Isolation, Identification and Synthesis of Hydromorphone Metabolites

Total Page:16

File Type:pdf, Size:1020Kb

Isolation, Identification and Synthesis of Hydromorphone Metabolites ISOLATION, IDENTIFICATION AND SYNTHESIS OF HYDROMORPHONE i METABOLITES: ANALYSIS AND ANTINOCICEPTIVE ACTIVITIES IN COMPARISON TO MORPHINE by MING ZHENG B.Sc. (Pharm.), Shanghai Medical University, 1987 M.Sc, The University of Ghent, 1990 M.Sc, The University of British Columbia, 1993 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Faculty of Pharmaceutical Sciences) We accept this thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA June 1997 © Ming Zheng, 1997 In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. Department of The University of British Columbia Vancouver, Canada DE-6 (2/88) ABSTRACT As active drug metabolites may have profound pharmacological and toxicological effects on patients, a thorough understanding of the metabolic fate of the parent drug and the potential pharmacological and toxicological activities of its metabolite(s) is essential to the effective and safe usage of the drug. Although hydromorphone is commonly used for the management of cancer and postoperative pain, information about the metabolic fate of this opioid analgesic is scant. Only hydromorphone-3-glucuronide and dihydromorphine-3-glucuronide have been reported in urine samples of rabbits following hydromorphone administration, while conjugates of unknown identities were reported for hydromorphone, dihydromorphine and dihydroisomorphine in urine samples from healthy male subjects. Thus the objectives of this study were to investigate the metabolic fate of hydromorphone in patient(s) receiving chronic hydromorphone therapy and to test for antinociceptive activities of the metabolites thus identified and synthesized. Hydromorphone-3-glucuronide, hydromorphone-3-sulfate, dihydromorphine, dihydroisomorphine, dihydromorphine-3-glucuronide, dihydroisomorphine-3- glucuronide and norhydromorphone were isolated from pooled urine samples of a cancer patient receiving chronic hydromorphone therapy. The metabolites were analyzed using a high-performance liquid chromatographic-tandem mass spectrometric (LC-MS-MS) method. Synthetic standards of these metabolites were prepared by adaptation of published methods for the synthesis of the same or structurally similar compounds. The identities of these metabolites in urine were thus confirmed by Ill comparison of the retention times and ion transitions with those of the synthetic standards using the LC-MS-MS method. The presence of hydromorphone-3-glucuronide, dihydromorphine-3-glucuronide, and unconjugated dihydromorphine and dihydroisomorphine was confirmed for the first time in pooled urine samples of a human subject. Hydromorphone-3-sulfate, dihydroisomorphine-3-glucuronide and norhydromorphone were novel metabolites of hydromorphone identified for the first time. Another novel metabolite of hydromorphone, nordihydroisomorphine, was tentatively identified. The urinary recovery of dihydroisomorphine-3-glucuronide was estimated to be 17-fold higher than the previously published result of conjugated dihydroisomorphine by other investigators. LC-MS-MS assays were also developed for the determination of morphine and its metabolites, and hydromorphone and its metabolites in plasma samples of male Sprague Dawley rats. The analytes were extracted from plasma samples by solid- phase extraction using C2 cartridges. The assays were linear over the concentration ranges determined. Both intra- and inter-assay variabilities were less than or equal to 12%. The LC-MS-MS assays developed were applied to pharmacokinetic studies of morphine, hydromorphone, dihydromorphine, dihydroisomorphine and norhydromorphone in male Sprague Dawley rats following intraperitoneal administration. Following morphine administration, morphine-3-glucuronide was detected as the predominant metabolite of morphine, whereas normorphine was detected as a minor metabolite. The slopes of the apparent elimination phases for morphine-3-glucuronide IV and morphine were not significantly different, suggesting the elimination rate constant of morphine-3-glucuronide