Azelastine and allergen transduction signal in MC9 mast cells

Summary MC9 mast cells, sensitized with monoclonal IgE antibody specific for 2,4-dinitrophenyl (DNP) group, were exposed to DNP-BSA and the pH and cytosolic calcium signals were recorded by using the fluorescent probes BCECF and Fura-2 respectively. DNP-BSA induced cell alkalinization was fully inhibited by azelastine with IC₅₀ (1.6±0.5 mol/l, mean±SEM, n = 5) similar to that required to inhibit histamine release (1.4 mol/l), Conversely, high azelastine concentrations (> 100 mol/l) were required to inhibit DNP-BSA-dependent cell calcium mobilization (IC₅₀200 mol/l, n = 3). Amiloride, but not the H₁ histamine antagonist pyrilamine, was able to inhibit the DNP-BSA induced pH signal. In acidified mast cells, azelastine potently inhibited Na⁺:H⁺ exchange activity (IC₅₀ = 7.7±3.6 × 10^–6 M, mean±SEM, n = 3). Conversely, in mouse spleen lymphocytes azelastine was unable to inhibit the amiloride-sensitive pH signal induced by concanavalin A. In conclusion, the inhibition of histamine release by azelastine is not due to an interference with the cytosolic calcium signal. Conversely, azelastine potently antagonized the allergen-dependent Na⁺: H⁺ exchange activation, suggesting an action on the protein kinase C signaling pathway. Correspondence to: R. P. Garay at the above address     

Glutamate: its role in learning,memory, and the aging brain

l-Glutamate is the most abundant of a group of endogenous amino acids in the mammalian central nervous system which presumably function as excitatory neurotransmitters and under abnormal conditions may behave as neurotoxins. As neurotransmitters, these compounds are thought to play an important role in functions of learning and memory. As neurotoxins, they are believed to be involved in the pathogenesis of a variety of neurodegenerative disorders in which cognition is impaired. Moreover, brain structures which are considered anatomical substrata for learning and memory may be particularly vulnerable to the neurotoxic actions of these excitatory amino acids, especially in the elderly who are also the segment of the population most susceptible to impairments of mnemonic function. This paper is a review of data concerning the role of excitatory amino acids in the processes of learning and memory and in the pathogenesis and treatment of disorders thereof.     

The role of nitric oxide (NO) in 5-HT-induced relaxations of the guinea-pig stomach

Summary In a previous study we showed that the relaxations induced after vagal stimulation of the guinea-pig stomach are mediated via nitric oxide (NO) or a NO-related substance. Intra-arterial injection (i.a.) of 5-hydroxytryptamine (5-HT) also induced relaxations in the guinea-pig stomach. Since it has been shown that in the guinea-pig colon 5-HT-induced relaxations are mediated via NO the aim of this study was to establish whether NO is involved in the 5-HT-induced relaxations in the guinea-pig stomach. Intra-arterial injection of 5-HT induced dose-dependent relaxations of the stomach. Since atropine and - and -adrenoceptor blocking agents did not influence the relaxation and since tetrodotoxin (TTX) blocked the relaxations, this effect is mediated via NANC-neurons. Administration of a NO-synthase-inhibitor N^G-nitro-l-arginine (L-NNA) concentration-dependently reduced the 5-HT-induced relaxations. Haemoglobin (a NO-scavanger) did not affect the relaxations to 5-HT, while addition of methylene blue, an inhibitor of soluble guanylate cyclase, reduced the relaxations by 50%. Addition of an opioid receptor agonist (loperamide), a 5-HT₁ antagonist (methiothepin or metergoline) or a 5-HT₄ receptor agonist (cisapride) or-antagonist (tropisetron in micromolar concentrations) inhibited the 5-HT-induced relaxations. Neither the 5-HT₄ receptor agonist renzapride, nor the novel 5-HT₄ receptor antagonist SDZ 205-557, affected the relaxations to 5-HT. These data indicate that 5-HT-induced relaxations of the guinea-pig stomach are mediated via NANC-inhibitory nerves on which inhibitory opioid-receptors are present. The use of selective agonists and antagonists indicates that 5-HT does not act via 5-HT₂, 5-HT₃ or 5-HT₄ receptors. 5-HT may act via 5-HT₁ receptors but the subtype involved, if any, has not yet been identified. The inhibitory neurotransmitter which is involved is NO or a NO-related substance. Correspondence to A. L. Meulemans at the above address     

