Tricyclic Agents Research Articles

Brugada electrocardiographic pattern due to tricyclic antidepressant overdose

The Brugada syndrome is an arrhythmogenic disease with characteristic coved ST-segment elevation 2 mm or greater in the right precordial leads (type 1 Brugada electrocardiogram [ECG] pattern or “Brugada sign”] and is estimated to be responsible for at least 20% of sudden deaths in patients with structurally normal hearts [ Circulation 2005;111(5):659-70]. The Brugada sign has been described in asymptomatic patients after exposure to various drugs. As published reports of the drug-induced Brugada sign have become increasingly prevalent, there is growing interest in the mechanisms responsible for this acquired ECG pattern and its clinical significance. We report a case of a patient who developed the type 1 Brugada ECG pattern after intentional overdose of a tricyclic antidepressant agent, review the literature concerning tricyclic antidepressant agent–induced Brugada sign, discuss potential mechanisms, and evaluate the clinical significance of this ECG abnormality.

Acute amitriptyline intoxication: an analysis of 44 children

The tricyclic antidepressant agents, particularly amitriptyline and dothiepin, are recognized for their potentially lethal cardiovascular and neurological effects in poisoned patients. In this article, the clinical and laboratory findings of 44 children with amitriptyline intoxication are reviewed. Our purpose was to investigate amitriptyline intoxication in childhood. Of 44 patients, 21 (47.7%) were boys, 23 (52.3%) were girls, and the ages ranged from 12 months to 14 years (mean +/- SD; 4.09 +/- 2.9 years). All children except one who took an overdose of amitriptyline to decrease his pain accidentally ingested an overdose of amitriptyline. The amount of amitriptyline ingested was between 2 mg/kg and 97.5 mg/kg (mean +/- SD; 13.6 +/- 17.7 mg/kg per dose) (the drug dosage was not known in 13 children). The most commonly observed clinical and laboratory findings were lethargy, tachycardia, convulsion, hyperglycemia and leukocytosis. In all patients except for two children who died the abnormal clinical and laboratory findings returned to normal within a few days after admission and they were discharged from the hospital in good health within the fourth day of admission. One of the children ingested 97.5 mg/kg amitriptyline and probably died due to status epilepticus and another child who died ingested 36 mg/ kg amitriptyline and died due to cardiopulmonary arrest. In conclusion, our findings showed that initial symptoms and signs of acute amitriptyline intoxication appeared severe, but they disappeared with only supportive care required in most children except for cases that ingested high doses of drug within a few days. In contrast to adults, we infrequently noted respiratory insufficiency, arrhythmia and hypotension in children with acute amitriptyline intoxication.

Recent advances in the diagnosis and management of diabetic neuropathy

The World Health Organisation estimated that in the year 2000, 150 million people had diabetes mellitus, and it is predicted that this number will rise to 366 million by the year 2030.[1][1] Neuropathy is a common complication of diabetes and is characterised by a progressive loss of peripheral

Fibromyalgie — Ein Update

Fibromyalgia is a common syndrome of unknown etiology characterized by chronic widespread pain and poly-symptomatic autonomic disturbances and often mental features. The American College of Rheumatology's classification criteria define fibromyalgia by widespread pain and 11 of 18 tender points. Fibromyalgia is a diagnosis of exclusion as long as stand none laboratory or technical tests. The major role in pathogenesis appears to be central and involves the subcortical pain modulation, psychical stress especially in early childhood, endocrinological and genetic factors. There is no evidence of abnormalities in muscle and tendon. The goal of therapy in fibromyalgia is pain, reduced physical function and sleep disturbance. Actual evidence of effects of pharmacological and nonpharmacological interventions are summarized. Tricyclic agents, aerobic exercises, patient education and combined therapies can reduce effectively symptoms and disability.