is much greater than that of morphine and the formation of morphine-3-glucuronide is the rate-limiting step for the elimination of this metabolite following morphine administration. Normorphine glucuronide was tentatively detected as a minor metabolite of morphine. Morphine-6-glucuronide was not detected, indicating that this metabolite is not formed in rats. The 3-O-glucuronide metabolites were detected as the common major metabolites following administration of hydromorphone, dihydromorphine and dihydroisomorphine. Norhydromorphone glucuronide was tentatively detected as a major metabolite following norhydromorphone administration. The slopes of the apparent elimination phases for the glucuronide metabolites were not significantly different from the slopes of the respective parent compounds, also suggesting that the elimination rate constants of these glucuronide metabolites are much greater than those of their respective parent compounds and the formation of these glucuronide metabolites is the rate-limiting step for the elimination of these glucuronides following administration of the parent compounds. The antinociceptive activities of hydromorphone, dihydromorphine, dihydroisomorphine and norhydromorphone were determined using the formalin test. Morphine was also tested as a reference standard for comparison of antinociceptive activities between these compounds. The values of Tmax, the time when maximum plasma concentrations are reached, for the above compounds determined from the pharmacokinetic studies were used for the design of the formalin test. The results showed that morphine, hydromorphone, dihydromorphine and dihydroisomorphine were equally effective in the formalin test. However, hydromorphone was five times as V potent as morphine, while dihydromorphine was equipotent to morphine and dihydroisomorphine was less potent than morphine. The antinociceptive activities of norhydromorphone were low and not significantly different at the three different doses tested. Preliminary tests were also conducted for hydromorphone-3-glucuronide, dihydromorphine-3-glucuronide and dihydroisomorphine-3-glucuronide. No antinociception was observed for these glucuronide metabolites at the doses tested. Research Supervisor Keith McErlane, Ph.D. vi TABLE OF CONTENTS Abstract ii Table of Contents vi List of Figures xi List of Tables xv List of Abbreviations xvii Acknowledgment xx Dedication xxi 1. INTRODUCTION 1 1.1 Morphine 4 1.1.1 The Chemical Structure of Morphine 4 1.1.2 Mechanisms of Action 6 1.1.2.1 Opioid Receptors 6 1.1.2.2 Nociceptive Pain 7 1.1.2.3 Mechanisms of Action 8 1.1.2.4 Peripheral Analgesia 10 .1.1.3 Clinical Pharmacokinetics of Morphine 11 1.1.4 Metabolism of Morphine 13 1.1.4.1 Glucuronidation of Morphine 14 1.1.4.2 N-Demethylation of Morphine 15 1.1.5 Pharmacology of the Metabolites of Morphine 16 1.1.5.1 Morphine-6-Glucuronide 16 1.1.5.2 Morphine-3-Glucuronide 18 1.1.5.3 Other Metabolites of Morphine 19 1.1.6 Accumulation of Morphine-3-Glucuronide and Morphine-6-Glucuronide in Patients with Renal Impairment 20 1.2 Hydromorphone 23 1.2.1 The Chemical Structure of Hydromorphone 23 1.2.2 Clinical Uses of Hydromorphone 24 1.2.3 Clinical Pharmacokinetics of Hydromorphone 25 1.2.4 Metabolism of Hydromorphone 27 1.2.5 Antinociceptive Activities of Dihydromorphine and Dihydroisomorphine 28 vii 1.3 Analytical Methods for the Measurement of Morphine, Hydromorphone and Their Metabolites in Biological Samples 29 1.3.1 Radioimmunoassays 29 1.3.2 Chromatographic Methods 30 1.3.2.1 Chromatographic Analysis of Morphine and Its Metabolites 30 1.3.2.2 Chromatographic Analysis of Hydromorphone and Its Metabolites 32 1.4 Antinociceptive Tests 33 1.4.1 Thermal Methods 34 1.4.1.1 Tail-Flick Test 34 1.4.1.2 Hot-Plate Test 35 1.4.2 Mechanical Method: the Tail-Clip Test 35 1.4.3 Chemical Methods 37 1.4.3.1 Writhing Test 37 1.4.3.2 Formalin Test 37 1.5 Thesis Hypothesis and Objectives 39 2. EXPERIMENTAL 41 2.1 Materials and Supplies 41 2.1.1 Drugs 41 2.1.2 Chemicals and Solvents 41 2.1.3 Animals 42 2.2 LC-MS-MS Instrumentation 42 2.3 Isolation and Identification of Hydromorphone and Its Metabolites from Pooled Urine