Effect of two serotonin antagonists on prolactin and thyrotrophin secretion in man

Preliminary reports have suggested that heparin may enhance the effectiveness of chemotherapy for lung cancer. The VALCSG initiated a study to evaluate further the efficacy and feasibility of administering a heparin and chemotherapy regimen. Treatment consisted of continuous iv heparin infusion for 48--72 hours followed by iv administration of cyclophosphamide (1100 mg/m2) and continued treatment with heparin and warfarin. Only one of the 19 patients (5%) with nonresectable or metastatic lung cancer showed evidence of objective tumor response. This indicated no benefit from the addition of heparin. The study also revealed some of the limitations and problems of such a treatment program.     

Inhibiting effects of reciprocation wariness on interpersonal relationships.

Students with high reciprocation wariness, a general fear of exploitation in interpersonal relationships, showed (1) a markedly reduced positive response to cooperative communication in a Prisoner's Dilemma bargaining task, (2) a greater negative response to uncooperative communication, and (3) an increased positive response to the prospect of long-term interaction. Friends and roommates of high-wary students evaluated them as unsympathetic, inconsiderate, and manipulative. Students who were supervised by high-wary dormitory resident assistants evaluated them as unapproachable, hesitant to develop close relationships, and unresponsive to student needs. Wariness was found to be unrelated to social goal orientation and Machiavellianism. Reciprocation wariness appears to inhibit the establishment and strengthening of interpersonal relationships. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Chemotactic migration of leucocytes through corneal layers: an in vitro study

The ability of polymorphonuclear leucocytes (PMNs) to migrate into the different corneal layers in the presence or absence of a chemotactic stimulus was investigated in rabbits. The epithelial and/or endothelial surfaces were damaged in some corneas and in others they were intact. One side of the cornea was kept in contact with a viable population of rabbit PMNs and the other side with a chemotactic agent (zymosan activated human serum). The migration of PMNs into the cornea was traced histologically. The PMNs could not penetrate intact epithelium and Descemet's membrane even under the influence of a chemotactic stimulus. The stroma allowed PMN migration only when the chemotactic agent was present. The endothelium offered no resistance to PMN invasion whether the chemotactic stimulus was present or not.     

Inhibiting effects of spermidine derivatives on Trypanosoma cruzi trypanothione reductase

Trypanothione reductase is a vital component of the antioxidant defenses of trypanosomes. This enzyme reduces trypanothione, a spermidine-glutathione conjugate. The inhibitory effects of several spermidine derivatives on the reduction of trypanothione by Trypanosoma cruzi trypanothione reductase were assessed. Spermidine derivatives containing hydrophobic aromatic substituents were found to be competitive inhibitors of trypanothione reductase. N4-acylated spermidine derivatives were less effective inhibitors than the corresponding N4-alkylated derivatives. The most effective compounds studied were N1, N8-bis(2-naphthylmethyl)spermidine and N4-(2-naphthylmethyl)spermidine, with Ki values of 9.5 and 108 microM, respectively.     