Physiopathologie et traitement des troubles fonctionnels intestinaux

Functional bowel disorders (FBD) are chronic digestive symptoms attributable to the lower gastrointestinal tract in the absence of any structural or biochemical explanation. The most common FBD is the irritable bowel syndrome (IBS), in which abdominal discomfort or pain is associated with disordered bowel habits (diarrhoea, constipation or both) or disturbed defecation. IBS pathophysiology is multifactorial and generally related to a “gut-brain axis” dysfunction. Serotonin (5-HT), a neurotransmitter found mainly in the gut, appears to represent a link in IBS pathophysiological processes. Recent studies have also highlighted the potential impact, in the onset of symptoms, of a micro-inflammatory condition and of an immunocompetent cell dysfunction, mainly mast cells, at the enteric nervous system level. In some patients, IBS appears as a post-infectious disorder, following an acute gastroenteritis. Traditional IBS management often relies on a combination of dietary measures, antispasmodic drugs and antidiarrhoeal or laxative drugs. Since it has been demonstrated that it is the main substratum of abdominal pain in a majority of IBS patients, visceral hypersensitivity appears the first therapeutic target. While tricyclic antidepressant agents given at low doses have become an option, the potential role of 5-HT has justified the development of new serotonergic agents, either 5-HT3 antagonists or 5-HT4 agonists, providing global relief of the multiple IBS symptoms. The influence of brain on gut-brain axis dysfunction cannot be omitted and psychotherapy, hypnosis or relaxation are useful, particularly in the most severe patients.

Die Wirkung von Botulinumtoxin A und B auf die vegetative kardiale Innervation

The objective of this study was to examine whether vegetative cardiac innervation is affected by local application of botulinum toxin A and B. For that purpose, heart rate variability (HRV) was measured in 29 patients treated with botulinum toxin A and 26 patients treated with botulinum toxin B both prior to and three weeks following injection. Among the 14 parameters studied, 9 and 10 had significantly changed in terms of decreased HRV following treatment with botulinum toxin A and B, respectively. Obviously, either type of botulinum toxin exerts a systemic effect, although a clear-cut difference between the two preparations was undetectable. By and large, the changes observed tend to be low compared to, for instance, cardiac effects known to occur with tricyclic agents. However, the results might be of relevance for the use of botulinum toxins in patients with a history of cardiac disease since a reduction in HRV correlates with an increased incidence of cardiovascular events. Therefore, an ECG study is advised prior to onset of therapy with botulinum toxin. In addition, nonjudicious use of botulinum toxin outside a defined range of medical indications should be reassessed.

Neurobiology of mood, anxiety, and emotions as revealed by studies of a unique antidepressant: tianeptine

Recent studies have provided evidence that structural remodeling of certain brain regions is a feature of depressive illness, and the postulated underlying mechanisms contribute to the idea that there is more to antidepressant actions that can be explained exclusively by a monoaminergic hypothesis. This review summarizes recent neurobiological studies on the antidepressant, tianeptine (S-1574, [3-chloro-6-methyl-5,5-dioxo-6,11-dihydro-(c,f)-dibenzo-(1,2-thiazepine)-11-yl) amino]-7 heptanoic acid, sodium salt), a compound with structural similarities to the tricyclic antidepressant agents, the efficacy and good tolerance of which have been clearly established. These studies have revealed that the neurobiological properties of tianeptine involve the dynamic interplay between numerous neurotransmitter systems, as well as a critical role of structural and functional plasticity in the brain regions that permit the full expression of emotional learning. Although the story is far from complete, the schema underlying the effect of tianeptine on central plasticity is the most thoroughly studied of any antidepressants. Effects of tianeptine on neuronal excitability, neuroprotection, anxiety, and memory have also been found. Together with clinical data on the efficacy of tianeptine as an antidepressant, these actions offer insights into how compounds like tianeptine may be useful in the treatment of neurobiological features of depressive disorders.

