DOCSLIB.ORG

Opposing Effects of Isoflurane and Sevoflurane on Neurogenic

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Opposing Effects of Isoflurane and Sevoflurane on Neurogenic Anesthesiology 2005; 102:1182–9 © 2005 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Opposing Effects of Isoflurane and Sevoflurane on Neurogenic Pulmonary Edema Development in an Animal Model Nobuhisa Kandatsu, M.D.,* Yong-Shan Nan, M.D.,† Guo-Gang Feng, M.D., Ph.D.,‡ Kimitoshi Nishiwaki, M.D., Ph.D.,§ Mitsuru Hirokawa, M.D.,* Kiyonori Ishikawa, D.D.,ʈ Toru Komatsu, M.D., Ph.D.,# Takashi Yokochi, M.D., Ph.D.,** Yasuhiro Shimada, M.D., Ph.D., F.C.C.P.,†† Naohisa Ishikawa, M.D., Ph.D.‡‡ Background: The current study was undertaken to investigate beds has also been shown to play a role in enhancing the effects of pretreatment with isoflurane and sevoflurane on increases in vascular pressure and permeability2,5 when the development of neurogenic pulmonary edema in an animal Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/102/6/1182/359309/0000542-200506000-00018.pdf by guest on 30 September 2021 model. sympathetic nerve activity is increased. Because anes- Methods: Rats were exposed to room air (control), 1.5% thetics have been thought to inhibit the activities of isoflurane, or 2.5% sevoflurane for 4 h. They were then anes- autonomic nerves, they have not been considered to thetized with intraperitoneal injections of pentobarbital so- affect NPE. However, it has been reported that some dium, and fibrinogen and thrombin were injected into the cis- inhaled anesthetic agents affect the vascular permeabil- terna magna to induce neurogenic pulmonary edema. 6 Results: Consecutive injections of fibrinogen and thrombin ity of biologic membranes to water and electrolytes ; caused increases in blood pressure, with the peak values ob- isoflurane increases the permeability of alveolar epithe- tained in the isoflurane and sevoflurane groups being lower lial cells7 and the alveolar–capillary membrane,8 and than the control values. The incidence of significant neurogenic halothane increases fluid conductance across the pulmo- pulmonary edema was 58%, 100%, and 8% in the control, isoflu- nary capillary bed,9 perhaps by interacting with oxi- rane, and sevoflurane groups, respectively. The lung water ra- ,tio, an index of severity of edema, was 4.86 ؎ 0.78, 6.15 ؎ 0.64, dants. In addition to direct actions on endothelial cells and 4.40 ؎ 0.32 in the control, isoflurane, and sevoflurane anesthetic effects on interstitial lung fluid clearance in groups, respectively. Furthermore, immunohistochemical the lungs could contribute to edema.10 Although auto- staining for vascular endothelial growth factor demonstrated nomic nerve activity may be enhanced by surgical ma- an increase of expression in the rat lungs exposed to isoflurane. 11 Treatment with an anti–vascular endothelial growth factor an- neuvers and contribute to the development of NPE, it tibody during exposure to isoflurane completely inhibited the is difficult to explain the development of NPE during effect of isoflurane to promote neurogenic pulmonary edema in anesthesia solely in relation to the actions of this model. neurotransmitters. Conclusion: Exposure to 1.5% isoflurane enhances the devel- Vasoactive substances released from vascular endothe- opment of neurogenic pulmonary edema development in this animal model, most likely via release of vascular endothelial lial cells, such as nitric oxide, bradykinin, and vascular growth factor from bronchial epithelial cells, an effect not ob- endothelial growth factor (VEGF), and agents released served with sevoflurane. by mast cells, such as histamine, can affect vascular smooth muscle and endothelial cells. In particular, VEGF THE pathogenesis of neurogenic pulmonary edema promotes endothelial cell viability, mitogenesis, chemo- (NPE) is not completely understood, but seems to be taxis, and vascular permeability. Recent in vitro vascular associated with enhanced sympathetic nerve activity.1 permeability studies have