Effects of ritanserin and chlordiazepoxide on sleep-wakefulness alterations in rats following chronic cocaine treatment

The effects of ritanserin, a 5-hydroxytryptamine-2 (5-HT₂) receptor antagonist, and chlordiazepoxide, a benzodiazepine agonist, on sleep-wakefulness disturbances in rats after acute administration of cocaine and after discontinuation of chronic cocaine treatment were examined. Intraperitoneal (IP) injection of chlordiazepoxide (10 mg/kg) but not ritanserin (0.63 mg/kg) prevented the increase of wakefulness (W) and the reduction of light slow wave sleep (SWS1) and deep slow wave sleep (SWS2) induced by an acute injection of cocaine (20 mg/kg IP). Daily injection of cocaine (20 mg/kg for 5 days, then 30 mg/kg for 5 days IP) at the onset of the light phase elicited an increase of W and a concomitant decrease of SWS1, SWS2 and paradoxical sleep (PS) in the light phase, followed by a rebound in SWS2 and PS in the subsequent dark phase. Following cocaine discontinuation, the circadian distribution of sleep-wakefulness states remained disturbed in saline-treated rats for at least 5 days. Both ritanserin (0.63 mg/kg IP/day) and chlordiazepoxide (10 mg/kg IP/day) reduced the alteration in the distribution of W and SWS2 throughout the light-dark cycle from the first day of administration on, but failed to prevent PS alterations. The mechanisms by which both compounds exert their effect are probably quite different. For chlordiazepoxide sedative and sleep-inducing properties probably play a major role. In contrast, for ritanserin SWS2-increasing properties and its ability to reverse preference for drugs of abuse without inducing aversion might be key factors.     

Survey on the pharmacodynamics of the new antipsychotic risperidone

This review reports on the pharmacodynamics of the new antipsychotic risperidone. The primary action of risperidone is serotonin 5-HT₂ receptor blockade as shown by displacement of radioligand binding (K_i: 0.16 nM), activity on isolated tissues (EC₅₀:0.5 nM), and antagonism of peripherally (ED₅₀: 0.0011 mg/kg) and centrally (ED₅₀:0.014 mg/kg) acting 5-HT₂ receptor agonists in rats. Risperidone is at least as potent as the specific 5-HT₂ receptor antagonist ritanserin in these tests. Risperidone is also a potent dopamine D₂ receptor antagonist as indicated by displacement of radioligand binding (K_i: 1.4 nM), activity in isolated striatal slices (IC₅₀: 0.89 nM), and antagonism of peripherally (ED₅₀: 0.0057 mg/kg in dogs) and centrally acting D₂ receptor agonists (ED₅₀: 0.056–0.15 mg/kg in rats). Risperidone shows all effects common to D₂ antagonists, including enhancement of prolactin release. However, some central effects such as catalepsy and blockade of motor activity occur at high doses only. Risperidone is 4–10 times less potent than haloperidol as a central D₂ antagonist in rats and it differs from haloperidol by the following characteristics: predominant 5-HT₂ antagonism; LSD antagonism; effects on sleep; smooth dose-response curves for D₂ antagonism; synergism of combined 5-HT₂/D₂ antagonism; pronounced effects on amphetamine-induced oxygen consumption; increased social interaction; and pronounced effects on dopamine (DA) turnover. Risperidone displays similar activity at pre- and postsynaptic D₂ receptors and at D₂ receptors from various rat brain regions. The binding affinity for D₄ and D₃ receptors is 5 and 9 times weaker, respectively, than for D₂ receptors; interaction with D₁ receptors occurs only at very high concentrations. The pharmacological profile of risperidone includes interaction with histamine H₁ and -adrenergic receptors but the compound is devoid of significant interaction with cholinergic and a variety of other types of receptors. Risperidone has excellent oral activity, a rapid onset, and a 24-h duration of action. Its major metabolite, 9-hydroxyrisperidone, closely mimics risperidone in pharmacodynamics. Risperidone can be characterized as a potent D₂ antagonist with predominant 5HT₂ antagonistic activity and optimal pharmacokinetic properties.Unpublished research reports are available from Documentation Service, Janssen Pharmaceutica, B-2340 Beerse, Belgium     

Method for the determination of the levels of beta-amyloid peptide in the CSF sampled from freely moving rats

INTRODUCTION: In the present study, a model was developed to determine the effect of secretase inhibition on beta-amyloid peptide (Abeta) levels in the cerebrospinal fluid (CSF) of freely moving adult rats. METHODS: Rats were chronically implanted with a cannula into the cisterna magna and CSF samples were collected at different time points from the same animal without anaesthesia. The levels of CSF Abeta were measured by a sandwich ELISA assay. RESULTS: Administration of DAPT, a functional gamma-secretase inhibitor, resulted in a substantial reduction of Abeta40 and Abeta42, confirming the in vivo functionality of the CSF as a biomarker source for endogenous APP processing modulation by secretase inhibitors. DISCUSSION: Thus, the present work provides clear evidence for the usefulness of CSF sampling from the freely moving rat model for testing the effectiveness of small molecule inhibitors of Abeta production.     

Diagnostic image (274). A neonate with a 'red eye'

A 4-day-old girl presented with a left periorbital cellulitis due to an infected dacryocystocele.     