Angina With “Normal” Coronary Arteries

Many women with angina are told that they have no significant heart disease following demonstration of normal or near-normal coronary arteries and are offered no specific treatment beyond reassurance. MEDLINE and the Cochrane Database of Systematic Reviews were searched from their start dates until June 2004 for analysis using specific key words including diagnosis and therapy of angina with normal angiography and angina with normal coronary arteries. Reference lists of published articles and data of meeting presentations were also consulted. Normal or nonobstructive coronary disease at angiography is not uncommon and occurs in 10% of women presenting with ST-segment elevation myocardial infarction compared with 6% in men. Patients with evidence of myocardial ischemia or myocardial infarction and nonobstructive atherosclerotic disease of the coronary arteries are more likely to be women and nonwhite. Symptoms are often indistinguishable from those with obstructive coronary artery disease. The prognosis of patients with unstable angina and nonobstructive atherosclerotic coronary artery disease is not benign and includes a 2% risk of death or myocardial infarction at 30 days of follow-up. Recent work has shown that at least 20% of women with normal or nonobstructive angiography have myocardial ischemia, likely due to atherosclerosis-related endothelial dysfunction, which itself is associated with an increased risk of later adverse cardiac events and development of frank future obstructive disease. Randomized placebo-controlled studies have demonstrated that tricyclic antidepressants, beta-blockers, angiotensin-converting enzyme inhibitors, L-arginine, statins, and exercise may relieve symptoms, vascular dysfunction, or both; however, longer-term studies evaluating cardiac event rates need to be performed. Patients with chest pain and normal or nonobstructive coronary angiograms are predominantly women, and many have a prognosis that is not as benign as commonly thought. Assessment of endothelial function may help identify patients at risk for future cardiac events. Therapy should be directed at symptom relief with tricyclic agents and beta-blockers, and aggressive antiatherosclerotic therapy with statins, angiotensin-converting enzyme inhibitors, or both should be applied when risk factors are present or prognostic risk is high. Large-scale randomized trials need to be conducted to determine optimal ways of preventing clinical events.

The vulval pain syndromes

Whilst there is increasing awareness of vulval pain, the diagnosis is still made belatedly often after a patient has had problems for months and sometimes years. The diagnosis should always be considered in patients with recurrent vulval discomfort, irritation or burning and/or in those who repeatedly complain of superficial dyspareunia. Typically there is no physical abnormality and multiple tests for infection are negative, or positive for organisms that are unlikely to account for the symptoms. Patients will often report that they have consulted several practitioners and tried a range of treatments; usually including antifungal agents, with limited or no benefit. The diagnosis is based on a typical history with negative examination findings except in Localised Vulval Dysesthesia (Vestibulodynia/Vulvar-vestibulitis) where patients will have ‘touch’ tenderness elicited by touching the vulval vestibule with a cotton swab. For many patients a definite diagnosis, supported by written information and access to support organisations and the Web, is therapeutic. Management then includes low-dose tricyclic agents given for their analgesic actions, sometimes in combination with topical local anaesthetic agents as well as referral, if possible, to a psychosexual specialist or a psychologist with an interest in chronic pain. Key to successful management is careful advice about taking tricyclics, which should be started in low dosage and gradually increased. Patients need to understand that any side effects will usually diminish in the first month of therapy and that benefits usually appear a few weeks into treatment and not overnight.

Tricyclic Antidepressant Poisoning

All tricyclic drugs are potentially able to cause the main acute CNS toxic syndromes of coma and convulsions. Dosulepin (dothiepin) seems more likely to cause convulsions than other drugs in this class, and amitriptyline also appears a more toxic tricyclic agent. Coma is the most useful sign indicative of toxic risk and appears to predict severe toxic complications (fits and arrhythmias) more reliably than ECG changes. Prophylactic therapy against convulsions has not been shown to be effective. Use of an anticholinesterase (physostigmine) is not recommended for management of coma. There is no good evidence base to support a particular anticonvulsant.