Samples of a Cancer Patient 43 2.3.1 Isolation of Hydromorphone and Its Metabolites from Pooled Urine Samples of a Cancer Patient 43 2.3.2 LC-MS-MS Conditions 44 2.3.2.1 LC-MS-MS Conditions for Identification of Hydromorphone, Dihydromorphine, Dihydroisomorphine, Hydromorphone- 3-Glucuronide, Dihydromorphine-3-Glucuronide and Dihydroisomorphine-3-Glucuronide 44 2.3.2.2 LC-MS-MS Conditions for Identification of Norhydromorphone and Hydromorphone-3-Sulfate 45 2.3.3 Chemical Synthesis 46 2.3.3.1 Synthesis of Dihydromorphine 46 2.3.3.2 Synthesis of Dihydroisomorphine 47 2.3.3.3 Synthesis of Hydromorphone-3-Glucuronide 48 2.3.3.4 Synthesis of Dihydromorphine-3-Glucuronide 49 2.3.3.5 Synthesis of Dihydroisomorphine-3-Glucuronide 50 VIII 2.3.3.6 Synthesis of Norhydromorphone 50 2.3.3.7 Synthesis of Hydromorphone-3-Sulfate 51 2.4
Recommended publications
  • Information to Users
    The direct and modulatory antinociceptive actions of endogenous and exogenous opioid delta agonists Item Type text; Dissertation-Reproduction (electronic) Authors Vanderah, Todd William. Publisher The University of Arizona. Rights Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. Download date 04/10/2021 00:14:57 Link to Item http://hdl.handle.net/10150/187190 INFORMATION TO USERS This ~uscript }las been reproduced from the microfilm master. UMI films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter face, while others may be from any type of computer printer. The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleedthrough, substandard margins, and improper alignment can adversely affect reproduction. In the unlikely. event that the author did not send UMI a complete mannscript and there are missing pages, these will be noted Also, if unauthorized copyright material had to be removed, a note will indicate the deletion. Oversize materials (e.g., maps, drawings, charts) are reproduced by sectioning the original, beginnjng at the upper left-hand comer and contimJing from left to right in equal sections with small overlaps. Each original is also photographed in one exposure and is included in reduced form at the back of the book. Photographs included in the original manuscript have been reproduced xerographically in this copy.
    [Show full text]
  • Drugs of Abuseon September Archived 13-10048 No
    U.S. DEPARTMENT OF JUSTICE DRUG ENFORCEMENT ADMINISTRATION WWW.DEA.GOV 9, 2014 on September archived 13-10048 No. v. Stewart, in U.S. cited Drugs of2011 Abuse EDITION A DEA RESOURCE GUIDE V. Narcotics WHAT ARE NARCOTICS? Also known as “opioids,” the term "narcotic" comes from the Greek word for “stupor” and originally referred to a variety of substances that dulled the senses and relieved pain. Though some people still refer to all drugs as “narcot- ics,” today “narcotic” refers to opium, opium derivatives, and their semi-synthetic substitutes. A more current term for these drugs, with less uncertainty regarding its meaning, is “opioid.” Examples include the illicit drug heroin and pharmaceutical drugs like OxyContin®, Vicodin®, codeine, morphine, methadone and fentanyl. WHAT IS THEIR ORIGIN? The poppy papaver somniferum is the source for all natural opioids, whereas synthetic opioids are made entirely in a lab and include meperidine, fentanyl, and methadone. Semi-synthetic opioids are synthesized from naturally occurring opium products, such as morphine and codeine, and include heroin, oxycodone, hydrocodone, and hydromorphone. Teens can obtain narcotics from friends, family members, medicine cabinets, pharmacies, nursing 2014 homes, hospitals, hospices, doctors, and the Internet. 9, on September archived 13-10048 No. v. Stewart, in U.S. cited What are common street names? Street names for various narcotics/opioids include: ➔ Hillbilly Heroin, Lean or Purple Drank, OC, Ox, Oxy, Oxycotton, Sippin Syrup What are their forms? Narcotics/opioids come in various forms including: ➔ T ablets, capsules, skin patches, powder, chunks in varying colors (from white to shades of brown and black), liquid form for oral use and injection, syrups, suppositories, lollipops How are they abused? ➔ Narcotics/opioids can be swallowed, smoked, sniffed, or injected.