Has Cox-2 a prognostic role in non-small-cell lung cancer? A systematic review of the literature with meta-analysis of the survival results

Cyclooxygenase-2 (COX-2) is overexpressed in lung cancer, especially in adenocarcinoma (ADC). Our aim was to determine the prognostic value of COX-2 on survival in patients with lung cancer. Studies evaluating the survival impact of COX-2 in lung cancer, published until December 2005, were selected. Data for estimation of individual hazard ratios (HR) for survival were extracted from the publications and combined in a pooled HR. Among 14 eligible papers, all dealing with non-small-cell lung cancer, 10 provided results for meta-analysis of survival data (evaluable studies). Cyclooxygenase-2 positivity was associated with reduced survival, improved survival or no statistically significant impact in six, one and seven studies, respectively. Combined HR for the 10 evaluable studies (1236 patients) was 1.39 (95% confidence intervals (CI): 0.97-1.99). In stage I lung cancer (six evaluable studies, 554 patients), it was 1.64 (95% CI: 1.21-2.24). No significant impact was shown in ADC. A slight detrimental effect on survival in patients with lung cancer is associated with COX-2 expression, but the statistical significance is not reached. This effect is statistically significant in stage I, suggesting that COX-2 expression could be useful at early stages to distinguish those with a worse prognosis.     

A comparison of the antinociceptive and adverse effects of the mu-opioid agonist morphine and the delta-opioid agonist SNC80

delta-Opioid receptor agonists have been postulated to induce analgesia without the adverse effects commonly associated with mu-opioids e.g. morphine. In the present study, we evaluated the occurrence of antinociceptive and opioid-like side effects in rats (n=5-7) treated with a single dose of subcutaneous morphine (0.01 to 40 mg/kg) or SNC80 (0.63 to 80 mg/kg). The antinociceptive effects of morphine and SNC80 were compared using a range of nociceptive tests including the tail withdrawal test, the acetic acid-induced abdominal constriction (writhing) assay, the automated formalin test and a model of inflammation-induced thermal hyperalgesia. The adverse effects of both drugs were examined in animal models for gastrointestinal (GI) inhibition (charcoal test; ricinus oil test), respiratory depression (blood-gas analysis), motor disturbances (automated rotarod model) and abuse liability (drug discrimination learning). Morphine displayed significant antinociceptive and adverse effects in all the animal models employed. SNC80 exhibited a significant effect in the writhing test and limited efficacy in a model of inflammation-induced thermal hypersensitivity. A delay in the occurrence of diarrhoea and some limited increases in PCO(2) were observed with the higher doses of SNC80 (> or =40 mg/kg). In conclusion, the delta-opioid agonist SNC80 lacks both the analgesic efficacy and adverse effects of mu-opioids. However, the activity of SNC80 in the inflammatory model suggests delta-opioid agonists may be useful analgesics in the treatment of some forms of inflammatory pain.     

Sleep and EEG patterns in the chronic constriction injury model of neuropathic pain

Chronic neuropathic pain patients often report sleep disturbances such as reduced amount of sleep and excessive daytime tiredness. The aim of this study was to evaluate possible abnormalities in sleep patterns in a widely used animal model of neuropathic pain. Adult male Sprague-Dawley rats were chronically implanted with electrodes for electroencephalogram (EEG) and electromyogram (EMG) registrations to allow continuous 24-h polygraphic recording. Subsequently, a chronic constriction injury (CCI) was inflicted on eight rats in accordance with the CCI model of neuropathic pain and a sham operation was performed on another eight rats. The polygraphic recordings were repeated 13, 27, 55, and 146 days after surgery. Although the CCI animals developed significant mechanical and cold allodynia and heat hyperalgesia, there were no significant differences between the CCI rats and the sham-operated control animals in the spontaneous EEG/EMG in homecage-like conditions. It is concluded that in the chronic phase, this neuropathic pain model does not produce clear sleep disturbances. Such an absence of general suffering from sleep disturbances is advantageous to the CCI model as it makes use of the model more acceptable ethically. Nonetheless, this outcome appears to be in contrast with the clinical situation in neuropathic pain and therefore could also be seen as a disadvantage for the face validity of the CCI model.     

Interaction Between 2 Nutraceutical Treatments and Host Immune Status in the Pediatric Critical Illness Stress‐Induced Immune Suppression Comparative Effectiveness Trial

Background and aims: The pediatric Critical Illness Stress‐induced Immune Suppression (CRISIS) trial compared the effectiveness of 2 nutraceutical supplementation strategies and found no difference in the development of nosocomial infection and sepsis in the overall population. We performed an exploratory post hoc analysis of interaction between nutraceutical treatments and host immune status related to the development of nosocomial infection/sepsis. Methods: Children from the CRISIS trial were analyzed according to 3 admission immune status categories marked by decreasing immune competence: immune competent without lymphopenia, immune competent with lymphopenia, and previously immunocompromised. The comparative effectiveness of the 2 treatments was analyzed for interaction with immune status category. Results: There were 134 immune‐competent children without lymphopenia, 79 previously immune‐competent children with lymphopenia, and 27 immunocompromised children who received 1 of the 2 treatments. A significant interaction was found between treatment arms and immune status on the time to development of nosocomial infection and sepsis (P < .05) and on the rate of nosocomial infection and sepsis per 100 patient days (P < .05). Whey protein treatment protected immune‐competent patients without lymphopenia from infection and sepsis, both nutraceutical strategies were equivalent in immune‐competent patients with lymphopenia, and zinc, selenium, glutamine, and metoclopramide treatment protected immunocompromised patients from infection and sepsis. Conclusions: The science of immune nutrition is more complex than previously thought. Future trial design should consider immune status at the time of trial entry because differential effects of nutraceuticals may be related to this patient characteristic.