Radiopharmaceutical

Last updated
A carbon-11 labelled radiopharmaceutical Radiopharmaceutical.jpg
A carbon-11 labelled radiopharmaceutical

Radiopharmaceuticals, or medicinal radiocompounds, are a group of pharmaceutical drugs containing radioactive isotopes. Radiopharmaceuticals can be used as diagnostic and therapeutic agents. Radiopharmaceuticals emit radiation themselves, which is different from contrast media which absorb or alter external electromagnetism or ultrasound. Radiopharmacology is the branch of pharmacology that specializes in these agents.

Contents

The main group of these compounds are the radiotracers used to diagnose dysfunction in body tissues. While not all medical isotopes are radioactive, radiopharmaceuticals are the oldest and remain the most common of such drugs.

Drug nomenclature

As with other pharmaceutical drugs, there is standardization of the drug nomenclature for radiopharmaceuticals, although various standards coexist. The International Nonproprietary Names (INNs), United States Pharmacopeia (USP) names, and IUPAC names for these agents are usually similar other than trivial style differences. [1] The details are explained at Radiopharmacology § Drug nomenclature for radiopharmaceuticals .

Specific radiopharmaceuticals

A list of nuclear medicine radiopharmaceuticals follows. Some radioisotopes are used in ionic or inert form without attachment to a pharmaceutical; these are also included. There is a section for each radioisotope with a table of radiopharmaceuticals using that radioisotope. The sections are ordered alphabetically by the English name of the radioisotope. Sections for the same element are then ordered by atomic mass number.

Calcium-47

47 Ca is a beta and gamma emitter.

NameInvestigationRoute of administrationIn-vitro / in-vivoImaging / non-imaging
Ca-47-Ca2+Bone metabolismIVIn-vitroNon-imaging

Carbon-11

11 C is a positron emitter.

NameInvestigationRoute of administrationIn-vitro / in-vivoImaging / non-imaging
C11-L-methyl-methionineBrain tumour imaging

Parathyroid imaging

IVIn-vivoImaging

Carbon-14

14C is a beta emitter.

NameInvestigationRoute of administrationIn-vitro / in-vivoImaging / non-imaging
C14-Glycocholic acid Breath test for small intestine bacterial overgrowthOralIn-vitroNon-imaging
C14-PABA (para-amino benzoic acid)Pancreatic studiesOralIn-vitroNon-imaging
C14-UreaBreath test to detect Helicobacter pylori OralIn-vitroNon-imaging
C14-d-xyloseBreath test for small intestine bacterial overgrowthOralIn-vitroNon-imaging

Chromium-51

51Cr is a gamma emitter.

NameInvestigationRoute of administrationIn-vitro / in-vivoImaging / non-imaging
Cr51-[heart scan/blood volumeRed cell volume heart scan; sites of sequestration; gastrointestinal blood lossIVIn-vitroNon-imaging
Cr51-Cr3+Gastrointestinal protein lossIVIn-vitroNon-imaging
Cr51-EDTA (ethylenediaminetetraacetic acid) Glomerular filtration rate measurementIVIn-vitroNon-imaging

Cobalt-57

57Co is a gamma emitter.

NameInvestigationRoute of administrationIn-vitro / in-vivoImaging / non-imaging
Co57-Cyanocobalamin (vitamin B12)Gastrointestinal absorptionOralIn-vitroNon-imaging

Cobalt-58

58Co is a gamma emitter.

NameInvestigationRoute of administrationIn-vitro / in-vivoImaging / non-imaging
Co58-Cyanocobalamin (vitamin B12)Gastrointestinal absorptionOralIn-vitroNon-imaging

Erbium-169

169Er is a beta emitter.

NameTreatment ofRoute of administration
Er169-ColloidArthritic conditionsIntra-articular

Fluorine-18

18F is a positron emitter with a half-life of 109 minutes. It is produced in medical cyclotrons, usually from oxygen-18, and then chemically attached to a pharmaceutical formulation.

NameInvestigationRoute of administrationIn-vitro / in-vivoImaging / non-imaging
F18-FDG (Fluorodeoxyglucose)Tumor imaging

Myocardial imaging

IVIn-vivoImaging
F18-Sodium FluorideBone imagingIVIn-vivoImaging
F18-FluorocholineProstate tumor imagingIVIn-vivoImaging
F18-DesmethoxyfallyprideDopamine receptor imagingIVIn-vivoImaging

Gallium-67

67Ga is a gamma emitter.