    [Show full text]
  • Chapter 329 [New] Uniform Controlled Substances Act
    CHAPTER 329 [NEW] UNIFORM CONTROLLED SUBSTANCES ACT Part I. General Provisions Section 329-1 Definitions 329-2 Hawaii advisory commission on drug abuse and controlled substances; number; appointment 329-3 Annual report 329-4 Duties of the commission Part II. Standards and Schedules 329-11 Authority to schedule controlled substances 329-12 Nomenclature 329-13 Schedule I tests 329-14 Schedule I 329-15 Schedule II tests 329-16 Schedule II 329-17 Schedule III Tests 329-18 Schedule III 329-19 Schedule IV tests 329-20 Schedule IV 329-21 Schedule V tests 329-22 Schedule V 329-23 Republishing and distribution of schedules Part III. Regulation of Manufacture, Distribution, Prescription, and Dispensing of Controlled Substances 329-31 Rules 329-31.5 Clinics 329-32 Registration requirements 329-33 Registration 329-34 Revocation and suspension of registration 329-35 Order to show cause 329-36 Records of registrants 329-37 Filing requirements 329-38 Prescriptions 329-39 Labels 329-40 Methadone treatment programs Part IV. Offenses and Penalties 329-41 Prohibited acts B-penalties 329-42 Prohibited acts C-penalties 329-43 Penalties under other laws 329-43.5 Prohibited acts related to drug paraphernalia Amended 0612 1 329-44 Notice of conviction to be sent to licensing board, department of commerce and consumer affairs 329-45 Repealed 329-46 Prohibited acts related to visits to more than one practitioner to obtain controlled substance prescriptions 329-49 Administrative penalties 329-50 Injunctive relief Part V. Enforcement and Administrative Provisions 329-51 Powers of enforcement personnel 329-52 Administrative inspections 329-53 Injunctions 329-54 Cooperative arrangements and confidentiality 329-55 Forfeitures 329-56 Burden of proof; liabilities 329-57 Judicial review 329-58 Education and research 329-59 Controlled substance registration revolving fund; established Part VI.
    [Show full text]
  • NIDA Drug Supply Program Catalog, 25Th Edition
    RESEARCH RESOURCES DRUG SUPPLY PROGRAM CATALOG 25TH EDITION MAY 2016 CHEMISTRY AND PHARMACEUTICS BRANCH DIVISION OF THERAPEUTICS AND MEDICAL CONSEQUENCES NATIONAL INSTITUTE ON DRUG ABUSE NATIONAL INSTITUTES OF HEALTH DEPARTMENT OF HEALTH AND HUMAN SERVICES 6001 EXECUTIVE BOULEVARD ROCKVILLE, MARYLAND 20852 160524 On the cover: CPK rendering of nalfurafine. TABLE OF CONTENTS A. Introduction ................................................................................................1 B. NIDA Drug Supply Program (DSP) Ordering Guidelines ..........................3 C. Drug Request Checklist .............................................................................8 D. Sample DEA Order Form 222 ....................................................................9 E. Supply & Analysis of Standard Solutions of Δ9-THC ..............................10 F. Alternate Sources for Peptides ...............................................................11 G. Instructions for Analytical Services .........................................................12 H. X-Ray Diffraction Analysis of Compounds .............................................13 I. Nicotine Research Cigarettes Drug Supply Program .............................16 J. Ordering Guidelines for Nicotine Research Cigarettes (NRCs)..............18 K. Ordering Guidelines for Marijuana and Marijuana Cigarettes ................21 L. Important Addresses, Telephone & Fax Numbers ..................................24 M. Available Drugs, Compounds, and Dosage Forms ..............................25