Adverse effects of neuromuscular blockers and their antagonists

Among all the drugs used for general anaesthesia, neuromuscular blockers appear to play a prominent role in the incidence of severe adverse reactions. It now seems likely that most serious adverse drug reactions occurring during anaesthesia are immunological in type. The frequency of life-threatening anaphylactic or anaphylactoid reactions occurring during anaesthesia has been estimated to be between 1 in 1000 and 1 in 25,000 anaesthetic procedures, with the neuromuscular blockers being involved in 80% of cases. The mortality from such serious reactions is reported to be in the range of 3.4 to 6%. The highly immunogenic drug, suxamethonium chloride (succinylcholine), was found to be the most hazardous agent. Drug-specific immunoglobulin E antibodies to suxamethonium chloride and other neuromuscular blockers have been demonstrated. This sensitivity to neuromuscular blockers seems to be a long-lasting phenomenon. During anaesthesia, the clinical features of an allergic reaction are often masked. Tachycardia and circulatory collapse may be the only signs of an allergic reaction, and they are easily misdiagnosed. Bronchospasm is reported to be present in about 40% of cases. Successful management of these patients includes stabilisation during the acute reaction and avoidance of future reactions. The latter is based on the identification of the causative drug and potentially cross-reacting compounds. The use of suxamethonium chloride is associated with many other adverse effects, such as fasciculations, myalgia, potassium release, changes in the heart rate, increases in intragastric and intraocular pressures, and malignant hyperthermia. Because of the dangers of hyperkalaemic cardiac arrest after suxamethonium chloride administration in children with unrecognised muscular dystrophy, there have now been moves to limit the use of this drug in children. Although neuromuscular blockers are designed to specifically block nicotinic cholinergic receptors at the neuromuscular junction, many bind to muscarinic cholinergic receptors on ganglia and smooth muscle, and alter parasympathetically mediated heart rate and airway calibre. Most benzylisoquinolinium muscle relaxants can induce histamine release, especially when they are administered rapidly, which can lead to disturbances of cardiovascular function. In addition, nondepolarising neuromuscular blockers have been implicated in causing generalised weakness following their long term administration to patients on an intensive care unit. The problem with these adverse drug reactions is their unpredictable nature. Therefore, prompt recognition with appropriate therapy can help to improve the outcome.     

Increased synovial endothelium binding and transendothelial migration of mononuclear cells during Salmonella infection

OBJECTIVE: To investigate the adhesion and extravasation capacity of peripheral blood mononuclear cells (PBMC) and the transport of bacterial antigens within these cells during Salmonella infection. METHODS: Thirteen patients who were part of 2 outbreaks of Salmonella enteritidis infection were included in this study. The capacity of PBMC from these patients to bind to vascular endothelium in inflamed synovium was tested using a Stamper-Woodruff-type frozen-section assay. The same cells were studied for the presence of Salmonella antigens by immunofluorescence staining. The transendothelial migration of mononuclear cells containing Salmonella or its components through unstimulated endothelial cell layer was quantified. RESULTS: The capacity of PBMC to adhere to synovial vessels was significantly increased during Salmonella infection (P=0.0003). Monocytes had a transiently high adhesive state between 2 and 5 weeks after the patients had eaten the contaminated food. The cells containing Salmonella antigens were concentrated in the transmigrated population. CONCLUSION: During acute Salmonella infection the increased binding of PBMC to vascular endothelium in inflamed synovium and enhanced transmigration of PBMC containing Salmonella may be the key factors leading to transport of bacterial antigens through the endothelial barrier and initiation of arthritis in susceptible individuals.     

Preferential potentiation of the effects of serotonin uptake inhibitors by 5-HT1A receptor antagonists in the dorsal raphe pathway: role of somatodendritic autoreceptors

5-HT1A autoreceptor antagonists enhance the effects of antidepressants by preventing a negative feedback of serotonin (5-HT) at somatodendritic level. The maximal elevations of extracellular concentration of 5-HT (5-HT(ext)) induced by the 5-HT uptake inhibitor paroxetine in forebrain were potentiated by the 5-HT1A antagonist WAY-100635 (1 mg/kg s.c.) in a regionally dependent manner (striatum > frontal cortex > dorsal hippocampus). Paroxetine (3 mg/kg s.c.) decreased forebrain 5-HT(ext) during local blockade of uptake. This reduction was greater in striatum and frontal cortex than in dorsal hippocampus and was counteracted by the local and systemic administration of WAY-100635. The perfusion of 50 micromol/L citalopram in the dorsal or median raphe nucleus reduced 5-HT(ext) in frontal cortex or dorsal hippocampus to 40 and 65% of baseline, respectively. The reduction of cortical 5-HT(ext) induced by perfusion of citalopram in midbrain raphe was fully reversed by WAY-100635 (1 mg/kg s.c.). Together, these data suggest that dorsal raphe neurons projecting to striatum and frontal cortex are more sensitive to self-inhibition mediated by 5-HT1A autoreceptors than median raphe neurons projecting to the hippocampus. Therefore, potentiation by 5-HT1A antagonists occurs preferentially in forebrain areas innervated by serotonergic neurons of the dorsal raphe nucleus.     