shown that it has the ability to Consistent with this concept, NPE is associated with an increase the microvascular permeability to a level 50,000 increased intravascular pressure and enhanced vascular times higher than with histamine.4,12,13 The current permeability in the pulmonary circulation, possibly me- study was undertaken to evaluate the effects of inhaled diated by sympathetic nerve neurotransmitters released anesthetics on VEGF expression and NPE development from nerve terminals, e.g., neuropeptide Y.2–4 Synergis- and to determine whether VEGF may mediate NPE de- tic interaction between neurotransmitters in vascular velopment in rats anesthetized with volatile anesthetics. Because sevoflurane has not been reported to increase vascular permeability, the effects of isoflurane on NPE * Instructor of Anesthesiology, # Professor of Anesthesiology and Chairman of the Department, ** Professor of Microbiology and Chairman of the Department, development were compared to those of sevoflurane. ‡ Research Fellow of Pharmacology, ʈ Instructor of Pharmacology, ‡‡ Professor of Pharmacology and Chairman of the Department, Aichi Medical University. † Graduate Student of Anesthesiology, § Associate Professor of Anesthesiology, †† Professor of Anesthesiology and Chairman of the Department, Nagoya Uni- versity School of Medicine, Nagoya, Japan. Materials and Methods Received from the Department of Anesthesiology, Aichi Medical University, Nagakute-cho, Aichi-gun, Aichi Prefecture, Japan. Submitted for publication Au- Animals gust 5, 2004. Accepted for publication March 3, 2005. Supported in part by grant All procedures were performed in accordance with No. 16390448 from the Japanese Ministry of Education, Science, Sports and Culture, Tokyo, Japan. the “Guiding Principles in the Care and Use of Animals in Address reprint requests to Dr. Ishikawa: Department of Pharmacology, Aichi the Field of Physiologic Sciences” published by the Phys- Medical University, School of Medicine, Nagakute-cho, Aichi-gun, Aichi Prefecture, iologic Society of Japan14 and with the previous approval Japan. Address electronic mail to: [email protected]. Individual article reprints may be purchased through the Journal Web site, www.anesthesiology.org. of the Animal Care Committee of Aichi Medical Univer- Anesthesiology, V 102, No 6, Jun 2005 1182 ISOFLURANE AND SEVOFLURANE EFFECTS ON NPE 1183 sity (Aichi-gun, Aichi Prefecture, Japan). Wistar male rats side of the cranium using a needle (26 gauge, 10 mm weighing 180–200 g (8–10 weeks old) were used. long). The vagus nerves were left intact. Rats were con- secutively treated with intracisternal injections of fibrin- Protocol ogen and thrombin, 0.075 ml each, at concentrations of The rats were randomly divided into three groups: 100 mg/ml and 200 U/ml, respectively. The severity of group 1, exposed to room air as the control (28 animals); pulmonary edema was graded from 0 to 3, with 0 for group 2, exposed to 1.5% isoflurane (1.09 minimum none and 3 for severe.15 When edema fluid appeared in alveolar concentration [MAC]) plus room air for4h(26 the tracheal tubes within 10 min, it was collected in animals); and group 3, exposed to 2.5% sevoflurane plastic tubes for later analysis, and the grade of edema (1.05 MAC) plus room air for 4 h (26 animals). Rats were formation was classified as grade 3. When edema fluid placed in transparent plastic boxes (depth 50 cm ϫ did not appear in the tracheal tubes within 10 min, the Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/102/6/1182/359309/0000542-200506000-00018.pdf by guest on 30 September 2021 height 50 cm ϫ width 80 cm) into which anesthetic chest walls were opened. Sometimes edema fluid then gases were pumped at the desired partial pressure spontaneously appeared in the tracheal tubes, and this through inlet tubes and an outdoor outlet tube. The was classified as grade 2. However, in a few cases, edema concentrations of the anesthetic agents in the boxes fluid only appeared in the tracheal tubes when the lungs were monitored along with