    [Show full text]
  • Schedules of Controlled Substances (.Pdf)
    PURSUANT TO THE TEXAS CONTROLLED SUBSTANCES ACT, HEALTH AND SAFETY CODE, CHAPTER 481, THESE SCHEDULES SUPERCEDE PREVIOUS SCHEDULES AND CONTAIN THE MOST CURRENT VERSION OF THE SCHEDULES OF ALL CONTROLLED SUBSTANCES FROM THE PREVIOUS SCHEDULES AND MODIFICATIONS. This annual publication of the Texas Schedules of Controlled Substances was signed by John Hellerstedt, M.D., Commissioner of Health, and will take effect 21 days following publication of this notice in the Texas Register. Changes to the schedules are designated by an asterisk (*). Additional information can be obtained by contacting the Department of State Health Services, Drugs and Medical Devices Unit, P.O. Box 149347, Austin, Texas 78714-9347. The telephone number is (512) 834-6755 and the website address is http://www.dshs.texas.gov/dmd. SCHEDULES Nomenclature: Controlled substances listed in these schedules are included by whatever official, common, usual, chemical, or trade name they may be designated. SCHEDULE I Schedule I consists of: -Schedule I opiates The following opiates, including their isomers, esters, ethers, salts, and salts of isomers, esters, and ethers, unless specifically excepted, if the existence of these isomers, esters, ethers, and salts are possible within the specific chemical designation: (1) Acetyl-α-methylfentanyl (N-[1-(1-methyl-2-phenethyl)-4-piperidinyl]-N- phenylacetamide); (2) Acetylmethadol; (3) Acetyl fentanyl (N-(1-phenethylpiperidin-4-yl)-N-phenylacetamide); (4) Acryl fentanyl (N-(1-phenethylpiperidin-4-yl)-N-phenylacrylamide) (Other name:
    [Show full text]
  • Morphine and Heroin Differentially Modulate in Vivo Hippocampal LTP in Opiate-Dependent Rat
    Neuropsychopharmacology (2007) 32, 1738–1749 & 2007 Nature Publishing Group All rights reserved 0893-133X/07 $30.00 www.neuropsychopharmacology.org Morphine and Heroin Differentially Modulate In Vivo Hippocampal LTP in Opiate-Dependent Rat 1,3 2,3 2,3 1,3 1 1 2 ,1 Guobin Bao , Lin Kang , Haohong Li , Yuting Li ,LuPu, Peng Xia , Lan Ma and Gang Pei* 1 Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of 2 Sciences, Shanghai, People’s Republic of China; Pharmacology Research Center, Shanghai Medical College and Institutes of Brain Science, Fudan University, Shanghai, People’s Republic of China Addictive drugs have been shown to severely influence many neuronal functions, which are considered as the underlying mechanisms for physiological and psychological dependences. We previously showed that in vivo LTP in rat hippocampal CA1 region is significantly reduced during withdrawal following chronic opiates treatment, and the reduced LTP can be restored by re-exposure of animals to corresponding drugs. Here, we further demonstrated that during opiates withdrawal, the re-exposure of morphine either systemically (subcutaneously) or locally (intracerebroventricularly) could restore the reduced LTP in heroin-dependent rats, but heroin could not restore the reduced LTP, in morphine-dependent rats, indicating differential modulations of hippocampal functions by those two opiates. In contrast, DAMGO, a mu-opioid receptor (MOR) agonist, could restore the reduced LTP, and CTOP, a MOR antagonist, could block the restoration in rats dependent on both opiates, showing that MOR is functional under such conditions. However, the upregulation of hippocampal PKA activity during morphine withdrawal could be suppressed by re-exposure of morphine but not that of heroin, suggesting a likely underlying mechanism of the differential modulation of LTP by two opiates.