NameInvestigationRoute of administrationIn-vitro / in-vivoImaging / non-imaging
Ga67-Ga3+Tumor imagingIVIn-vivoImaging
Ga67-Ga3+Infection/inflammation imagingIVIn-vivoImaging

Gallium-68

68Ga is a positron emitter, with a 68-minute half-life, produced by elution from germanium-68 in a gallium-68 generator or by proton irradiation of zinc-68.

NameInvestigationRoute of administrationIn-vitro / in-vivoImaging / non-imaging
Ga68-Dotatoc or Dotatate Neuroendocrine tumor imagingIVIn-vivoImaging
Ga68-PSMAProstate cancer imagingIVIn-vivoImaging

Hydrogen-3

3H or tritium is a beta emitter.

NameInvestigationRoute of administrationIn-vitro / in-vivoImaging / non-imaging
H3-waterTotal body waterOral or IVIn-vitroNon-imaging

Indium-111

111In is a gamma emitter.

NameInvestigationRoute of administrationIn-vitro / in-vivoImaging / non-imaging
In111-DTPA (diethylenetriaminepenta-acetic acid)Ventriculo-peritoneal shunt (LaVeen Shunt)intraperitoneal injectionIn-vivoImaging the radioactive substance
In111-DTPA (diethylenetriaminepenta-acetic acid)CisternographyIntra-cisternalIn-vivoImaging
In111-Leukocytes Infection/inflammation imagingIVIn-vivoImaging
In111-Platelets Thrombus imagingIVIn-vivoImaging
In111-Pentetreotide Somatostatin receptor imagingIVIn-vivoImaging
In111-Octreotide Somatostatin receptor imaging (Octreoscan)IVIn-vivoImaging

Iodine-123

Iodine-123 (I-123) is a gamma emitter. It is used only diagnostically, as its radiation is penetrating and short-lived.

NameInvestigationRoute of administrationIn-vitro / in-vivoImaging / non-imaging
I123-Iodide Thyroid uptakeOral or IVIn-vivoNon-imaging
I123-IodideThyroid imaging

Thyroid metastases imaging

Oral or IVIn-vivoImaging
I123-o-IodohippurateRenal imagingIVIn-vivoImaging
I123-MIBG (m-iodobenzylguanidine)Neuroectodermal tumour imagingIVIn-vivoImaging
I123-FP-CITSPECT imaging of Parkinson's DiseaseIVIn-vivoImaging

Iodine-125

125I is a gamma emitter with a long half-life of 59.4 days (the longest of all radioiodines used in medicine). Iodine-123 is preferred for imaging, so I-125 is used diagnostically only when the test requires a longer period to prepare the radiopharmaceutical and trace it, such as a fibrinogen scan to diagnose clotting. I-125's gamma radiation is of medium penetration, making it more useful as a therapeutic isotope for brachytherapy implant of radioisotope capsules for local treatment of cancers.

NameInvestigationRoute of administrationIn-vitro / in-vivoImaging / non-imaging
I125-fibrinogenClot imagingIVIn-vivoImaging

Iodine-131

131I is a beta and gamma emitter. It is used both to destroy thyroid and thyroid cancer tissues (via beta radiation, which is short-range), and also other neuroendocrine tissues when used in MIBG. It can also be seen by a gamma camera, and can serve as a diagnostic imaging tracer, when treatment is also being attempted at the same time. However iodine-123 is usually preferred when only imaging is desired.

Diagnostic

NameInvestigationRoute of administrationIn-vitro / in-vivoImaging / non-imaging
I131-Iodide Thyroid uptakeOralIn-vivoNon-imaging
I131-IodideThyroid metastases imagingOral or IVIn-vivoImaging
I131-MIBG (m-iodobenzylguanidine)Neuroectodermal tumor imagingIVIn-vivoImaging

Therapeutic

NameTreatment ofRoute of administration
I131-Iodide Thyrotoxicosis IV or Oral
I131-IodideNon-toxic goiter IV or Oral
I131-Iodide Thyroid carcinoma IV or Oral
I131-MIBG (m-iodobenzylguanidine)Malignant diseaseIV

Iron-59

59Fe is a beta and gamma emitter.