the gases in the air using an were gently compressed, and this was classified as grade isoflurane, sevoflurane, and respiratory oxygen/carbon 1. When edema fluid did not appear even with such dioxide analyzer (Capnomac; Datex Instrumentarium compression, the grade was 0. Finally, in all rats, lungs Co. Ltd., Helsinki, Finland). In 12 animals in groups 2 and were dissected out, weighed, and dried at 80°C over- 3, 0.1 ml anti-VEGF antibody (rabbit polyclonal anti- night. The difference between wet and dry weights, mouse VEGF immunoglobulin G; VEGF Ab-1, 1 mg/ml; relative to the dried lung weight, was used as the lung NeoMarkers, Fremont, CA) was injected into the exter- water ratio, an index of the severity of pulmonary nal cervical vein before the exposure to 1.5% isoflurane edema. or 2.5% sevoflurane. After this 4-h period, animals were moved outside of Immunohistochemistry VEGF mRNA Analysis the plastic boxes used for exposure to inhaled anesthet- Immunohistochemical and VEGF messenger RNA ics and then anesthetized with intraperitoneal injections (mRNA) expression studies were performed in two rats of pentobarbital sodium (35 mg/kg body weight) for the from groups 2 and 3 and four rats from group 1 (con- induction of NPE (see next two paragraphs). Tracheal trols). After opening the chest by a central incision with tubes were inserted after a tracheotomy was performed the aid of mechanical ventilation, a plastic catheter for in the midcervical region. Catheters were introduced infusion was inserted into the pulmonary artery through into the right femoral vein and artery, the former for the right ventricle. Blood was washed out with saline, blood sampling, and the latter for measurement of arte- and then paraform aldehyde, dissolved with phosphate rial blood pressure and heart rates (Multipurpose Poly- buffer (pH 7.4) at a concentration of 4%, was infused at gram, W-1100; Nihon Kohden, Tokyo, Japan). To measure a constant pressure of 80 cm H2O. Thereafter, one lung arterial oxygen tension immediately before the induction of from each animal was excised, immersed in the same NPE, 0.1 ml arterial blood was collected from rat femoral fixative for 12 h, and embedded in paraffin with an arteries.
Load more

Recommended publications
  • Endogenous Metabolites: JHU NIMH Center Page 1
    S. No. Amino Acids (AA) 24 L-Homocysteic acid 1 Glutaric acid 25 L-Kynurenine 2 Glycine 26 N-Acetyl-Aspartic acid 3 L-arginine 27 N-Acetyl-L-alanine 4 L-Aspartic acid 28 N-Acetyl-L-phenylalanine 5 L-Glutamine 29 N-Acetylneuraminic acid 6 L-Histidine 30 N-Methyl-L-lysine 7 L-Isoleucine 31 N-Methyl-L-proline 8 L-Leucine 32 NN-Dimethyl Arginine 9 L-Lysine 33 Norepinephrine 10 L-Methionine 34 Phenylacetyl-L-glutamine 11 L-Phenylalanine 35 Pyroglutamic acid 12 L-Proline 36 Sarcosine 13 L-Serine 37 Serotonin 14 L-Tryptophan 38 Stachydrine 15 L-Tyrosine 39 Taurine 40 Urea S. No. AA Metabolites and Conjugates 1 1-Methyl-L-histidine S. No. Carnitine conjugates 2 2-Methyl-N-(4-Methylphenyl)alanine 1 Acetyl-L-carnitine 3 3-Methylindole 2 Butyrylcarnitine 4 3-Methyl-L-histidine 3 Decanoyl-L-carnitine 5 4-Aminohippuric acid 4 Isovalerylcarnitine 6 5-Hydroxylysine 5 Lauroyl-L-carnitine 7 5-Hydroxymethyluracil 6 L-Glutarylcarnitine 8 Alpha-Aspartyl-lysine 7 Linoleoylcarnitine 9 Argininosuccinic acid 8 L-Propionylcarnitine 10 Betaine 9 Myristoyl-L-carnitine 11 Betonicine 10 Octanoylcarnitine 12 Carnitine 11 Oleoyl-L-carnitine 13 Creatine 12 Palmitoyl-L-carnitine 14 Creatinine 13 Stearoyl-L-carnitine 15 Dimethylglycine 16 Dopamine S. No. Krebs Cycle 17 Epinephrine 1 Aconitate 18 Hippuric acid 2 Citrate 19 Homo-L-arginine 3 Ketoglutarate 20 Hydroxykynurenine 4 Malate 21 Indolelactic acid 5 Oxalo acetate 22 L-Alloisoleucine 6 Succinate 23 L-Citrulline 24 L-Cysteine-glutathione disulfide Semi-quantitative analysis of endogenous metabolites: JHU NIMH Center Page 1 25 L-Glutathione, reduced Table 1: Semi-quantitative analysis of endogenous molecules and their derivatives by Liquid Chromatography- Mass Spectrometry (LC-TripleTOF “or” LC-QTRAP).