    [Show full text]
  • Use of Chronic Opioid Therapy in Chronic Noncancer Pain CHRONIC NONCANCER PAINNONCANCER CHRONIC Evidence Review
    CLINICAL GUIDELINE FOR THE USE OF CHRONIC OPIOID THERAPY IN CLINICAL GUIDELINE FOR THE USE OF CHRONIC OPIOID THERAPY IN GUIDELINE FOR THE Use of Chronic Opioid Therapy in Chronic Noncancer Pain CHRONIC NONCANCER PAIN Evidence Review The American Pain Society in Conjunction with The American Academy of Pain Medicine EVIDENCE REVIEW APS-AAPM Clinical Guidelines for the Use of Chronic Opioid Therapy in Chronic Noncancer Pain TABLE OF CONTENTS Page Introduction 1 Purpose of evidence review ...................................................................... 1 Background 1 Previous guidelines ................................................................................... 2 Scope of evidence review 3 Key questions............................................................................................ 3 Populations................................................................................................ 7 Interventions.............................................................................................. 8 Outcomes.................................................................................................. 8 Conflict of interest............................................................................................. 10 Methods 10 Literature search and strategy................................................................... 10 Inclusion and exclusion criteria.................................................................. 11 Data extraction and synthesis ..................................................................
    [Show full text]
  • A Model of Chronic Pain in the Rat: Functional Correlates of Alterations in the Activity of Opioid Systems
    The Journal of Neuroscience, January 1987, 7(i): 77-87 A Model of Chronic Pain in the Rat: Functional Correlates of Alterations in the Activity of Opioid Systems M. J. Millan,’ A. Czbnkowski,’ C. W. T. Pilcher,’ 0. F. X. Almeida,’ M. H. Millan,’ F. C. Colpaert,2 and A. Her& ‘Department of Neuropharmacology, Max-Planck-lnstitut ftir Psychiatric, D-8033 Planegg-Martinsried, F.R.G., and ‘Janssen Pharmaceutics Research Laboratories, B-2340 Beerse, Belgium lntradermal inoculation of rats at the tail base with Myco- It is suggested that polyarthritis is a complex condition bacterium bufyricurn led to the gradual development of an entailing many changes, both behavioral and endocrinolog- arthritic swelling of the limbs which peaked at 3 weeks and ical. Further, arthritic rats cannot simply be described as subsided thereafter. Arthritic rats displayed a loss of body “hyperalgesic”: of critical importance is the nature of the weight, hypophagia, and hypodipsia in addition to a disrup- nociceptive stimulus applied. The parallel alterations in tion of the diurnal rhythms of ingestive behavior and of core spinal cord pools of DYN and K-reCeptOrS (see also Millan temperature. The activity of adenohypophyseal B-endor- et al., 1986) and the changes in the influence on nociception phin- (&EP) secreting corticotrophs, in contrast to prolactin- of K-agonists and x-antagonists suggest an increased activ- (PRL) secreting lactotrophs, was increased in arthritic rats. ity of spinal DYN. Thus, spinal K-receptors may play a role Indeed, hypertrophy of the adrenal glands was seen. Ar- in the modulation of nociception under chronic pain. Finally, thritic rats also showed an elevation in spinal cord levels of there is a clear distinction between the functional response immunoreactive dynorphin (DYN), an endogenous ligand of of K- as compared with K-reCt?ptOrS to chronic pain in the the K-opioid receptor.