Paroxetine augmentation to tianeptine treatment causes exacerbation of depressive symptoms: presentation of two cases

We present two cases whose depressive symptoms partially remitted with tianeptine treatment but exacerbated after paroxetine augmentation to tianeptine. Although tianeptine has structural similarities with tricyclic antidepressants, unlike tricyclic agents or selective serotonin- reuptake inhibitors(SSRIs), it enhances 5-HT reuptake in brain, leading to decreased availability of the transmitter in the synaptic cleft. Thus, efficacy of tianeptine as an antidepressant agent caused a challenge to the concept of serotonergic deficit theory in depression. Both paroxetine and tianeptine are found equivalently effective in treatment of major depression, but no data are available for combined use of these two agents.

Antidépresseurs. Classifications

Antidepressant drugs may be distributed according to their chemical structure (tricyclic agents, monoamine-oxidase inhibitors), or according to the date of their integration into the pharmacopedia (2 nd generation antidepressant drugs). They may be also distributed according to their mechanism of action (specific or non-specific monoaminergic activity, pre- or post-synaptic activity, serotonin recapture inhibition), or according to their biochemical effects (anticholinergic, antihistaminic, or alpha-adrenergic activity). The therapeutic classification (sedative agents, medians, stimulant agents) is useful in anticipating the mode of action and potential adverse effects.

Delayed Gastric Emptying in Functional Dyspepsia.

Functional dyspepsia is a complex syndrome with a poorly defined pathophysiology, resulting in uncertainties in its therapeutic approach. Abnormalities in gastrointestinal motility and sensitivity alone or combined seem to play a role in a substantial subgroup of patients. Drugs capable of prokinetic effects, such as antidopaminergics (eg, metoclopramide, domperidone, levosulpiride) and serotonin 5-HT4 receptor agonists (eg, tegaserod) can be potentially used in the treatment of dyspeptic patients. Furthermore, 5-HT4 receptor agonists do not appear to increase the gastric fundus tone which may also contribute to improved symptoms in subsets of patients. Alosetron, a 5-HT3 receptor antagonist, has been investigated mainly in irritable bowel syndrome, and the few studies performed in functional dyspepsia have provided conflicting results. Erythromycin and related derivatives, the motilides, represent another class of prokinetic compounds able to accelerate gastric emptying and potentially indicated in functional dyspepsia. The stimulatory effect on fundic tone and the occurrence of tachyphilaxis hamper the efficacy of these drugs in the long-term treatment. kappa-opioid receptor agonists might be useful for functional digestive syndromes because of their antinociceptive effects, but there are few available results and most are inconclusive. Results are also needed to prove efficacy of antidepressants (tricyclic agents and 5-HT reuptake inhibitors). Future clinical trials should be performed so that the formal structure required by good clinical practice can be adapted to detect significant effects in subgroups of patients with functional dyspepsia. Therapy should be ideally targeted to the different pathophysiologic abnormalities of these subgroups. The identification of the mechanisms leading to symptom generation should facilitate the development of newer and more effective therapeutic strategies in functional dyspepsia.

Amitriptyline for inpatients and SSRIs for outpatients with depression? Systematic review and meta-regression analysis.

Although the selective serotonin reuptake inhibitors (SSRIs) are widely used as first-line agents in depression, amitriptyline, a reference tricyclic (TCA) agent, has the edge in terms of efficacy over control antidepressants (ADs), but it is not clear whether this advantage can be attributed to a more favourable profile in inpatients, but not in outpatients, with depression. The aim of this study was to investigate the contribution of study setting on outcome in clinical trials comparing amitriptyline with any other AD. A systematic review and meta-regression analysis of amitryptiline randomised clinical trials was carried out. The electronic search yielded 181 randomised clinical trials, 47% enrolling inpatients and 53% outpatients with depression. Both on a dichotomous and continuous out-come, amitriptyline was more effective than control agents in in-patients [Peto odds ratio (OR): 1.22, 95%, Confidence Interval (CI): 1.04, 1.42; Standardised Mean Difference (SMD): 0.28, 95 %,Cl: 0.08, 0.46], but not in outpatients (Peto OR: 1.01, 95%, CI: 0.88,1.17; SMD: 0.10,95% CI: -0.02,0.23). Among inpatients amitriptyline was significantly more effective than TCA and nonsignificantly more effective than the SSRIs. Among outpatients no statistically significant differences emerged between amitriptyline and TCA and between amitriptyline and the SSRIs. Amitriptylinewas less well tolerated than control agents in outpatients (Peto OR: 0.90, 95%, CI: 0.81, 0.99), but not in inpatients (Peto OR:1.09, 95% CI: 0.95, 1.25). These data suggest that a reasonable approach could be the first-line prescription of newer agents in the routine outpatient care of depressive subjects, and the use of amitriptyline in inpatients with severe depression.