    [Show full text]
  • Opposing Effects of Dehydroepiandrosterone And
    European Journal of Endocrinology (2000) 143 687±695 ISSN 0804-4643 EXPERIMENTAL STUDY Opposing effects of dehydroepiandrosterone and dexamethasone on the generation of monocyte-derived dendritic cells M O Canning, K Grotenhuis, H J de Wit and H A Drexhage Department of Immunology, Erasmus University Rotterdam, The Netherlands (Correspondence should be addressed to H A Drexhage, Lab Ee 838, Department of Immunology, Erasmus University, PO Box 1738, 3000 DR Rotterdam, The Netherlands; Email: [email protected]) Abstract Background: Dehydroepiandrosterone (DHEA) has been suggested as an immunostimulating steroid hormone, of which the effects on the development of dendritic cells (DC) are unknown. The effects of DHEA often oppose those of the other adrenal glucocorticoid, cortisol. Glucocorticoids (GC) are known to suppress the immune response at different levels and have recently been shown to modulate the development of DC, thereby influencing the initiation of the immune response. Variations in the duration of exposure to, and doses of, GC (particularly dexamethasone (DEX)) however, have resulted in conflicting effects on DC development. Aim: In this study, we describe the effects of a continuous high level of exposure to the adrenal steroid DHEA (1026 M) on the generation of immature DC from monocytes, as well as the effects of the opposing steroid DEX on this development. Results: The continuous presence of DHEA (1026 M) in GM-CSF/IL-4-induced monocyte-derived DC cultures resulted in immature DC with a morphology and functional capabilities similar to those of typical immature DC (T cell stimulation, IL-12/IL-10 production), but with a slightly altered phenotype of increased CD80 and decreased CD43 expression (markers of maturity).
    [Show full text]
  • Fluorinated Analogues of Glutamic Acid and Glutamine R
    γ-Fluorinated analogues of glutamic acid and glutamine R. Dave, B. Badet, Patrick Meffre To cite this version: R. Dave, B. Badet, Patrick Meffre. γ-Fluorinated analogues of glutamic acid and glutamine. Amino Acids, Springer Verlag, 2003, 24 (3), pp.245-261. 10.1007/s00726-002-0410-9. hal-02002676 HAL Id: hal-02002676 https://hal.archives-ouvertes.fr/hal-02002676 Submitted on 11 Feb 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. γ-Fluorinated analogues of glutamic acid and glutamine Review Article 1 2 1 R. Dave , B. Badet , and P. Meffre 1 UMR 7573-C.N.R.S., ENSCP, Paris, France 2 UPR 2301-CNRS, ICSN, Gif-sur-Yvette, France Summary. γ-Fluorinated analogues of glutamic acid and glutamine N-bromosuccinimide; NFSi, N-fluorobenzenesulfonimide; NMR, are compounds of biological interest. Syntheses of such compounds nuclear magnetic resonance; 2-PrOH, isopropanol; PTSA, p- are extensively reviewed in this article. 4-Fluoroglutamic acid toluenesulfonic acid; TCDI, thiocarbonyldiimidazole; TEMPO, was prepared as a mixture of racemic diastereomers by Michael 2,2,6,6-tetramethyl piperidine-1-oxyl; TFA, trifluoroacetic acid. reaction, inverse-Michael reaction or by electrophilic / nucleophilic fluorination.