    [Show full text]
  • ESTIMATED WORLD REQUIREMENTS of NARCOTIC DRUGS in GRAMS for 2013 (January Update)
    ESTIMATED WORLD REQUIREMENTS OF NARCOTIC DRUGS IN GRAMS FOR 2013 (January update) Afghanistan Oxycodone 43 000 Codeine 50 000 Oxymorphone 300 Dextropropoxyphene 2 000 000 Pethidine 65 000 Diphenoxylate 20 000 Remifentanil 9 100 Fentanyl 6 Sufentanil 1 Methadone 6 000 Thebaine 45 000 Morphine 4 000 Armenia Pethidine 80 000 Codeine 3 000 Pholcodine 100 000 Fentanyl 21 Albania Methadone 10 000 Codeine 35 000 Morphine 4 500 Fentanyl 40 Thebaine 10 Methadone 9 000 Trimeperidine 650 Morphine 3 000 Aruba* Pethidine 2 500 Alfentanil 3 Pholcodine 1 000 Bezitramide 1 Remifentanil 8 Cocaine 70 Sufentanil 1 Codeine 85 Algeria Dextromoramide 1 Alfentanil 500 Dextropropoxyphene 85 Codeine 1 000 000 Fentanyl 130 Etorphine 1 Hydrocodone 2 Fentanyl 1 000 Methadone 150 Morphine 11 000 Morphine 340 Pethidine 3 000 Opium 450 Pholcodine 2 500 000 Oxycodone 26 Sufentanil 30 Pethidine 404 Andorra Piritramide 20 Fentanyl 80 Remifentanil 19 Methadone 1 000 Ascension Island Morphine 500 Alfentanil 1 Oxycodone 1 500 Fentanyl 1 Pethidine 500 Morphine 2 Remifentanil 4 Pethidine 9 Angola* Australia Alfentanil 2 Alfentanil 400 Codeine 30 000 Cannabis 21 500 Dextromoramide 375 Cocaine 20 000 Dihydrocodeine 375 Codeine 9 800 000 Fentanyl 45 Conc. of poppy straw Morphine 11 000 AOA 4 000 000 Pethidine 13 000 ATA 85 000 000 Sufentanil 2 Dextromoramide 10 Anguilla Dextropropoxyphene 1 925 000 Fentanyl 1 Difenoxin 7 Morphine 20 Dihydrocodeine 285 000 Pethidine 300 Diphenoxylate 80 000 Antigua and Barbuda* Ethylmorphine 10 Cocaine 9 Etorphine 2 Codeine 169 Fentanyl 40 000
    [Show full text]
  • Coupling of a New, Active Morphine Derivative to Sepharose for Affinity Chromatography (6-Succinylmorphine/Opiate Receptors/Antibodies/Naloxone) ERIC J
    Proc. Nat. Acad. Sci. USA Vol. 69, No. 7, pp. 1835-1837, July 1972 Coupling of a New, Active Morphine Derivative to Sepharose for Affinity Chromatography (6-succinylmorphine/opiate receptors/antibodies/naloxone) ERIC J. SIMON, WILLIAM P. DOLE, AND JACOB M. HILLER Department of Medicine, New York University Medical Center, New York, N.Y. 10016 Communicated by Michael Heidelberger, May 2, 1972 ABSTRACT A new, pharmacologically active morphine Nuclear Corp., Boston, Mass.). Affinose 101 (ethylamino- derivative, 6-succinylmorphine, was synthesized. The prop- Sepharose) was purchased from Bio-Rad Labotatories, Rich- erties of this compound and evidence for its structure are presented. Succinylmorphine was covalently coupled to mond, Calif., and the water-soluble carbodiimide, 1-ethyl-3- ethylamino- Sepharose. Morphine-Sepharose containing (3-dimethylaminopropyl)carbodiimide, from Pierce Chemical up to 40 jig of morphine did not block the electrically Co., Rockford, Ill. Silicic acid-coated thin-layer plates (Sil- stimulated contraction of isolated guinea pig ileum, but plate F-22) were purchased from Brinkmann Instrument Co., after alkaline hydrolysis of beads containing 2 ug of mor- phine the supernatant completely blocked contraction. Westbury, N.Y. This block was reversed by the specific morphine antago- Methods. Free phenolic groups were measured with the Folin nist naloxone. Antibodies to morphine were removed from serum by morphine-Sepharose, but not by ethylamino- phenol reagent, as described for proteins by Lowry et al. (3). Sepharose, providing evidence of the efficacy of the beads Ultraviolet spectroscopy was done in water at pH 2 with a for affinity chromatography. Zeiss spectrophotometer. Infrared- spectroscopy was done for us by Dr.