Retention behaviour of anti-emetic serotonin antagonists in reversed phase high performance liquid chromatography

Granisetron, Ondansetron and Tropisetron, three 5-HT3 antagonists showing anti-emetic activity, were analysed by HPLC on lipophilic stationary phases. The addition of an amine or quaternary ammonium salt to the eluents was a powerful tool in the analysis of these basic substances. The influence on chromatographic parameters of pH, ionic strength and various counter-ions in the aqueous phase as well as of different organic modifiers is discussed. Some of the proposed experimental conditions allow a more strictly partition-based separation mechanism and can produce chromatographic parameters suitable for structure-activity studies. These experimental conditions are also suitable for analysis of the considered compounds in pharmaceutical dosage forms or in biological fluids.     

Comparison of the effects of serotonin in the hippocampus and the entorhinal cortex

Among the molecular, cellular, and systemic events that have been proposed to modulate the function of the hippocampus and the entorhinal cortex (EC), one of the most frequently cited possibilities is the activation of the serotonergic system. Neurons in the hippocampus and in the EC receive a strong serotonergic projection from the raphe nuclei and express serotonin (5-HT) receptors at high density. Here we review the various effects of 5-HT on intrinsic and synaptic properties of neurons in the hippocampus and the EC. Although similar membrane-potential changes following 5-HT application have been reported for neurons of the entorhinal cortex and the hippocampus, the effects of serotonin on synaptic transmission are contrary in both areas. Serotonin mainly depresses fast and slow inhibition of the principal output cells of the hippocampus, whereas it selectively suppresses the excitation in the entorhinal cortex. On the basis of these data, we discuss the possible role of serotonin under physiological and pathophysiological circumstances.     

Electromyographic effects of serotonin application into the lateral vestibular nucleus

Electromyographic responses (EMGs) of limb muscles were studied during microiontophoretic application of 5-hydroxytryptamine (5-HT) into the lateral vestibular nucleus (LVN) or the spinal vestibular nucleus (SpVe) of anaesthetized rats. The aim was to ascertain whether the level of 5-HT in these nuclei was able to modulate muscle responsiveness. Increased levels of 5-HT in LVN (and to a weaker extent in SpVe) enhanced the EMGs of proximal extensor muscles and depressed those of flexors. The 5-HT2A receptor antagonist ketanserin, applied into the LVN, prevented 5-HT effects on EMG-evoked responses. It is concluded that 5-HT can modulate the motor output via the vestibulospinal pathway, exerting a differential control over flexor and extensor muscles.     

Concentration-dependent effects of pentoxifylline on migration and myelin phagocytosis by macrophages

The effects of pentoxifylline (POX) on macrophage migration and myelin uptake were studied in an in vitro model of myelin phagocytosis. The POX is a phosphodiesterase inhibitor which inhibits TNF-alpha (tumor necrosis factor alpha) production and reduces ICAM-1 (intercellular adhesion molecule-1) expression by macrophages. Both of these molecules have earlier been shown to be involved in the process of myelin recognition and degradation. In the present series of experiments, cocultured peripheral nerves and macrophages were treated with different concentrations of POX. Untreated controls were massively invaded by macrophages which ingested the degenerating myelin sheaths. High concentrations of POX (100 microg ml(-1)) inhibited macrophage invasion of the nerves. Lower POX concentrations (50 microg ml(-1)), in contrast, lead to an increased myelin uptake by phagocytic cells without affecting macrophage migration. These data indicate that POX may regulate different effector functions of macrophages such as migration and myelin phagocytosis during Wallerian degeneration. This is important for inflammatory demyelinating conditions in the central or peripheral nervous system (PNS) in which macrophages are also important effector cells. Since POX is used as an immunomodulatory drug in demyelinating diseases, its effects on the described macrophage functions may be of high relevance. An increased myelin uptake during Wallerian degeneration may also support a more efficient axonal regeneration by removing axonal outgrowth inhibitors.     