    [Show full text]
  • The Role of Glutamine in the Complex Interaction Between Gut Microbiota and Health: a Narrative Review
    International Journal of Molecular Sciences Review The Role of Glutamine in the Complex Interaction between Gut Microbiota and Health: A Narrative Review 1, , 1 1, 1 Simone Perna * y , Tariq A. Alalwan , Zahraa Alaali y , Tahera Alnashaba , Clara Gasparri 2, Vittoria Infantino 3 , Layla Hammad 1, Antonella Riva 4, Giovanna Petrangolini 4 , Pietro Allegrini 4 and Mariangela Rondanelli 5,6 1 Department of Biology, College of Science, University of Bahrain, 32038 Sakhir, Bahrain; [email protected] (T.A.A.); [email protected] (Z.A.); [email protected] (T.A.); [email protected] (L.H.) 2 Endocrinology and Nutrition Unit, Azienda di Servizi alla Persona “Istituto Santa Margherita”, University of Pavia, Pavia 27100, Italy; [email protected] 3 Department of Biomedical Science and Human Oncology, University of Bari, Bari 70121, Italy; [email protected] 4 Research and Development Department, Indena SpA, 20139 Milan, Italy; [email protected] (A.R.); [email protected] (G.P.); [email protected] (P.A.) 5 IRCCS Mondino Foundation, Pavia 27100, Italy; [email protected] 6 Department of Public Health, Experimental and Forensic Medicine, Unit of Human and Clinical Nutrition, University of Pavia, Pavia 27100, Italy * Correspondence: [email protected] or [email protected]; Tel.: +973-39-37-99-46 The two authors contributed equally to this work. y Received: 21 August 2019; Accepted: 20 October 2019; Published: 22 October 2019 Abstract: The scientific literature has demonstrated that glutamine is one of the main beneficial amino acids. It plays an important role in gut microbiota and immunity. This paper provides a critical overview of experimental studies (in vitro, in vivo, and clinical) investigating the efficacy of glutamine and its effect on gut microbiota.
    [Show full text]
  • Effects of Amanita Muscaria Extract on Different in Vitro Neurotoxicity
    Food and Chemical Toxicology 132 (2019) 110687 Contents lists available at ScienceDirect Food and Chemical Toxicology journal homepage: www.elsevier.com/locate/foodchemtox Effects of Amanita muscaria extract on different in vitro neurotoxicity models at sub-cellular and cellular levels T Magdalena Kondeva-Burdinaa,*, Maria Voynovaa, Aleksandar Shkondrovb, Denitsa Aluania, Virginia Tzankovaa, Ilina Krastevab a Laboratory of Drug Metabolism and Drug Toxicity, Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of Sofia, 2 Dunav St., 1000, Sofia, Bulgaria b Department of Pharmacognosy, Faculty of Pharmacy, Medical University of Sofia, 2 Dunav St., 1000, Sofia, Bulgaria ARTICLE INFO ABSTRACT Keywords: Muscimol is the main compound found in Amanita muscaria. Several studies have proven that muscimol has Amanita muscaria suppressive effects on essential tremor, without impairing speech and coordination. The effects of muscimol in Isolated rat brain microsomes Parkinson-affected patients is also described in a number of studies. These studies describe the free radical Synaptosomes scavenging and antioxidant activity of the mushroom extract. We have evaluated the possible neuroprotective Mitochondria effects of a standardized extract from A. muscaria, containing high amounts of muscimol, on different models of Neuroblastoma cell line SH-SY5Y neurotoxicity in rat brain microsomes, mitochondria, synaptosomes as well as on neuroblastoma cell line SH- Neuroprotection ff Human recombinant monoaminoxidase-B SY5Y. The possible inhibitory e ect on human recombinant monoaminoxidase-B (hMAOB) enzyme was also enzyme studied. The extract revealed statistically significant neuroprotective effects on the in vitro neurotoxicity models and no inhibitory activity on hMAOB. 1. Introduction without influencing the speech and movements of the patients (Ferreira et al., 2007).
    [Show full text]
  • DHEA), the Most Abundant Sex Steroid, Is Primarily Secreted by the Adrenal Gland and a Precursor Hormone Used by Athletes for Performance Enhancement
    Int. J. Med. Sci. 2016, Vol. 13 730 Ivyspring International Publisher International Journal of Medical Sciences 2016; 13(10): 730-740. doi: 10.7150/ijms.16132 Research Paper Dehydroepiandrosterone Supplementation Combined with Whole-Body Vibration Training Affects Testosterone Level and Body Composition in Mice Wen-Chyuan Chen 1,2, Yi-Ming Chen 1,3, Chi-Chang Huang 3, and Yen-Dun Tzeng4 1. Center for General Education, Chang Gung University of Science and Technology, Taoyuan 33301, Taiwan; 2. Department of Otorhinolaryngology-Head and Neck Surgery, Sleep Center, Linkou-Chang Gung Memorial Hospital, Taoyuan 33301, Taiwan. 3. Graduate Institute of Sports Science, National Taiwan Sport University, Taoyuan 33301, Taiwan; Emails: [email protected] (Y.-M.C.); 4. Division of General Surgery, Department of Surgery, Kaohsiung Veterans General Hospital, 813 Kaohsiung, Taiwan. Corresponding author: Kaohsiung Veterans General Hospital, No.386, Dazhong 1st Rd., Zuoying Dist., Kaohsiung City 81362, Taiwan (Y.-D.T.). Tel.: +886-7-3422121 (ext. 3008) (Y.-D.T.). Electronic addresses: [email protected] (Y.-D.T.). © Ivyspring International Publisher. Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited. See http://ivyspring.com/terms for terms and conditions. Received: 2016.05.11; Accepted: 2016.08.19; Published: 2016.09.16 Abstract Dehydroepiandrosterone (DHEA), the most abundant sex steroid, is primarily secreted by the adrenal gland and a precursor hormone used by athletes for performance enhancement. Whole-body vibration (WBV) is a well-known light-resistance exercise by automatic adaptations to rapid and repeated oscillations from a vibrating platform, which is also a simple and convenient exercise for older adults.
