CHEMISTRY AND ACTION: DRUG TERM INDEXING IN THE MEDICAL SUBJECT HEADINGS

Most of the “things” we are interested when we conduct a literature search are really quite complicated. For example, no one really want’s literature on “bacterial pneumonia”; what they really want is something more specific: treatments for the disease, or how to diagnose the disease, the epidemiology of the disease, as so on.

The Medical Subject Headings (MeSH) try to address this issue by providing a list of some 80 subheadings which can be used to qualify a heading: “Pneumonia, Bacterial / drug therapy” or “Pneumonia, Bacterial / diagnosis”. And so, we are already used to the complexities of MeSH.

Similarly, drug topics also pose a particular problem. For example, all of the following papers concern the same drug, aspirin, but they are all concerned with a different effect or action of the drug: TI: Randomized clinical trial of the antiplatelet effects of aspirin-clopidogrel combination versus aspirin alone after lower limb angioplasty. TI: Aspirin is efficacious for the treatment of acute migraine. TI: Effects of acetylsalicylic acid on sore throat pain and other pain symptoms associated with acute upper respiratory tract infection. TI: A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women.

Years ago, the MeSH tree structures included hierarchies for drugs that reflected their pharmacological actions. There was an “Antibiotic” hierarchy that broke down into narrower and narrower categories until eventually specific antibiotic headings were listed. So under antibiotics were headings for broad types of antibiotics: “Aminoglycosides”, “Antibiotics, Lactam”, etc. A heading like “Antibiotics, Lactam” would in turn break down into categories like “Cephalosporins”, “Penicillins”, etc.

The difficulty with this approach is that many drugs, such as aspirin, don’t fit into single pharmacological categories. This led to the following situation: when the “Analgesic” heading was exploded, it would retrieve papers assigned the MeSH heading “aspirin”, but often the papers assigned this heading weren’t about the analgesic effects of aspirin, but about one of it’s other effects (e.g. inhibition of platelet aggregation).

So all the specific drug terms were removed from any MeSH categories which were essentially describing a “pharmacologic action”.

Now the only categories which list specific drugs in their hierarchies are the chemical groups to which the drugs belong.

At the same time as this change was made in the hierarchies, the following indexing practice was initiated:

When a paper concerns use of a drug to treat a disease or when the paper concerns some other aspect of the drug when used therapeutically (administration & dosage, pharmacology, adverse effects, etc.) the subject indexer must assign:

1. The MeSH heading for the drug or the narrowest chemical heading available. 2. The heading or headings that describe the pharmacologic action of the drug.

Often the same subheadings will be applied to both headings when the aspect they describe has to do with the drug biological action (e.g. therapeutic effect, adverse effect) or it’s use as a drug (e.g. administration & dosage)

TI: Metformin therapy and diabetes in pregnancy. MAJOR MESH: • Breast Feeding / • Hypoglycemic Agents / therapeutic use • Metformin / therapeutic use • Pregnancy in Diabetics / drug therapy MINOR MESH: • Metformin / analysis • Metformin / pharmacokinetics • Milk, Human / chemistry • Practice Guidelines / • Risk Assessment /

A CAREFUL LOOK AT A SPECIFIC MESH DRUG HEADING: ASPIRIN

The MeSH scope note for Aspirin notes the various therapeutic or pharmacologic actions of this drug:

Scope Note: The prototypical analgesic used in the treatment of mild to moderate pain. It has anti-inflammatory and antipyretic properties and acts as an inhibitor of cyclooxygenase which results in the inhibition of the biosynthesis of prostaglandins. Aspirin also inhibits platelet aggregation and is used in the prevention of arterial and venous thrombosis.