NameInvestigationRoute of administrationIn-vitro / in-vivoImaging / non-imaging
Fe59-Fe2+ or Fe3+Iron metabolismIVIn-vitroNon-imaging

Krypton-81m

81Krm is a gamma emitter.

NameInvestigationRoute of administrationIn-vitro / in-vivoImaging / non-imaging the radioactive substance
Kr81m-GasLung ventilation imagingInhalationIn-vivoImaging
Kr-81m-Aqueous solutionLung perfusion imagingIVIn-vivoImaging

Lutetium-177

177Lu is a beta emitter.

NameTreatment ofRoute of administrationIn-vitro / in-vivo
177Lu-DOTA-TATE gastroenteropancreatic neuroendocrine tumors (GEP-NETs)IVIn-vivo

Nitrogen-13

13N is a positron emitter.

NameInvestigationRoute of administrationIn-vitro / in-vivoImaging / non-imaging
N13-Ammonia Myocardial blood flow imagingIVIn-vivoImaging

Oxygen-15

15O is a positron emitter.

NameInvestigationRoute of administrationIn-vitro / in-vivoImaging / non-imaging
O15-WaterCerebral blood flow imaging

Myocardial blood flow imaging

IV bolusIn-vivoImaging

Phosphorus-32

32P is a beta emitter.

NameTreatment ofRoute of administration
P32-Phosphate Polycythemia and related disordersIV or Oral

Radium-223

223Ra is an alpha emitter.

NameTreatment ofRoute of administration
Ra223 cation (223RaCl2) metastatic cancer in bone IV

Rubidium-82

82Rb is a positron and gamma emitter.

NameInvestigation ofRoute of administration
Rb-82 chloride Myocardial ImagingIV

Samarium-153

153Sm is a beta and gamma emitter.

NameTreatment ofRoute of administration
Sm153-EDTMP (Ethylenediaminotetramethylenephosphoric acid)Bone metastasesIV

Selenium-75

75Se is a gamma emitter.

NameInvestigationRoute of administrationIn-vitro / in-vivoImaging / non-imaging
Se75-Selenorcholesterol Adrenal gland imagingIVIn-vivoImaging
Se75-SeHCAT (23-Seleno-25-homo-tauro-cholate) Bile salt absorptionOralIn-vivoImaging

Sodium-22

22Na is a positron and gamma emitter.

NameInvestigationRoute of administrationIn-vitro / in-vivoImaging / non-imaging
Na22-Na+Electrolyte studiesOral or IVIn-vitroNon-imaging

Sodium-24

24Na is a beta and gamma emitter.

NameInvestigationRoute of administrationIn-vitro / in-vivoImaging / non-imaging
Na24-Na+Electrolyte studiesOral or IVIn-vitroNon-imaging

Strontium-89

89Sr is a beta emitter.

NameTreatment ofRoute of administration
Sr89-ChlorideBone metastasesIV

Technetium-99m

Technetium-99m is a gamma emitter. It is obtained on-site at the imaging center as the soluble pertechnetate which is eluted from a technetium-99m generator, and then either used directly as this soluble salt, or else used to synthesize a number of technetium-99m-based radiopharmaceuticals.

NameInvestigationRoute of administrationIn-vitro / in-vivoImaging / non-imaging
Tc99m-pertechnetate Thyroid uptake and thyroid imaging

Stomach and salivary gland imaging
Meckel's diverticulum imaging
Brain imaging
Micturating cystogram
First pass blood flow imaging
First pass peripheral vascular imaging

IVIn-vivoImaging
Tc99m-pertechnetateLacrimal imagingEye dropsIn-vivoImaging
Tc99m-Human albumin Cardiac blood pool imagingIVIn-vivoImaging
Tc99m-Human albuminPeripheral vascular imagingIVIn-vivoImaging
Tc99m-Human albumin macroaggregates or microspheresLung perfusion imagingIVIn-vivoImaging
Tc99m-Human albumin macroaggregates or microspheresLung perfusion imaging with venographyIVIn-vivoImaging
Tc99m-Phosphonates and phosphates (MDP/HDP)Bone imagingIVIn-vivoImaging
Tc99m-Phosphonates and phosphatesMyocardial imagingIVIn-vivoImaging
Tc99m-DTPA (diethylenetriaminepenta-acetic acid)Renal imaging
First pass blood flow studies
Brain imaging
IVIn-vivoImaging
Tc99m-DTPA (diethylenetriaminepenta-acetic acid)Lung ventilation imagingAerosol inhalationIn-vivoImaging
Tc99m-DMSA(V) (dimercaptosuccinic acid)Tumor imagingIVIn-vivoImaging
Tc99m-DMSA(III) (dimercaptosuccinic acid)Renal imagingIVIn-vivoImaging
Tc99m-ColloidBone marrow imaging