    [Show full text]
  • Pigments of Fly Agaric (Amanita Muscaria) Florian Stintzinga,C,* and Willibald Schliemannb
    Pigments of Fly Agaric (Amanita muscaria) Florian Stintzinga,c,* and Willibald Schliemannb a Institute of Food Science and Biotechnology, Section Plant Foodstuff Technology, Hohenheim University, August-von-Hartmann-Str. 3, D-70599 Stuttgart, Germany b Department of Secondary Metabolism, Leibniz Institute of Plant Biochemistry, Weinberg 3, D-06120 Halle (Saale), Germany c Present address: WALA Heilmittel GmbH, Dorfstraße 3, D-73087 Bad Boll/Eckwälden, Germany. E-mail: [email protected] * Author for correspondence and reprint requests Z. Naturforsch. 62c, 779Ð785 (2007); received July 2/August 3, 2007 The complex pigment pattern of fly agaric (Amanita muscaria) cap skins has been studied by LC-DAD and mass spectrometry. Among the betaxanthins the corresponding derivatives of serine, threonine, ethanolamine, alanine, Dopa, phenylalanine and tryptophan are re- ported for the first time to contribute to the pigment pattern of fly agarics. Betalamic acid, the chromophoric precursor of betaxanthins and betacyanins, muscaflavin and seco-dopas were also detected. Furthermore, the red-purple muscapurpurin and the red muscarubrin were tentatively assigned while further six betacyanin-like components could not be structur- ally allocated. Stability studies indicated a high susceptibility of pigment extracts to degrada- tion which led to rapid colour loss thus rendering a complete characterization of betacyanin- like compounds impossible at present. Taking into account these difficulties the presented results may be a starting point for a comprehensive characterization of the pigment composi- tion of fly agarics. Key words: Amanita muscaria, Fly Agaric, Betalains Introduction Recent reviews on betalains in general (Zry¨d and Christinet, 2004) and on the chemistry of The reddish colour of the cap skin of the toad- natural products of A.
    [Show full text]
  • Pharmacological Studies on a Locust Neuromuscular Preparation
    J. Exp. Biol. (1974). 6i, 421-442 421 *&ith 2 figures in Great Britain PHARMACOLOGICAL STUDIES ON A LOCUST NEUROMUSCULAR PREPARATION BY A. N. CLEMENTS AND T. E. MAY Woodstock Research Centre, Shell Research Limited, Sittingbourne, Kent {Received 13 March 1974) SUMMARY 1. The structure-activity relationships of agonists of the locust excitatory neuromuscular synapse have been reinvestigated, paying particular attention to the purity of compounds, and to the characteristics and repeatability of the muscle response. The concentrations of compounds required to stimu- late contractions of the retractor unguis muscle equal in force to the neurally evoked contractions provided a measure of the relative potencies. 2. Seven amino acids were capable of stimulating twitch contractions, glutamic acid being the most active, the others being analogues or derivatives of glutamic or aspartic acid. Aspartic acid itself had no excitatory activity. 3. Excitatory activity requires possession of two acidic groups, separated by two or three carbon atoms, and an amino group a to a carboxyl. An L-configuration appears essential. The w-acidic group may be a carboxyl, sulphinyl or sulphonyl group. Substitution of any of the functional groups generally causes total loss of excitatory activity, but an exception is found in kainic acid in which the nitrogen atom forms part of a ring. 4. The investigation of a wide variety of compounds revealed neuro- muscular blocking activity among isoxazoles, hydroxylamines, indolealkyl- amines, /?-carbolines, phenazines and phenothiazines. No specific antagonist of the locust glutamate receptor was found, but synaptic blocking agents of moderately high activity are reported. INTRODUCTION The study of arthropod neuromuscular physiology has been impeded by the lack of an antagonist which can be used to block excitatory synaptic transmission by a specific postsynaptic effect.