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As with all chemicals, aspirin is included in the MeSH tree structure based on its chemical classification:

MeSH Tree Stuctures (hierarchical categories) under which Aspirin is found:

Chemicals and Drugs Category Chemicals and Drugs Category Chemicals and Drugs Category Organic Chemicals Organic Chemicals Organic Chemicals Carboxylic Acids Carboxylic Acids Phenols Acids, Carbocyclic Hydroxy Acids Hydroxybenzoic Acids Benzoic Acids Hydroxybenzoic Acids Salicylic Acids Hydroxybenzoic Acids Salicylic Acids Aspirin Salicylic Acids Aspirin Aspirin

Note that all the categories are “chemical”, none pertain to the “pharmacological action” of aspirin.

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Here is the complete list of pharmacological action headings from MeSH. Note that no specific drugs or chemicals are listed.

MESH PHARMACOLOGICAL ACTIONS CATEGORY Note: there are no narrower terms for any of the headings.

Abortifacient Agents Adrenergic Agonists Air Pollutants, Occupational Abortifacient Agents, Adrenergic alpha-Agonists Air Pollutants, Radioactive Nonsteroidal Adrenergic alpha-Antagonists Alcohol Deterrents Abortifacient Agents, Adrenergic Antagonists Aldosterone Antagonists Steroidal Adrenergic beta-Agonists Alkylating Agents Adhesives Adrenergic beta-Antagonists Amebicides Adjuvants, Anesthesia Adrenergic Uptake Inhibitors Anabolic Agents Adjuvants, Immunologic Aerosol Propellants Analgesics Adjuvants, Pharmaceutic Affinity Labels Analgesics, Non-Narcotic Adrenal Cortex Hormones Agglutinins Analgesics, Opioid Adrenergic Agents Air Pollutants Androgen Antagonists Androgens Antimetabolites, Chelating Agents Anesthetics Antineoplastic Chemical Warfare Agents Anesthetics, Combined Antimitotic Agents Chemosterilants Anesthetics, Dissociative Antimutagenic Agents Cholagogues and Choleretics Anesthetics, General Antinematodal Agents Cholinergic Agents Anesthetics, Inhalation Antineoplastic Agents Cholinergic Agonists Anesthetics, Intravenous Antineoplastic Agents, Cholinergic Antagonists Anesthetics, Local Alkylating Cholinesterase Inhibitors Angiogenesis Inducing Antineoplastic Agents, Cholinesterase Reactivators Agents Hormonal Chromogenic Compounds Angiogenesis Inhibitors Antineoplastic Agents, Coagulants Angiogenesis Modulating Phytogenic Coccidiostats Agents Antioxidants Coloring Agents Angiotensin II Type 1 Antiparasitic Agents Complement Inactivating Receptor Blockers Antiparkinson Agents Agents Angiotensin-Converting Antiperspirants Complex Mixtures Enzyme Inhibitors Antiplatyhelmintic Agents Contraceptive Agents Anion Exchange Resins Antiprotozoal Agents Contraceptive Agents, Antacids Antipruritics Female Anthelmintics Antipsychotic Agents Contraceptive Agents, Male Anti-Allergic Agents Antirheumatic Agents Contraceptives, Oral Anti-Anxiety Agents Antisense Elements Contraceptives, Oral, Anti-Arrhythmia Agents (Genetics) Combined Anti-Asthmatic Agents Antisickling Agents Contraceptives, Oral, Anti-Bacterial Agents Antispermatogenic Agents Hormonal Anti-Dyskinesia Agents Antithyroid Agents Contraceptives, Oral, Anti-HIV Agents Antitreponemal Agents Sequential Anti-Infective Agents