved in patients with normal renal function. The favourable drug interaction profile of sertraline as compared with other SSRIs used to treat OCD has been partly explained by its weak inhibitory effects on some hepatic cytochrome P450 isoenzymes.In conclusion, sertraline is an effective primary treatment option for adults, adolescents and children with OCD and has broadened the range of available agents for this often disabling condition. In addition, it is better tolerated than clomipramine and thus may be preferred for the treatment of specific patient groups, particularly those susceptible to the adverse effects of TCAs.Pharmacodynamic PropertiesSertraline, a naphthylamine derivative, is one of several selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs) that have demonstrated efficacy in the treatment of obsessive-compulsive disorder (OCD). The cause of OCD has not yet been conclusively established, but a dysregulation of serotonergic functioning appears to be involved.Sertraline is a potent and highly selective inhibitor of serotonin reuptake. The resultant effect is an increase in synaptic serotonin levels, enhanced serotonergic activity and subsequent downregulation of serotonergic subsystems. Although sertraline produces only minor inhibition of noradrenaline (norepinephrine) reuptake, biogenic amines other than serotonin may also be involved in mediating its therapeutic activity.CNS &sgr;1-receptors have been implicated in the pharmacological activity of sertraline and it has also been suggested that the drug may exert clinical effects via &ggr;-aminobutyric acid neuronal pathways. Sertraline shows no marked affinity for 5-HT1A, 5-HT1B, 5-HT2, histamine H1, muscarinic or dopamine D2receptors, or &agr;1-, &agr;2- or &bgr;-adrenoceptorsin vitro.Increased vigilance has been observed in healthy volunteers after single 100 to 400mg doses of the drug. Sertraline was also associated with improved cognitive performance and alertness in healthy volunteers aged 50 to 67 years.Pharmacokinetic PropertiesThe pharmacokinetics of sertraline appear to be broadly similar in male and female healthy adults, in elderly individuals aged ≥65 years and in children and adolescents. Sertraline has a linear pharmacokinetic profile after single or multiple oral doses of 50 to 200mg. It is slowly absorbed after oral administration and steady-state plasma concentrations are reached approximately 1 week after treatment initiation. The volume of distribution of sertraline (>20 L/kg) indicates that it is extensively distributed in body tissues.After absorption, sertraline undergoes substantial first-pass metabolism in the liver. Its primary metabolite is demethyl-sertraline, which subsequently undergoes oxidative deamination to produce conjugated and unconjugated metabolites. The metabolites of sertraline have been shown to have virtually no effects on serotonin reuptake. Sertraline is eliminated in approximately equal amounts in the urine and faeces. As the plasma elimination half-life of the drug is 25 to 26 hours, it is administered on a once-daily basis.The pharmacokinetics of sertraline (administered as single or multiple oral doses) are not significantly altered in patients with mild, moderate or severe renal impairment, although clearance may be reduced in patients with end-stage renal disease. Because sertraline is metabolised in the liver, its clearance is reduced in patients with hepatic disease.The favourable drug interaction profile of sertraline has been partly explained by its weak inhibitory effect on the hepatic cytochrome P450 (CYP) isoenzymes CYP2D6, CYP3A3/4, CYP2C19, CYP2C9/10 and CYP1A2. In contrast, the SSRIs fluoxetine and paroxetine have substantial inhibitory effects on CYP2D6, and fluvoxamine has marked inhibitory effects on CYP1A2 and CYP2C19. Thus, these SSRIs have a greater propensity than sertraline to interact with drugs metabolised by these enzymes. As sertraline is highly plasma protein bound, it has the potential to interact with other highly protein bound drugs. However, no reports of such interactions have yet been published.Therapeutic EfficacySeveral placebo-controlled trials in nondepressed adults with OCD have demonstrated that sertraline 50 to 200 mg/day produces significantly greater improvements than placebo on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), Clinical Global Impression (CGI) Severity Scale and on various other OCD assessment scales. Sertraline has been shown to be effective both as short term treatment (≤16 weeks) and as longer term maintenance therapy over 1 to 2 years. In a 12-week placebo-controlled trial (n = 324 adults), 60.4 and 49% of sertraline and placebo recipients, respectively, responded to study medication. During a 40-week extension phase of this study, the clinical efficacy of sertraline was sustained, with improvements in Y-BOCS, National Institute of Mental Health Global Obsessional-Compulsive Scale (NIMH) and CGI Severity Scale scores indicating that sertraline was significantly more effective than placebo.The only study that has compared sertraline 50 to 200 mg/day with clomipramine 50 to 200 mg/day demonstrated that both agents produced significant improvements on the Y-BOCS and several other OCD assessment scales. Sertraline and clomipramine showed equal efficacy among patients completing the trial. However, intention-to-treat analysis revealed a significant advantage for sertraline over clomipramine which was explained in part by the higher treatment discontinuation rate because of adverse events in the latter group.A recent meta-analysis of data from large placebo-controlled trials revealed that sertraline, fluoxetine and fluvoxamine have similar efficacies in OCD; however, all 3 agents appeared to be significantly less effective than clomipramine. These results may be partly explained by inclusion of treatment-naive patients in earlier trials of clomipramine. In contrast, the more recent trials of SSRIs included a higher proportion of treatment-experienced patients who had not responded to previous treatment with clomipramine or with other SSRIs.In noncomparative investigations that included patients with paraphilias (classified as OCD spectrum disorders), sertraline 50 to 200 mg/day produced marked improvements on most sexuality scales and significantly decreased obsession scores.Sertraline, in dosages of 25 to 200 mg/day, has also demonstrated clinical efficacy in children and adolescents (aged 6 to 17 years) with OCD. Significant improvements in mean Children's Y-BOCS. NIMH and CGI Severity Scale scores, compared with baseline values, were evident after 5 weeks' sertraline treatment.TolerabilitySertraline 50 to 200 mg/day was generally well tolerated by adults and paediatric patients with OCD who participated in clinical trials. The incidence and severity of sertraline-related adverse events appeared to be dose related. In a placebo-controlled trial conducted in 324 nondepressed adults with OCD, the most common adverse events reported during 12 weeks' sertraline treatment (50 to 200 mg/day) were headache, insomnia, nausea, diarrhoea, decreased libido and anorexia. These events occurred with an incidence ≥10% greater than with placebo. All of the sertraline-related adverse events (except headache) decreased in incidence during a 40-week extension of the 12-week trial. There was a significantly higher incidence of insomnia, nausea, agitation and tremor in children and adolescents with OCD receiving sertraline treatment than in similar patients who received placebo.Unlike the tricyclic antidepressants (TCAs), sertraline is associated with minimal anticholinergic activity and is essentially devoid of cardiovascular effects. Moreover, in contrast to the sedative effects of the TCAs, sertraline does not generally appear to impair psychomotor performance. Results of a recent comparative study showed that there was a significantly higher treatment discontinuation rate because of adverse events in patients receiving clomipramine (25.6%) than in the sertraline treatment group (10.5%).Sertraline has a wide therapeutic index and appears to be less harmful in overdosage than the TCAs.Dosage and AdministrationThe optimal starting dosage of sertraline for treating adult and paediatric patients with OCD is 50 mg/day. Thereafter, the dosage may, if necessary, be increased in 50mg increments (over several weeks or months) to a maximum of 200 mg/day. Dosage modification is not usually required for patients with mild to moderate renal impairment, but dosage reduction is recommended for patients with hepatic disease.

ISSN:1172-7047    

出版商:ADIS    

年代:1997

数据来源: ADIS