GI Bleeding

IVIn-vivoImaging
Tc99m-ColloidLymph node imagingInterstitialIn-vivoImaging
Tc99m-ColloidEsophageal transit and reflux imaging

Gastric emptying imaging

OralIn-vivoImaging
Tc99m-ColloidLacrimal imagingEye dropsIn-vivoImaging
Tc99m-HIDA (Hepatic iminodiacetic acid)Functional biliary system imagingIVIn-vivoImaging
Tc99m-Denatured (heat damaged) red blood cellsRed cell volume

Spleen imaging

IVIn-vitroNon-imaging
Tc99m-Whole red blood cellsGI bleeding

Cardiac blood pool imaging
Peripheral vascular imaging

IVIn-vivoImaging
Tc99m-MAG3 (mercaptoacetyltriglycine)Renal imaging

First pass blood flow imaging

IVIn-vivoImaging
Tc99m-Exametazime (HMPAO)Cerebral blood flow imagingIVIn-vivoImaging
Tc99m-Exametazime labelled leucocytesInfection/inflammation imagingIVIn-vivoImaging
Tc99m-Sestamibi (MIBI - methoxy isobutyl isonitrile) Parathyroid imaging

Non-specific tumor imaging
Thyroid tumor imaging
Breast imaging
Myocardial imaging

IVIn-vivoImaging
Tc99m-Sulesomab (IMMU-MN3 murine Fab'-SH antigranulocyte monoclonal antibody fragments)Infection/inflammation imagingIVIn-vivoImaging
Tc99m-TechnegasLung ventilation imagingInhalationIn-vivoImaging
Tc99m-Human immunoglobulinInfection/inflammation imagingIVIn-vivoImaging
Tc99m-TetrofosminParathyroid imaging

Myocardial imaging

IVIn-vivoImaging
Tc99m-ECD (ethyl cysteinate dimer)Brain imaging-----IVIn-vivoImaging

Thallium-201

201Tl is a gamma emitter.

NameInvestigationRoute of administrationIn-vitro / in-vivoImaging / non-imaging
Tl201-Tl+Non-specific tumor imaging

Thyroid tumor imaging
Myocardial imaging
Parathyroid imaging

IVIn-vivoImaging

Xenon-133

133Xe is a gamma emitter.

NameInvestigationRoute of administrationIn-vitro / in-vivoImaging / non-imaging
Xe133-gasLung ventilation studiesInhalationIn-vivoImaging
Xe133 in isotonic sodium chloride solutionCerebral blood flowIVIn-vivoImaging

Yttrium-90

90Y is a beta emitter.

NameTreatment ofRoute of administration
Y90-SilicateArthritic conditionsIntra-articular
Y90-SilicateMalignant diseaseIntracavitary

See also

Related Research Articles

<span class="mw-page-title-main">Positron emission tomography</span> Medical imaging technique

Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in metabolic processes, and in other physiological activities including blood flow, regional chemical composition, and absorption. Different tracers are used for various imaging purposes, depending on the target process within the body.

A synthetic radioisotope is a radionuclide that is not found in nature: no natural process or mechanism exists which produces it, or it is so unstable that it decays away in a very short period of time. Examples include technetium-95 and promethium-146. Many of these are found in, and harvested from, spent nuclear fuel assemblies. Some must be manufactured in particle accelerators.

Radionuclide therapy uses radioactive substances called radiopharmaceuticals to treat medical conditions, particularly cancer. These are introduced into the body by various means and localise to specific locations, organs or tissues depending on their properties and administration routes. This includes anything from a simple compound such as sodium iodide that locates to the thyroid via trapping the iodide ion, to complex biopharmaceuticals such as recombinant antibodies which are attached to radionuclides and seek out specific antigens on cell surfaces.