    [Show full text]
  • The Common Inhalational Anesthetic Sevoflurane Induces Apoptosis and Increases Β-Amyloid Protein Levels
    ORIGINAL CONTRIBUTION The Common Inhalational Anesthetic Sevoflurane Induces Apoptosis and Increases ␤-Amyloid Protein Levels Yuanlin Dong, MD; Guohua Zhang, MD, PhD; Bin Zhang, MD; Robert D. Moir, PhD; Weiming Xia, PhD; Edward R. Marcantonio, MD; Deborah J. Culley, MD; Gregory Crosby, MD; Rudolph E. Tanzi, PhD; Zhongcong Xie, MD, PhD Objective: To assess the effects of sevoflurane, the most Z-VAD decreased the effects of sevoflurane on apopto- commonly used inhalation anesthetic, on apoptosis and sis and A␤. Sevoflurane-induced caspase-3 activation was ␤-amyloid protein (A␤) levels in vitro and in vivo. attenuated by the ␥-secretase inhibitor L-685,458 and was potentiated by A␤. These results suggest that sevoflu- Subjects: Naive mice, H4 human neuroglioma cells, and rane induces caspase activation which, in turn, en- H4 human neuroglioma cells stably transfected to ex- hances ␤-site amyloid precursor protein–cleaving en- press full-length amyloid precursor protein. zyme and A␤ levels. Increased A␤ levels then induce further rounds of apoptosis. Interventions: Human H4 neuroglioma cells stably transfected to express full-length amyloid precursor pro- Conclusions: These results suggest that inhalational an- tein were exposed to 4.1% sevoflurane for 6 hours. Mice esthetic sevoflurane may promote Alzheimer disease neu- received 2.5% sevoflurane for 2 hours. Caspase-3 acti- ropathogenesis. If confirmed in human subjects, it may vation, apoptosis, and A␤ levels were assessed. be prudent to caution against the use of sevoflurane as an anesthetic, especially in those suspected of possess- ␤ Results: Sevoflurane induced apoptosis and elevated lev- ing excessive levels of cerebral A . els of ␤-site amyloid precursor protein–cleaving en- zyme and A␤ in vitro and in vivo.
    [Show full text]
  • Bulk Drug Substances Nominated for Use in Compounding Under Section 503B of the Federal Food, Drug, and Cosmetic Act
    Updated June 07, 2021 Bulk Drug Substances Nominated for Use in Compounding Under Section 503B of the Federal Food, Drug, and Cosmetic Act Three categories of bulk drug substances: • Category 1: Bulk Drug Substances Under Evaluation • Category 2: Bulk Drug Substances that Raise Significant Safety Risks • Category 3: Bulk Drug Substances Nominated Without Adequate Support Updates to Categories of Substances Nominated for the 503B Bulk Drug Substances List1 • Add the following entry to category 2 due to serious safety concerns of mutagenicity, cytotoxicity, and possible carcinogenicity when quinacrine hydrochloride is used for intrauterine administration for non- surgical female sterilization: 2,3 o Quinacrine Hydrochloride for intrauterine administration • Revision to category 1 for clarity: o Modify the entry for “Quinacrine Hydrochloride” to “Quinacrine Hydrochloride (except for intrauterine administration).” • Revision to category 1 to correct a substance name error: o Correct the error in the substance name “DHEA (dehydroepiandosterone)” to “DHEA (dehydroepiandrosterone).” 1 For the purposes of the substance names in the categories, hydrated forms of the substance are included in the scope of the substance name. 2 Quinacrine HCl was previously reviewed in 2016 as part of FDA’s consideration of this bulk drug substance for inclusion on the 503A Bulks List. As part of this review, the Division of Bone, Reproductive and Urologic Products (DBRUP), now the Division of Urology, Obstetrics and Gynecology (DUOG), evaluated the nomination of quinacrine for intrauterine administration for non-surgical female sterilization and recommended that quinacrine should not be included on the 503A Bulks List for this use. This recommendation was based on the lack of information on efficacy comparable to other available methods of female sterilization and serious safety concerns of mutagenicity, cytotoxicity and possible carcinogenicity in use of quinacrine for this indication and route of administration.