Metabolism and distribution in the rat of peak E substance,a constituent inl-tryptophan product implicated in eosinophilia-myalgia syndrome

Peak E substance, 1,1-ethylidenebis[tryptophan], a contaminant found inl-tryptophan tablets, has been suggested as a causative agent for eosinophilia-myalgia syndrome (EMS). Peak E substance (50 mg/kg) was administered perorally to Wistar rats to determine its metabolism and distribution. A purification procedure using Bond Elut C₈ cartridges followed by HPLC was developed for the determination of peak E substance. The plasma concentration of peak E substance was 136 ng/ml at 1 h, and urinary excretion was 717 ng at 5 h and 10342 ng for 5–24 h, showing slow excretion of peak E substance into urine. The amount of peak E substance in the contents of the large intestine at 5 h, however, was 3136 g, much greater than urinary excretion for 24 h, indicating considerable transfer of peak E substance to large intestine without decomposition by gastric fluid in the stomach. We have detected for the first time not only the occurrence of peak E substance in plasma and urine, but also 1-methyl-tetrahydro--carboline-3-carboxylic acid (MTCA) in blood and organs of rats treated with peak E substance, thereby suggesting MTCA as one of the the metabolites of peak E substance. The amount of MTCA in the contents of the large intestine as well as in urine of rats treated with peak E substance was significantly greater than inl-tryptophantreated rats (50 mg/kg p.o.), demonstrating that MTCA was more readily produced from peak E substance than froml-tryptophan. Finally, we propose acetaldehydeinduced production of MTCA from peak E substance.     

Accumulation of 1-methyl-tetrahydro-Β-carboline-3-carboxylic acid in blood and organs of rat. A possible causative substance of eosinophilia-myalgia syndrome associated with ingestion ofl-tryptophan

1-Methyl-tetrahydro--carboline-3-carboxylic acid (MTCA) may cause eosinophilia-myalgia syndrome (EMS) associated with ingestion ofl-tryptophan. The distribution and excretion of MTCA were studied in rats which had received perorally a single 1.6 mg/kg dose of MTCA. MTCA concentrations in blood, kidney, liver, brain, heart, spleen, lung and gastrocnemius muscle were measured by HPLC combined with fluorometric detection. The concentration of MTCA in each organ reached a maximum at 1 h and then gradually declined. However, a significant level of MTCA still remained at 5 h, when 52% of ingested MTCA remained in the contents of the large intestine. Twenty-nine percent of the ingested MTCA was excreted in urine over the course of 24 h. A higher dose (10 mg/kg) of MTCA resulted in significant elevations in the concentrations and amounts of MTCA in the various organs. In addition, chronic treatment with a 10 mg/kg dose of MTCA for 6 weeks further increased the concentrations and amounts of MTCA in each organ. However, no histological changes were observed in any of the organs after chronic treatment. This is the first report which demonstrates accumulation of MTCA in the blood and various organs, including muscle, of rats.     

Audit of intensive care unit admissions from the operating room

An audit of 265 intensive care unit (ICU) admissions from the operating room was performed for the year 1991. In a quality assurance exercise we identified 34 unanticipated ICU admissions (UIAs) by a retrospective peer review of the medical charts. Of these UIAs, 16 were deemed predictable and seven preventable. Five of the seven potentially preventable UIAs were judged to have had inappropriate intravenous fluid management. This has prompted changes in our education programme. In an assessment of our resource management, we evaluated prospectively collected data on the Apache II scores on the day of admission, the incidence of ICU-specific interventions, length of stay in ICU, and outcomes. ICU-specific interventions were not initially required in 36% of admissions and these patients had a low risk (1.1%) of eventually requiring ICU-specific interventions. In comparison with patients requiring ICU-specific interventions, they had lower Apache II scores (10.2 vs 13.1), shorter ICU stays (medians of one vs two days), lower ICU mortality (0 vs 8.2%), P < 0.05, but hospital mortality was not different (7.4 vs 15.3%). This audit has prompted re-organisation of our intensive care services, so that patients not requiring ICU-specific interventions will be managed in an intermediate care area with nurse.patient ratios of 1:3 or 4, in comparison with 1:1 or 2 ratios in the intensive care area.     