    [Show full text]
  • Opioid Peptides: Medicinal Chemistry, 69
    Opioid Peptides: Medicinal Chemistry DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Alcohol, Drug Abuse, and Mental Health Administration Opioid Peptides: Medicinal Chemistry Editors: Rao S. Rapaka, Ph.D. Gene Barnett, Ph.D. Richard L. Hawks, Ph.D. Division of Preclinical Research National Institute on Drug Abuse NIDA Research Monograph 69 1986 DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Alcohol, Drug Abuse, and Mental Health Administration National Institute on Drug Abuse 5600 Fishers Lane Rockville, Maryland 20857 For sale by the Superintendent of Documents, U.S. Government Printing Office Washington, D.C. 20402 NIDA Research Monographs are prepared by the research divisions of the National Institute on Drug Abuse and published by its Office of Science. The primary objective of the series is to provide critical reviews of research problem areas and techniques, the content of state-of-the-art conferences, and integrative research reviews. Its dual publication emphasis is rapid and targeted dissemination to the scientific and professional community. Editorial Advisors MARTIN W. ADLER, Ph.D. SIDNEY COHEN, M.D. Temple University School of Medicine Los Angeles, California Philadelphia, Pennsylvania SYDNEY ARCHER, Ph.D. MARY L. JACOBSON Rensselaer Polytechnic lnstitute National Federation of Parents for Troy, New York Drug Free Youth RICHARD E. BELLEVILLE, Ph.D. Omaha, Nebraska NB Associates, Health Sciences Rockville, Maryland REESE T. JONES, M.D. KARST J. BESTEMAN Langley Porter Neuropsychiatric lnstitute San Francisco, California Alcohol and Drug Problems Association of North America WashIngton, DC DENISE KANDEL, Ph.D. GILBERT J. BOTVIN, Ph.D. College of Physicians and Surgeons of Cornell University Medical College Columbia University New York, New York New York, New York JOSEPH V.
    [Show full text]
  • English → French → English
    Anglais → Français - A - Acetorphine Acétorphine Acetorphine hydrochloride Chlorhydrate d’acétorphine Acetyl-alpha-methylfentanyl Acétyl-alpha-méthylfentanyl Acetyldihydrocodeine Acétyldihydrocodéine Acetyldihydrocodeine hydrochloride Chlorhydrate d’acétyldihydrocodéine Acetylmethadol Acétylméthadol Alfentanil Alfentanil Alfentanil hydrochloride Chlorhydrate d’alfentanil Allobarbital Allobarbital Allobarbital-aminophenazone Allobarbital-aminophénazone Allylprodine Allylprodine Allylprodine hydrochloride Chlorhydrate d’allylprodine Alphacetylmethadol Alphacétylméthadol Alphacetylmethadol hydrochloride Chlorhydrate d’alphacétylméthadol Alphameprodine Alphaméprodine Alphamethadol Alphaméthadol Alpha-methylfentanyl Alpha-méthylfentanyl Alpha-methylfentanyl hydrochloride Chlorhydrate d’alpha-méthylfentanyl Alpha-methylthiofentanyl Alpha-méthylthiofentanyl Alpha-methylthiofentanyl hydrochloride Chlorhydrate d’alpha-méthylthiofentanyl Alphaprodine Alphaprodine Alphaprodine hydrochloride Chlorhydrate d’alphaprodine Alprazolam Alprazolam Amfepramone Amfépramone Amfepramone glutamate Glutamate d’amfépramone Amfepramone hydrochloride Chlorhydrate d’amfépramone Amfepramone resinate Amfépramone résinate Amfetamine Amfétamine Amfetamine acetylsalicylate Acétylsalicylate d’amfétamine Amfetamine adipate Adipate d’amfétamine Amfetamine p-aminophenylacetate Acétate p-aminophényle d’amfétamine Amfetamine aspartate Aspartate d’amfétamine Amfetamine (4-chlorophenoxy) acetate Acétate (chlorophénoxy-4) d’amfétamine Amfetamine hydrochloride Chlorhydrate d’amfétamine
    [Show full text]