Antitrichomonal Agents Contraceptives, Oral, Anti-Infective Agents, Local Antitubercular Agents Synthetic Anti-Infective Agents, Urinary Antitussive Agents Contraceptives, Postcoital Anti-Inflammatory Agents Antiviral Agents Contraceptives, Postcoital, Anti-Inflammatory Agents, Appetite Depressants Hormonal Non-Steroidal Appetite Stimulants Contraceptives, Postcoital, Anti-Obesity Agents Aromatase Inhibitors Synthetic Anti-Retroviral Agents Astringents Contrast Media Anti-Ulcer Agents Autonomic Agents Convulsants Antibiotics, Antifungal Biocompatible Materials Cosmetics Antibiotics, Antineoplastic Blood Substitutes Cross-Linking Reagents Antibiotics, Antitubercular Bone Cements Cryoprotective Agents Anticarcinogenic Agents Bone Density Conservation Culture Media Anticestodal Agents Agents Cyclooxygenase 2 Inhibitors Anticholesteremic Agents Bronchoconstrictor Agents Cyclooxygenase Inhibitors Anticoagulants Bronchodilator Agents Cysteine Proteinase Inhibitors Anticonvulsants Buffers Cytotoxins Antidepressive Agents Calcium Channel Agonists Defoliants, Chemical Antidepressive Agents, Calcium Channel Blockers Delayed-Action Preparations Second-Generation Carbonic Anhydrase Dental Disinfectants Antidepressive Agents, Inhibitors Dental Materials Tricyclic Carcinogens Dermatologic Agents Antidiarrheals Carcinogens, Environmental Dermotoxins Antidiuretic Agents Cardiotonic Agents Detergents Antidotes Cardiovascular Agents Dialysis Solutions Antiemetics Cariogenic Agents Dipeptidyl-Peptidase IV Antifibrinolytic Agents Cariostatic Agents Inhibitors Antifoaming Agents Cathartics Disinfectants Antifungal Agents Caustics Diuretics Antihypertensive Agents Central Nervous System Diuretics, Osmotic Antilipemic Agents Agents Dopamine Agents Antimalarials Central Nervous System Dopamine Agonists Antimanic Agents Depressants Dopamine Antagonists Antimetabolites Central Nervous System Dopamine Uptake Inhibitors Stimulants Drug Carriers Emetics Hemostatics Narcotic Antagonists Emollients Heparin Antagonists Narcotics Endocannabinoids Herbicides Nasal Decongestants Endothelium-Dependent Histamine Agents Natriuretic Agents Relaxing Factors Histamine Agonists Neuromuscular Agents Environmental Pollutants Histamine Antagonists Neuromuscular Blocking Enzyme Activators Histamine H1 Antagonists Agents Enzyme Inhibitors Histamine H1 Antagonists, Neuromuscular Depolarizing Enzyme Reactivators Non-Sedating Agents Estradiol Antagonists Histamine H2 Antagonists Neuromuscular Estrogen Antagonists Histamine H3 Antagonists Nondepolarizing Agents Estrogen Receptor HIV Fusion Inhibitors Neuroprotective Agents Modulators HIV Protease Inhibitors Neurotoxins Estrogens Hormone Antagonists Neurotransmitter Agents Estrogens, Non-Steroidal Hormones Neurotransmitter Uptake Excipients Hormones, Hormone Inhibitors Excitatory Amino Acid Agents Substitutes, and Hormone Nicotinic Agonists Excitatory Amino Acid Antagonists Nicotinic Antagonists Agonists Hydroxymethylglutaryl-CoA Nitric Oxide Donors Excitatory Amino Acid Reductase Inhibitors Nootropic Agents Antagonists Hypnotics and Sedatives Noxae Expectorants Hypoglycemic Agents Nucleic Acid Synthesis Explosive Agents Immunologic Factors Inhibitors