Caesarean section and phaeochromocytoma resection in a patient with Von Hippel Lindau disease

This report describes the anaesthetic management of a women with a term gestation, Von Hippel Lindau disease (VHLD), and a phaeochromocytoma, scheduled for a combined phaeochromocytoma resection and Caesarean section. Von Hippel Lindau disease is characterized by diffuse haemangioblastomas of the central nervous system (CNS) and viscera. It is also associated with phaeochromocytomas and renal cell carcinomas. Patients frequently have asymptomatic spinal cord and intracranial pathology. The patient and her fetus presented a challenge because of the anaesthetic restrictions imposed by VHLD, and her pregnancy. She was also at risk of developing malignant hypertension from the phaeochromocytoma. The patient was not a candidate for regional anaesthesia because of the possibility of spinal cord haemangioblastomas. She had received adrenergic blockade with phentolamine (total 30 mg a day) and propranolol (total 40 mg a day) since the 27th wk of gestation in order to control hypertension secondary to the phaeochromocytoma. General anaesthesia was administered with aggressive management of hypertension with adrenergic blockers (labetalol 1.0 mg · kg^?1 and esmolol 0.75 mg · kg^?1) and sodium nitroprusside 1.5 μg · kg^?1 (total). Before delivery of the baby, opioids, which could have resulted in a fetus with CNS depression, were avoided. After delivery, opioids (sufentanil 0.4 ng · kg^?1 hr^?1) were used to limit the use of inhalational anaesthesia which may contribute to uterine atony. Postoperative pain was managed with an intravenous narcotic infusion. Both patients had uneventful postoperative courses.     

Aortocaval compression in the sitting and lateral decubitus positions during extradural catheter placement in the parturient

We prospectively studied the incidence of concealed aortocaval compression in parturients at term during identification of the extradural space. Forty ASA I or II parturients, at term and in active labour, who requested extradural analgesia were randomly allocated to one of two groups. Parturients in the first group (n = 22) were positioned in the left lateral decubitus position and those in the second group (n = 18) were in the sitting position. Cardiac output (CO) was recorded at one-minute intervals for five minutes before extradural catheter placement (supine position with a 15° wedge under the right side), and during and thereafter for five minutes (in the supine wedged position), using the BoMED NCCOM3-R7 thoracic electrical bioimpedance (TEB) monitor. The average of five CO_TEB recordings before positioning the patient were compared with the average of five CO_TEB measurements during and after extradural space identification. A change of >25% CO_TEB was considered beyond machine variability. Upper limb arterial pressure was recorded at one-minute intervals. In the left lateral decubitus position, 17 of 22 patients demonstrated a >25% reduction in CO_TEB compared with five of 18 patients in the sitting position (X²,P <0.01). The percentage change in CO_TEB in the lateral decubitus position (?29.8%, 95% CI ?17% to ?44%) was greater than the sitting position (?9.8%, 95% CI +36% to ?32%) (P <0.01). A decreased incidence of aortocaval compression during identification of the extradural space was demonstrated in the sitting position when compared with the left lateral decubitus position.     

Continuous regional anaesthesia in infants

Physiological immaturity of the respiratory musculature and central respiratory control centres leads to an increased risk of apnoea and respiratory complications following general anaesthesia in neonates. Regional anaesthetic techniques may obviate the need for general anaesthesia and lessen the risks of perioperative morbidity. Although these techniques have been described in infants, previous reports have dealt with singleshot techniques for brief surgical procedures (< 60 min). Experience with prolonged operative cases using regional anaesthesia via indwelling catheters in infants is limited. We present our experience with four infants in whom either caudal epidural or spinal anaesthesia was administered via indwelling catheters for operative procedures that lasted 90 to 180 min. We believe this technique is an alternative to general anaesthesia in these patients. A cause de l’immaturité physiologique de sa musculature et de son centre respiratoires, le nouveau-né est plus sujet à l’apnée et aux complications après une anesthésie générale. L’anesthésie régionale peut remplacer en partie l’anesthésie générale et diminuer ainsi la morbidité périopératoire. Les techniques régionales sont bien décrites pour l’enfant mais elles sont utilisées en doses uniques pour des interventions brèves (< 60 min). L’expérience d’interventions sous régionale avec des cathéters en place est limitée. Nous présentons ici notre expérience avec quatre enfants auxquels on a administré une caudale ou une rachianesthésie continue pour des interventions de 90 à 180 min. Nous croyons que ces techniques sont des alternatives valables à l’anesthésie générale chez ces patients.