Irritable bowel syndrome

The prevalence of irritable bowel syndrome (IBS) ranges in all countries of the world between 6 and 25%, in Germany between 15 and 22%. The divergent rates of prevalence are mainly due to different definitions of IBS in epidemiological studies. In Germany, 20-50% of persons with IBS symptoms seek medical help. IBS patients produce high direct and indirect costs. The following psychophysiological mechanisms of IBS are presumed to be empirically validated: visceral hypersensitivity, postinfectious sequelae, psychiatric disorders, and psychosocial stress. Tricyclic antidepressant agents and psychotherapy (hypnosis, cognitive behavioral therapy, and psychodynamic therapy) are effective for treatment of IBS forms dominated by pain. In one controlled study, the combination of pharmacological therapy and cognitive behavioral therapy was superior to pharmacological therapy alone.

Review article: approaches to endoscopic-negative reflux disease: part of the GERD spectrum or a unique acid-related disorder?

Endoscopic-negative reflux disease (ENRD) is the most common presentation of gastro-oesophageal reflux disease (GERD)-affecting up to 70% of these individuals. In the last three decades therapeutic studies have focused solely on the treatment of patients with erosive oesophagitis. However, more recent studies have shifted our attention to defining, understanding and treating those with ENRD. GERD has traditionally been approached as a spectrum with ENRD at the mild end and complicated GERD (i.e. patients with erosive oesophagitis, stricture and Barrett's oesophagus) being at the other end, suggesting that patients' disease may progress over time along the spectrum. Current data indicate that ENRD should be approached as a unique entity rather than a part of the GERD spectrum and that over time only a few patients with ENRD will develop GERD-related complications. Patients with ENRD are a heterogenous group of patients with different aetiologies for their heartburn symptoms, including motor events, reflux of acidic or nonacidic gastric contents, minute changes in intraesophageal pH (pH < 4), mucosal hypersensitivity, and emotional or psychological abnormalities. By dropping the spectrum concept, which emphasizes oesophageal mucosal injury, we can focus our attention on the specific mechanisms that lead to symptom generation in each of the three unique groups of GERD (ENRD, erosive oesophagitis and Barrett's oesophagus) and on the specific therapeutic modalities that benefit each of these individual groups. Acid suppressive therapy with proton pump inhibitors is highly effective in healing erosions and controlling symptoms in those with erosive oesophagitis. In those with ENRD the resolution or control of heartburn with proton pump inhibitor therapy is greater than that with placebo or H2 receptor antagonist, but not as consistent nor as impressive as the results observed in studies of patients with erosive oesophagitis. By considering the mechanisms involved in ENRD symptom generation, future studies that include high-dose proton pump inhibitors, promotility agents (alone or in combination with proton pump inhibitors), transient lower oesophageal sphincter reducers, or pain modulators (e.g. tricyclic antidepressant agents) may prove beneficial.

Do Adenosine Receptors Play a Role in Amitriptyline‐Induced Cardiovascular Toxicity in Rats?