Fat Substitutes Immunosuppressive Agents Ointment Bases Fatty Acid Synthesis Immunotoxins Oligodeoxyribonucleotides, Inhibitors Incretins Antisense Fertility Agents Indicators and Reagents Oligonucleotides, Antisense Fertility Agents, Female Insect Repellents Ophthalmic Solutions Fertility Agents, Male Insecticides Oxidants Fertilizers Insulin Antagonists Oxidants, Photochemical Fibrin Modulating Agents Intercalating Agents Oxytocics Fibrinolytic Agents Interferon Inducers Parasympatholytics Filaricides Ion Exchange Resins Parasympathomimetics Fixatives Ionophores Peripheral Nervous System Flavoring Agents Iron Chelating Agents Agents Fluorescent Dyes Irritants Peroxisome Proliferators Folic Acid Antagonists Keratolytic Agents Pesticide Synergists Food Additives Leprostatic Agents Pesticides Food Coloring Agents Leukotriene Antagonists Pharmaceutic Aids Food Preservatives Lipotropic Agents Pharmaceutical Solutions Free Radical Scavengers Lipoxygenase Inhibitors Phosphodiesterase Inhibitors Fungicides, Industrial Luminescent Agents Photoaffinity Labels GABA Agents Luteolytic Agents Photosensitizing Agents GABA Agonists Membrane Transport Phytoestrogens GABA Antagonists Modulators Plant Growth Regulators GABA Modulators Menstruation-Inducing Agents Plasma Substitutes Ganglionic Blockers Micronutrients Plasticizers Ganglionic Stimulants Mineralocorticoids Platelet Aggregation Gastrointestinal Agents Miotics Inhibitors Glucocorticoids Mitogens Poisons Glycine Agents Mitosis Modulators Potassium Channel Blockers Gout Suppressants Molecular Probes Preservatives, Growth Inhibitors Molluscacides Pharmaceutical Growth Substances Monoamine Oxidase Progestins GTP Phosphohydrolase Inhibitors Prostaglandin Antagonists Activators Mouthwashes Protease Inhibitors Hallucinogens Muscarinic Agonists Protective Agents Hazardous Substances Muscarinic Antagonists Protein Kinase Inhibitors Hemagglutinins Muscle Relaxants, Central Protein Synthesis Inhibitors Hematinics Mutagens Psychotropic Drugs Hematologic Agents Mydriatics Pulmonary Surfactants Hemolytic Agents Myeloablative Agonists Pyrogens Radiation-Protective Agents Serotonin Agents Tear Gases Radiation-Sensitizing Agents Serotonin Agonists Teratogens Radioactive Pollutants Serotonin Antagonists Tissue Adhesives Radiopharmaceuticals Serotonin Uptake Inhibitors Tocolytic Agents Reducing Agents Siderophores Toothpaste Renal Agents Sodium Channel Blockers Trace Elements Reproductive Control Agents Sodium Chloride Symporter Tranquilizing Agents Resins, Synthetic Inhibitors Trypanocidal Agents Respiratory System Agents Sodium Potassium Chloride Trypsin Inhibitors Reverse Transcriptase Symporter Inhibitors Tubulin Modulators Inhibitors Soil Pollutants Uncoupling Agents Riot Control Agents, Solvents Uricosuric Agents Chemical Spermatocidal Agents Vasoconstrictor Agents Rodenticides Sulfhydryl Reagents Vasodilator Agents Schistosomicides Sunscreening Agents Vehicles Sclerosing Solutions Surface-Active Agents Vitamin B Complex Selective Estrogen Receptor Surgical Fixation Devices Vitamins Modulators Sweetening Agents Water Pollutants, Chemical Sensory System Agents Sympatholytics Serine Proteinase Inhibitors Sympathomimetics