<span class="mw-page-title-main">Single-photon emission computed tomography</span> Nuclear medicine tomographic imaging technique

Single-photon emission computed tomography is a nuclear medicine tomographic imaging technique using gamma rays. It is very similar to conventional nuclear medicine planar imaging using a gamma camera, but is able to provide true 3D information. This information is typically presented as cross-sectional slices through the patient, but can be freely reformatted or manipulated as required.

<span class="mw-page-title-main">Nuclear medicine</span> Medical specialty

Nuclear medicine or nucleology is a medical specialty involving the application of radioactive substances in the diagnosis and treatment of disease. Nuclear imaging, in a sense, is "radiology done inside out" because it records radiation emitted from within the body rather than radiation that is transmitted through the body from external sources like X-ray generators. In addition, nuclear medicine scans differ from radiology, as the emphasis is not on imaging anatomy, but on the function. For such reason, it is called a physiological imaging modality. Single photon emission computed tomography (SPECT) and positron emission tomography (PET) scans are the two most common imaging modalities in nuclear medicine.

A radioactive tracer, radiotracer, or radioactive label is a chemical compound in which one or more atoms have been replaced by a radionuclide so by virtue of its radioactive decay it can be used to explore the mechanism of chemical reactions by tracing the path that the radioisotope follows from reactants to products. Radiolabeling or radiotracing is thus the radioactive form of isotopic labeling. In biological contexts, use of radioisotope tracers are sometimes called radioisotope feeding experiments.

<span class="mw-page-title-main">Scintigraphy</span> Diagnostic imaging test in nuclear medicine

Scintigraphy, also known as a gamma scan, is a diagnostic test in nuclear medicine, where radioisotopes attached to drugs that travel to a specific organ or tissue (radiopharmaceuticals) are taken internally and the emitted gamma radiation is captured by gamma cameras, which are external detectors that form two-dimensional images in a process similar to the capture of x-ray images. In contrast, SPECT and positron emission tomography (PET) form 3-dimensional images and are therefore classified as separate techniques from scintigraphy, although they also use gamma cameras to detect internal radiation. Scintigraphy is unlike a diagnostic X-ray where external radiation is passed through the body to form an image.

<span class="mw-page-title-main">Radiopharmacology</span> Pharmacologic study of radiated medical compounds

Radiopharmacology is radiochemistry applied to medicine and thus the pharmacology of radiopharmaceuticals. Radiopharmaceuticals are used in the field of nuclear medicine as radioactive tracers in medical imaging and in therapy for many diseases. Many radiopharmaceuticals use technetium-99m (Tc-99m) which has many useful properties as a gamma-emitting tracer nuclide. In the book Technetium a total of 31 different radiopharmaceuticals based on Tc-99m are listed for imaging and functional studies of the brain, myocardium, thyroid, lungs, liver, gallbladder, kidneys, skeleton, blood and tumors.

<span class="mw-page-title-main">Technetium-99m generator</span> A device used to extract the short-lived radioactive isotope Tc-99m from a longer-lived Mo-99 source

A technetium-99m generator, or colloquially a technetium cow or moly cow, is a device used to extract the metastable isotope 99mTc of technetium from a decaying sample of molybdenum-99. 99Mo has a half-life of 66 hours and can be easily transported over long distances to hospitals where its decay product technetium-99m is extracted and used for a variety of nuclear medicine diagnostic procedures, where its short half-life is very useful.

<span class="mw-page-title-main">Iodine-131</span> Isotope of iodine

Iodine-131 is an important radioisotope of iodine discovered by Glenn Seaborg and John Livingood in 1938 at the University of California, Berkeley. It has a radioactive decay half-life of about eight days. It is associated with nuclear energy, medical diagnostic and treatment procedures, and natural gas production. It also plays a major role as a radioactive isotope present in nuclear fission products, and was a significant contributor to the health hazards from open-air atomic bomb testing in the 1950s, and from the Chernobyl disaster, as well as being a large fraction of the contamination hazard in the first weeks in the Fukushima nuclear crisis. This is because 131I is a major fission product of uranium and plutonium, comprising nearly 3% of the total products of fission. See fission product yield for a comparison with other radioactive fission products. 131I is also a major fission product of uranium-233, produced from thorium.