The aim of the our study was to investigate the role of adenosine receptors on cardiovascular toxicity induced by amitriptyline, a tricyclic antidepressant agent. Therefore, the hypothesis of this study was that adenosine receptor antagonists would improve and/or prevent amitriptyline-induced hypotension and conduction abnormalities in an anesthetized rat model of amitriptyline intoxication. Two separate experimental protocols were performed. Amitriptyline intoxication was induced by the infusion of amitriptyline 0.94 mg/kg/min until 40-45% reduction of mean arterial pressure (MAP). Sodium cromoglycate (10 mg/kg) was injected i.v. to inhibit the A3 receptor-mediated activation of mast cells. In protocol 1, after amitriptyline infusion, while control animals (n=8) were given dextrose solution, treatment groups received a selective adenosine A1 antagonist DPCPX (8-cyclopentyl-1,3-Dipropylxanthine, 20 microg/kg/min, n=8) or a selective A2a antagonist CSC (8-(3-chlorostyryl) caffeine, 24 microg/kg/min, n=8) for 60 minutes. In protocol 2, after the sodium cromoglycate, while control group of rats (n=8) recevied a dextrose solution, treatment groups of rats were administered DPCPX (20 microg/kg/min, n=8) or CSC (24 microg/kg/min, n=8) infusion to block adenosine A1 and A2a receptors for 20 minutes before amitriptyline infusion. After pretreatment with adenosine antagonists, all rats were given a dose of 0.94 mg/kg/min of amitriptyline infusion during 60 minutes. Outcome measures were mean arterial pressure (MAP), heart rate (HR), QRS duration and survival rate. In protocol 1, amitriptyline infusion significantly reduced MAP and prolonged QRS within 15 minutes. HR was not changed significantly during the experiments. While dextrose did not improve MAP and QRS prolongation, DPCPX or CSC administration developed a significant improvement in MAP compared to the dextrose group within 10 min (88.5 +/- 2.8%, 75.6 +/- 4.7% and 50.1 +/- 14.7%, p<0.01, p<0.05, respectively). Both DPCPX and CSC decreased QRS prolongation (p<0.05) and increased median survival time significantly (log-rank test, p<0.00001). In protocol 2, pretreatment with DPCPX or CSC prevented the reduction in MAP due to amitriptyline toxicity compared to rats administered dextrose infusion (99.5 +/- 2.6%, 102.4 +/- 2.6%, 81.8 +/- 5.4, p<0.01 at 30 min; 98.0 +/- 2.9%, 93.5 +/- 6.0%, 64.9 +/- 4.7, p<0.001, p<0.01 at 40 min, respectively). Pretreatment with DPCPX or CSC also prevented the QRS prolongation (p<0.05) and increased median survival time significantly (log-rank test, p<0.0001). Adenosine antagonists were found to be effective in improving hypotension, QRS prolongation and survival time in our rat model of amitriptyline toxicity. Additionally, amitriptyline-induced cardiotoxicity was abolished by pretreatment with adenosine receptor antagonists. These results suggest that adenosine receptors may have a role in the pathophysiology of amitriptyline-induced cardiovascular toxicity. Adenosine A1 and A2a receptor antagonists may be promising agents for reversing amitriptyline-induced cardiovascular toxicity.

Human liver aldehyde oxidase: inhibition by 239 drugs.

The authors tested 239 frequently used drugs and other compounds for their potential to inhibit the drug-metabolizing enzyme, aldehyde oxidase, in human liver cytosol. A sensitive, moderate throughput HPLC-MS assay was developed for 1-phthalazinone, the aldehyde oxidase-catalyzed product of phthalazine oxidation. Inhibition of this activity was examined for the 239 drugs and other compounds of interest at a test concentration of 50 microM. Thirty-six compounds exhibited greater than 80% inhibition and were further examined for measurement of IC50. The most potent inhibitor observed was the selective estrogen receptor modulator, raloxifene (IC50=2.9 nM), and tamoxifen, estradiol, and ethinyl estradiol were also potent inhibitors. Other classes of drugs that demonstrated inhibition of aldehyde oxidase included phenothiazines, tricyclic antidepressants, tricyclic atypical antipsychotic agents, and dihydropyridine calcium channel blockers, along with some other drugs, including loratadine, cyclobenzaprine, amodiaquine, maprotiline, ondansetron, propafenone, domperidone, quinacrine, ketoconazole, verapamil, tacrine, and salmeterol. These findings are discussed in context to potential drug interactions that could be observed between these agents and drugs for which aldehyde oxidase is involved in metabolism and warrant investigation of the possibility of clinical drug interactions mediated by inhibition of this enzyme.