Action of adenosine receptor antagonists on hypoxia-induced effects in the rat hippocampus in vitro

1. We have studied three hypoxia-induced phenomena in the CA1 stratum pyramidale of the rat hippocampal slice: (a) the increase in extracellular potassium ion concentration ([K+]e) measured with ion-sensitive microelectrodes, (b) the intracellularly-recorded pyramidal cell hyperpolarization and (c) the extracellularly-recorded depression of the synaptically-evoked field potential recorded in stratum pyramidale. 2. The extracellular potassium ion concentration ([K+]e) rose from 3 mM to 4.1-4.4 mM at a time when the pyramidal cells hyperpolarized by about 6 mV and neurotransmission was virtually abolished. 3. Presumed glial cells depolarized in response to hypoxia. The shape and time course of this response was remarkably similar to the rise in [K+]e so induced. This is consistent with findings that glial cell membrane potential is dependent on transmembrane K+ gradient. 4. We investigated the effects of theophylline (100 microM) and 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 0.1 microM) on these effects. We have found that these compounds attenuated by about half the hypoxia-induced increase in [K+]e; however, they did not reduce the hypoxia-induced hyperpolarization. We have confirmed that they dramatically reduced the suppression of excitatory transmission caused by the hypoxia. We conclude that adenosine A1 receptors may be involved in the alteration of K+ homeostasis in the hippocampal slice during hypoxia.     

Effects of serotonin and the serotonin blocker metergoline on meal patterns and macronutrient selection

Serotonin [5-hydroxytryptamine(5-HT)] in the paraventricular nucleus (PVN) of rats has a suppressive effect on feeding behavior and causes a selective decrease in carbohydrate ingestion, specifically at the onset of the natural (dark) feeding period. Studies conducted here provide further evidence for this phenomena, showing a similar dose-related decrease in carbohydrate ingestion at dark onset after PVN injection of 5-HT or of the agonists, d-norfenfluramine or fluoxetine, which act through endogenous 5-HT. To further characterize the effects of this indoleamine on the macrostructure of feeding, a computer-automated data acquisition system was used to analyze macronutrient feeding patterns in freely feeding animals maintained on the pure diets of protein, carbohydrate, and fat. Results indicate that PVN administration of 5-HT at dark onset decreases intake of the carbohydrate nutrient by decreasing meal size, feeding time, and feeding rate for this nutrient and increasing the satiating effect of carbohydrate. These effects, which occur specifically during the first meal after injection, are opposite those seen after peripheral administration of the 5-HT receptor antagonist, metergoline. This drug stimulates feeding through a selective increase in carbohydrate intake, characterized by an increase in meal size, percent composition, and feeding time for this nutrient and a decrease in the satiety ratio for carbohydrate. These results implicate the serotonergic system in the termination of carbohydrate-rich meals that are prevalent during the early hours of the natural feeding cycle.     

The effects of neurotransmitter antagonists and glucose on luteinizing hormone secretion in growth-restricted wethers