MeSH does include a tool for indexers to help them determine which pharmacological actions apply to a given drug. These are essentially long lists of the all drugs that fall into a particular pharmacological action category. The list includes both MeSH headings and non-headings:

Analgesics Fibrinolytic Agents Anti-Inflammatory Agents, [Pharmacological Action] [Pharmacological Action] Non-Steroidal : : [Pharmacological Action] Antipyrine (MeSH Term) Ancrod (MeSH Term) : Apazone (MeSH Term) Anistreplase (MeSH Term) antiflammin P2 (Subst. Name) Arteparon (Substance Name) aprosulate (Substance Name) Antipyrine (MeSH Term) Arthrotec (Substance Name) ardeparin (Substance Name) Apazone (MeSH Term) Aspirin (MeSH Term) asarone (Substance Name) Arteparon (Substance Name) azulene (Substance Name) Aspirin (MeSH Term) Arthrotec (Substance Name) B 4162 (Substance Name) Batroxobin (MeSH Term) Aspirin (MeSH Term) baicalin (Substance Name) benzarone (Substance Name) azulene (Substance Name) : Brinolase (MeSH Term) baicalin (Substance Name) : balsalazide (Substance Name) :

Analgesics, Non-Narcotic Cyclooxygenase Inhibitors [Pharmacological Action] [Pharmacological Action] : : 4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3- Apazone (MeSH Term) amine (MeSH Term) Arteparon (Substance Name) 4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl) Arthrotec (Substance Name) benzenesulfonamide (Substance Name) Aspirin (MeSH Term) acetylsalicylic acid lysinate (Substance Name) azulene (Substance Name) Aspirin (MeSH Term) baicalin (Substance Name) celecoxib (Substance Name) balsalazide (Substance Name) Diclofenac (MeSH Term) : :

Here are several records that illustrate the actual indexing assigned to papers about aspirin. Only the drug and pharmacological headings are shown. Note that the fourth paper (Effects of aspirin during exercise …) does was not assigned a pharmacological action heading. Even indexers make mistakes!

Record 1 • Aspirin/adverse effects TI: Aspirin for the primary prevention of • Cyclooxygenase cardiovascular events in women and Inhibitors/therapeutic use men: a sex-specific meta-analysis of • Platelet Aggregation randomized controlled trials. Inhibitors/administration and SO: JAMA. 2006 Jan 18; 295(3): 306-13 dosage Major MeSH: • Platelet Aggregation • Aspirin/therapeutic use; Inhibitors/adverse effects • Platelet Aggregation Inhibitors/therapeutic use Record 4 Minor MeSH: TI: Effects of aspirin during exercise on the • Aspirin/adverse effects incidence of high-altitude headache: a • Platelet Aggregation randomized, double-blind, placebo- Inhibitors/adverse effects controlled trial. SO: Headache. 2001 Jun; 41(6): 542-5 Record 2 Major MeSH: TI: Sex differences in platelet reactivity and • Aspirin/therapeutic use response to low-dose aspirin therapy. Minor MeSH: SO: JAMA. 2006 Mar 22; 295(12): 1420-7 Major MeSH: Record 5 • Aspirin/therapeutic use; TI: Efficacy and safety of metamizol vs. • Cyclooxygenase acetylsalicylic acid in patients with Inhibitors/therapeutic use; moderate episodic tension-type • Platelet Aggregation headache: a randomized, double-blind, Inhibitors/therapeutic use placebo- and active-controlled, Minor MeSH: multicentre study. • Aspirin/pharmacology SO: Cephalalgia. 2001 Jun; 21(5): 604-10 • Cyclooxygenase Major MeSH: Inhibitors/pharmacology • Analgesics, Non- • Platelet Aggregation Narcotic/therapeutic use; Inhibitors/pharmacology • Anti-Inflammatory Agents, Non- Steroidal/therapeutic use; Record 3 • Aspirin/therapeutic use; TI: A randomized trial of low-dose aspirin in • Dipyrone/therapeutic use the primary prevention of Minor MeSH: cardiovascular disease in women. • Analgesics, Non-Narcotic/adverse SO: N Engl J Med. 2005 Mar 31; 352(13): effects 1293-304 • Anti-Inflammatory Agents, Non- Major MeSH: Steroidal/administration and dosage • Aspirin/therapeutic use; • Anti-Inflammatory Agents, Non- • Platelet Aggregation Steroidal/adverse effects Inhibitors/therapeutic use • Aspirin/adverse effects Minor MeSH: • Dipyrone/administration and • Anti-Inflammatory Agents, Non- dosage Steroidal/therapeutic use • Dipyrone/adverse effects • Aspirin/administration and dosage