Discriminative stimulus properties of antidepressant agents: a review.

Though drug discrimination techniques have proven invaluable in characterizing the interoceptive properties of drugs of abuse, antipsychotics and anxiolytics, with the exception of some fragmentary data with tricyclic agents, surprisingly few studies have been undertaken with antidepressants. Nevertheless, the preferential dopamine (DA) reuptake inhibitor, bupropion, elicits a robust discriminative stimulus in rodents. Moreover, in rats trained on a two-lever FR-10 schedule for food reward, the selective serotonin (5-HT) reuptake inhibitor (SSRI), citalopram, and the noradrenaline (NA) reuptake inhibitor (NARI), reboxetine, elicit discriminative stimuli at doses that selectively elevate extracellular levels of 5-HT and NA, respectively. In generalization tests, mixed inhibitors of 5-HT and NA reuptake, such as venlafaxine, substitute for both citalopram and reboxetine, while SSRIs substitute for citalopram but not for reboxetine. Intriguingly, selective NARIs appear to substitute both for reboxetine and for citalopram though, owing to long-term instability of the citalopram cue, the latter observation will require confirmation. Bupropion and the atypical antidepressant, mirtazapine - a 5-HT2/alpha2-adrenoceptor (AR) antagonist devoid of affinity for 5-HT and NA reuptake sites - substitute for neither citalopram nor reboxetine, indicating that 'antidepressant' effects per se do not account for their interoceptive properties. Moreover, mirtazapine abolishes the citalopram cue, an action mimicked by the selective 5-HT2C antagonist, SB242,084. The discriminative stimulus elicited by reboxetine is blocked by the alpha1-AR antagonist, prazosin. In contrast, it is not significantly attenuated by the alpha2-AR antagonist, RX821,002, nor by betaxolol or ICI118,551, antagonists at alpha1- and alpha2-ARs, respectively. These observations indicate that 5-HT2C receptors and alpha1-ARs contribute to the discriminative stimulus properties of SSRIs and NARIs, respectively. The present article reviews the literature devoted to the discriminative stimulus properties of antidepressant agents as training drugs, focusing in particular upon novel data with citalopram and reboxetine. In addition, several open questions and future research directions are evoked. It would be of considerable interest to extend such drug discrimination studies to other classes of antidepressants or potential antidepressants, including venlafaxine, mirtazapine and antagonists at neuropeptide (corticotropin releasing factor1 and neurokinin1) receptors.

Phase II study of XR 5000 (DACA), an inhibitor of topoisomerase I and II, administered as a 120-h infusion in patients with non-small cell lung cancer

XR5000 is a tricyclic carboxamide-based cytotoxic agent that binds to DNA by intercalation and stimulates DNA cleavage by inhibition of both topoisomerase I and II. The aim of this study was to evaluate the antitumoral activity and safety profile of XR5000 given as second-line chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). Patients received XR5000 at the dose of 3010 mg/m 2 as a 120-h central venous infusion every 3 weeks. The 15 patients (median age 56 years, range 48–71 years) enrolled had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (3 patients), 1 (11 patients) or 2 (1 patient). A total of 32 cycles of XR5000 (median 2, range 1–6) were given to 14 patients. No objective response (assessed according to World Health Organization (WHO) criteria) was documented in the 12 evaluable patients by an external review panel; in 4 out of the 12 patients disease stabilisation was recorded. The following toxicities graded according to the Common Toxicity Criteria (CTC) version 2.0. were observed: one grade 3 and two grade 4 granulocytopenia, one grade 3 and one grade 4 thrombocytopenia, one grade 3 deep venous thrombosis, one grade 3 fatigue, and grade 3 undocumented epileptic seizures which led to death in 2 patients. With only 4 out of 12 patients reaching stable disease when using this dose and regimen, further evaluation of XR5000 in advanced NSCLC is not justified.