    [Show full text]
  • Improved Method of Administering Beta-Hydroxy
    (19) TZZ _ ¥_T (11) EP 2 512 236 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A01N 37/00 (2006.01) A61K 31/19 (2006.01) 19.10.2016 Bulletin 2016/42 (86) International application number: (21) Application number: 10838355.5 PCT/US2010/061367 (22) Date of filing: 20.12.2010 (87) International publication number: WO 2011/075741 (23.06.2011 Gazette 2011/25) (54) IMPROVED METHOD OF ADMINISTERING BETA-HYDROXY-BETA-METHYLBUTYRATE (HMB) VERBESSERTES VERFAHREN ZUR VERABREICHUNG VON BETA-HYDROXY-BETA-METHYLBUTYRAT (HMB) PROCÉDÉ AMÉLIORÉ PERMETTANT D’ADMINISTRER DU BÊTA-HYDROXY-BÊTA-MÉTHYLBUTYRATE (HMB) (84) Designated Contracting States: • NISSEN, Steve AL AT BE BG CH CY CZ DE DK EE ES FI FR GB Ames GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO Iowa 50014 (US) PL PT RO RS SE SI SK SM TR • ABUMRAD, Naji Nashville (30) Priority: 18.12.2009 US 287857 P Tennessee 37220 (US) (43) Date of publication of application: (74) Representative: Evans, Jacqueline Gail Victoria 24.10.2012 Bulletin 2012/43 Marches Intellectual Property Limited Wyastone Business Park (73) Proprietor: Metabolic Technologies, Inc. Wyastone Leys Ames, IA 50010 (US) Ganarew Monmouth NP25 3SR (GB) (72) Inventors: • RATHMACHER, John (56) References cited: Story City US-A- 4 992 470 US-A- 5 028 440 Iowa 50248 (US) US-A- 5 087 472 US-A- 6 031 000 • FULLER, John US-A1- 2004 220 266 US-A1- 2005 215 640 Zearing US-A1- 2005 215 640 Iowa 50278 (US) • BAIER, Shawn Remarks: Polk City Thefile contains technical information submitted after Iowa 50226 (US) the application was filed and not included in this specification Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations.
    [Show full text]
  • The Effects of L-Glutamate, L-Glutamine, and L-Aspartic Acid on the Amylase Production of E
    Journal of Emerging Investigators The Effects of L-glutamate, L-glutamine, and L-aspartic Acid on the Amylase Production of E. coli Transformed with pAmylase Kevin S. Liu and Brittany Franckowiak Wilde Lake High School, Howard County, MD Summary glands, hydrolyzes dietary starch into disaccharides Amylase catalyzes the hydrolysis of dietary starch into and trisaccharides. These saccharides are further oligosaccharides. In humans, amylase is produced by the converted by other enzymes to glucose and used as pancreas and salivary glands and is important in food a source of cellular energy (1). Consequently, amylase digestion. Human amylase also has broad applications for has an important role in digestion, where the secretion of therapeutic use in patients with pancreatic insufficiency, necessitating an efficient process for amylase production. amylase is vital to proper nutrient digestion and absorption E. coli transfected with human amylase cDNA can be (2, 3). Abnormal or unhealthy enzyme secretion by the used to produce amylase to fulfill these pharmaceutical pancreas can result in nutrient malabsorption and other production needs. It was reported that the production symptoms that lead to malnutrition (4). of Thermus maltogenic amylase in E. coli is enhanced by In addition to their role in digestion, amylases are also adding L-glutamate and L-glutamine. The purpose of this important ingredients in the food industry. Specifically, experiment was to determine whether the amino acids alpha and beta amylases are used in brewing beers and L-glutamate, L-glutamine, and L-aspartic acid could liquors made from starch-derived sugars. Amylases, increase human amylase expression in E. coli.
    [Show full text]