<span class="mw-page-title-main">Pertechnetate</span> Chemical compound or ion

The pertechnetate ion is an oxyanion with the chemical formula TcO
4
. It is often used as a convenient water-soluble source of isotopes of the radioactive element technetium (Tc). In particular it is used to carry the 99mTc isotope which is commonly used in nuclear medicine in several nuclear scanning procedures.

<span class="mw-page-title-main">Isotopes of iodine</span> Nuclides with atomic number of 53 but with different mass numbers

There are 37 known isotopes of iodine (53I) from 108I to 144I; all undergo radioactive decay except 127I, which is stable. Iodine is thus a monoisotopic element.

<span class="mw-page-title-main">Sodium pertechnetate</span> Chemical compound

Sodium pertechnetate is the inorganic compound with the formula NaTcO4. This colourless salt contains the pertechnetate anion, TcO
4
that has slightly distorted tetrahedron symmetry both at 296 K and at 100 K while the coordination polyhedron of the sodium cation is different from typical for scheelite structure. The radioactive 99m
Tc
O
4
anion is an important radiopharmaceutical for diagnostic use. The advantages to 99m
Tc
include its short half-life of 6 hours and the low radiation exposure to the patient, which allow a patient to be injected with activities of more than 30 millicuries. Na[99m
Tc
O
4
]
is a precursor to a variety of derivatives that are used to image different parts of the body.

Iodine-125 (125I) is a radioisotope of iodine which has uses in biological assays, nuclear medicine imaging and in radiation therapy as brachytherapy to treat a number of conditions, including prostate cancer, uveal melanomas, and brain tumors. It is the second longest-lived radioisotope of iodine, after iodine-129.

Iodine-123 (123I) is a radioactive isotope of iodine used in nuclear medicine imaging, including single-photon emission computed tomography (SPECT) or SPECT/CT exams. The isotope's half-life is 13.2230 hours; the decay by electron capture to tellurium-123 emits gamma radiation with a predominant energy of 159 keV. In medical applications, the radiation is detected by a gamma camera. The isotope is typically applied as iodide-123, the anionic form.

<span class="mw-page-title-main">Radioactivity in the life sciences</span>

Radioactivity is generally used in life sciences for highly sensitive and direct measurements of biological phenomena, and for visualizing the location of biomolecules radiolabelled with a radioisotope.

<span class="mw-page-title-main">Technetium-99m</span> Metastable nuclear isomer of technetium-99

Technetium-99m (99mTc) is a metastable nuclear isomer of technetium-99, symbolized as 99mTc, that is used in tens of millions of medical diagnostic procedures annually, making it the most commonly used medical radioisotope in the world.

Nuclear medicine physicians, also called nuclear radiologists or simply nucleologists, are medical specialists that use tracers, usually radiopharmaceuticals, for diagnosis and therapy. Nuclear medicine procedures are the major clinical applications of molecular imaging and molecular therapy. In the United States, nuclear medicine physicians are certified by the American Board of Nuclear Medicine and the American Osteopathic Board of Nuclear Medicine.

Gallium (<sup>68</sup>Ga) gozetotide Radiopharmaceutical medication

Gallium (68Ga) gozetotide or Gallium (68Ga) PSMA-11 sold under the brand name Illuccix among others, is a radiopharmaceutical made of 68Ga conjugated to prostate-specific membrane antigen (PSMA) targeting ligand, Glu-Urea-Lys(Ahx)-HBED-CC, used for imaging prostate cancer by positron emission tomography (PET). The PSMA targeting ligand specifically directs the radiolabeled imaging agent towards the prostate cancerous lesions in men.

Theranostics, also known as theragnostics, is an emerging field in precision medicine that combines diagnostic and therapeutic approaches to provide the potential for personalized treatment and real-time monitoring of the effectiveness of treatments. Improvements in imaging techniques and targeted therapies are the basis of the field of theranostics. When medical imaging is coupled with the development of novel radiotracers and contrast agents, theranostics may provide opportunities for precise diagnosis and targeted therapy.

References

  1. Iverson (2007), "15.9.2 Radiopharmaceuticals", in Cheryl; et al. (eds.), AMA Manual of Style (10th ed.), Oxford, Oxfordshire: Oxford University Press, ISBN   978-0-19-517633-9.