Previous studies have reported some significant participation by gastric alcohol dehydrogenase (ADH) in alcohol metabolism, similar to that by hepatic ADH. However, the localization of this ADH in the stomach is not yet determined and there has been no study on the localization of ADH in the stomach of alcoholics before and after abstinence from alcohol. The aim of the present study was to reveal any changes between before and after abstinence from alcohol in the immunohistochemical localization of ADH using biopsy specimens from the gastric mucosa. Twenty male alcoholics (aged 47.8 +/- 7.4 yrs) gave signed informed consent for this investigation. Esophago-gastro-duodenoscopy (EGD) and gastric corpus biopsy were performed just before abstinence and at one month later. ADH in the biopsy specimens was immunohistochemically examined with an anti-ADH antibody, using confocal laser scanning microscopy. The fluorescence intensity for ADH was compared for each pair of specimens before and after abstinence from alcohol using an image analyzer. Age, total alcohol consumption, degree of gastritis, and the liver function tests of all patients were also analyzed. The strongly immuno-positive cells for ADH in the gastric mucosa were identified as parietal cells. The fluorescence intensity for ADH was significantly higher in those specimens obtained after abstinence than in those before abstinence (p < 0.005). The immunoreactibility for ADH in the cells assessed by confocal laser scanning microscopy was greatly improved after abstinence of alcohol, suggesting recovered alcohol metabolism in the gastric mucosa after abstinence from alcohol. The present study, demonstrating the cellular ADH localization in the gastric mucosa before and after abstinence from alcohol, may contribute to clarifying gastric alcohol metabolism in alcoholics.     

An investigation into the effects of 5-HT agonists and receptor antagonists on ethanol self-administration in the rat

Pharmacological manipulation leading to altered 5-HT function has been widely demonstrated to reduce ethanol intake in free choice tests. The aim of the present study was to examine the effects of a range of compounds known to influence 5-HT neurotransmission, including selective 5-HT receptor agonists and antagonists, on ethanol ingestion and maintained behaviour in an operant self-administration paradigm. Female Sprague-Dawley rats were trained to respond for 8% ethanol (v/v) in a 60-min test by a previously described technique. The number of responses and ethanol reinforcers (dipper deliveries), ethanol consumption (g/kg of body weight), and locomotor activity (LMA) were measured following administration of 5-HT agonists (5-HT, d-fenfluramine, fluoxetine, buspirone, TFMPP, and DOI) and antagonists (metergoline, ritanserin, and ondansetron) 30 min prior to testing. d-Fenfluramine, fluoxetine, buspirone, TFMPP, and DOI all produced a reduction in ethanol ingestion and maintained behaviour at doses that failed to reduce LMA. Conversely, metergoline and ritanserin only reduced ethanol self-administration at doses that concomitantly reduced LMA. 5-HT and ondansetron were without effect on any measure. These results demonstrate that, under the present experimental conditions, activation of central 5-HT1A, 5-HT1B, and 5-HT2 receptors reduced ethanol intake and reinforced behaviour in an operant paradigm.     

Ultrastructural and biochemical studies on the neuroprotective effects of excitatory amino acid antagonists in the ischemic rat retina

The effects of glutamate receptor agonists were evaluated, by utilizing the electron microscope, in a photothrombotic occlusion model of rat retinal vessels in order to study the ischemic damage and its antagonism in each morphologically identified population of retinal neurons. Rats were systemically injected with rose bengal fluorescein dye and one of their eyes was then exposed to bright light. This treatment caused neuronal damage and reduced the activities of the neuronal marker enzymes, choline acetyltransferase and glutamate decarboxylase, by approximately 75%. A single intravitreal injection of 2,3-dihydroxy-6-nitro-7-sulfamoylbenzoquinoxaline (NBQX, 10-50 nmol), an antagonist of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors, or of thiokynurenate (100-400 nmol), which also antagonizes N-methyl-D-aspartate (NMDA) receptors, performed immediately after the lesion, significantly reduced this loss. The electron microscope examination showed major damage in each type of retinal neuron, the pigment epithelium, and the microvessels. NBQX or thiokynurenic acid reduced, in a comparable manner, the effects of ischemia on the pigment epithelium, the photoreceptors, and the bipolar and the horizontal cells. NBQX was particularly efficient in reducing the damage to the amacrine cells located in the inner nuclear layer. The displaced amacrine and ganglion cells were not protected by NBQX but were almost completely spared in animals treated with thiokynurenate. These results show that antagonism of AMPA receptors is sufficient to reduce ischemic damage in a large number of retinal neurons, but that neuroprotection in the ganglion cell layer may be obtained only with agents which also antagonize NMDA receptors.