This article is about the specific antibiotic called tetracycline. For other uses, see tetracycline antibiotics.
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This article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (January 2011) |
Tetracycline
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| Systematic (IUPAC) name |
(4S,6S,12aS)-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,6,10,12,12a-pentahydroxy-6-methyl-1,11-dioxonaphthacene-2-carboxamide
OR
(4S,6S,12aS)-4-(dimethylamino)-3,6,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide |
| Clinical data |
| Trade names |
Sumycin |
| AHFS/Drugs.com |
monograph |
| MedlinePlus |
a682098 |
| Licence data |
US FDA:link |
| Pregnancy cat. |
D (AU) D (US) |
| Legal status |
℞ Prescription only |
| Routes |
oral, topical (skin and eye), intramuscular, intravenous |
| Pharmacokinetic data |
| Bioavailability |
60-80% oral, while fasting
<40% intramuscular |
| Metabolism |
Not metabolised |
| Half-life |
6-11 hours |
| Excretion |
Fecal and renal |
| Identifiers |
| CAS number |
60-54-8 Y
64-75-5 (hydrochloride) |
| ATC code |
A01AB13 D06AA04 J01AA07 S01AA09 S02AA08 S03AA02 QG01AA90 QG51AA02 QJ51AA07 |
| PubChem |
CID 643969 |
| DrugBank |
DB00759 |
| ChemSpider |
10257122 Y |
| UNII |
F8VB5M810T Y |
| KEGG |
D00201 Y |
| ChEBI |
CHEBI:27902 Y |
| ChEMBL |
CHEMBL1440 Y |
| Chemical data |
| Formula |
C22H24N2O8 |
| Mol. mass |
444.435 g/mol |
SMILES
- C[C@]1(c2cccc(c2C(=O)C3=C([C@]4([C@@H](C[C@@H]31)[C@@H](C(=C(C4=O)C(=O)N)O)N(C)C)O)O)O)O
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InChI
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InChI=1S/C22H24N2O8/c1-21(31)8-5-4-6-11(25)12(8)16(26)13-9(21)7-10-15(24(2)3)17(27)14(20(23)30)19(29)22(10,32)18(13)28/h4-6,9-10,15,25,27-28,31-32H,7H2,1-3H3,(H2,23,30)/t9-,10-,15-,21+,22-/m0/s1 Y
Key:OFVLGDICTFRJMM-WESIUVDSSA-N Y
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Y (what is this?) (verify)
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Tetracycline (INN) ( /ˌtɛtrəˈsaɪkliːn/) is a broad-spectrum polyketide antibiotic produced by the Streptomyces genus of Actinobacteria, indicated for use against many bacterial infections. It is a protein synthesis inhibitor. It is commonly used to treat acne today, and, more recently, rosacea, and is historically important in reducing the number of deaths from cholera. Tetracycline is marketed under the brand names Sumycin, Tetracyn, and Panmycin, among others. Actisite is a thread-like fiber formulation used in dental applications. It is also used to produce several semisynthetic derivatives, which together are known as the tetracycline antibiotics. The term "tetracycline" is also used to denote the four-ring system of this compound; "tetracyclines" are related substances that contain the same four-ring system.
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Contents
- 1 Mechanism of action
- 2 Spectrum of bacterial susceptibility and resistance
- 3 History
- 4 Cautions, contraindications, side effects
- 5 Indications
- 6 Other uses
- 7 Cell culture
- 8 Notes
- 9 External links
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Mechanism of action
Tetracyclines bind to the 30S subunit of microbial ribosomes. They inhibit protein synthesis by blocking the attachment of charged aminoacyl-tRNA to the A site on the ribosome. Thus, they prevent introduction of new amino acids to the nascent peptide chain.[1] The action is usually inhibitory and reversible upon withdrawal of the drug. Resistance to the tetracyclines results from changes in permeability of the microbial cell envelope. In susceptible cells, the drug is concentrated from the environment and does not readily leave the cells. In resistant cells, the drug is not actively transported into the cells or leaves it so rapidly, inhibitory concentrations are not maintained. This is often plasmid-controlled. Mammalian cells are not vulnerable to the effect of tetracyclines, as these contain no 30S ribosomal subunits, so do not accumulate the drug.
Spectrum of bacterial susceptibility and resistance
Tetracyclines have a broad spectrum of antibiotic action. Originally, they possessed some level of bacteriostatic activity against almost all medically relevant aerobic and anaerobic bacterial genera, both Gram-positive and Gram-negative, with a few exceptions, such as Pseudomonas aeruginosa and Proteus spp., which display intrinsic resistance. However, acquired (as opposed to inherent) resistance has proliferated in many pathogenic organisms and greatly eroded the formerly vast versatility of this group of antibiotics. Resistance amongst Staphylococcus spp., Streptococcus spp., Neisseria gonorrhoeae, anaerobes, members of the Enterobacteriaceae and several other previously sensitive organisms is now quite common. Tetracyclines remain especially useful in the management of infections by certain obligately intracellular bacterial pathogens such as Chlamydia, Mycoplasma and Rickettsia. They are also of value in spirochaetal infections, such as syphilis, leptospirosis and Lyme disease. Certain rare or exotic infections, including anthrax, plague and brucellosis, are also susceptible to tetracyclines. These agents also have activity against certain eukaryotic parasites, including those responsible for diseases such as malaria and balantidiasis.
History
The tetracyclines, a large family of antibiotics, were discovered as natural products by Benjamin Minge Duggar in 1945 and first described in 1948.[2] Under Yellapragada Subbarao, Benjamin Duggar made his discovery of the first tetracycline antibiotic, chlortetracycline (Aureomycin), at Lederle Laboratories in 1945.[3]
In 1950, Harvard Professor Robert Woodward determined the chemical structure of the related substance, oxytetracycline (Terramycin); the patent protection for its fermentation and production was also first issued in 1950. A research team of seven scientists (K.J. Brunings, Francis A. Hochstein, C.R. Stephens, L.H. Conover, Abraham Bavley, Richard Pasternack, and Peter P. Regna) at Pfizer,[4][5] in collaboration with Woodward, participated in the two-year research leading to the discovery.[6]
Pfizer was of the view that it deserved the right to a patent on tetracycline and filed its Conover application in October 1952. Cyanamid filed its Boothe-Morton application for similar rights in March 1953, while Heyden Chemicals filed its Minieri application in September 1953, named after scientist P. Paul Minieri, to obtain a patent on tetracycline and its fermentation process. This resulted in tetracycline litigation in which the winner would have to prove beyond reasonable doubt of priority invention and tetracycline’s natural state.[7]
Nubian mummies studied in the 1990s were found to contain significant levels of tetracycline; the beer brewed at the time could have been the source.[8] Tetracycline sparked the development of many chemically altered antibiotics, so has proved to be one of the most important discoveries made in the field of antibiotics.[citation needed] It is used to treat many Gram-positive and Gram-negative bacteria.[citation needed] Like some other antibiotics, it is also used in the treatment of acne.[citation needed]
Cautions, contraindications, side effects
Use of the tetracycline antibiotics group is problematic; they can:[citation needed]
- Stain developing teeth (even when taken by the mother during pregnancy)
- Discolor permanent teeth (yellow-gray-brown), from infancy and childhood to eight years old
- Be inactivated by Ca2+ ion, so are not to be taken with milk, yogurt, and other dairy products
- Be inactivated by aluminium, iron and zinc, not to be taken at the same time as indigestion remedies (common antacids and over-the-counter heartburn medicines)
- Cause skin photosensitivity. so exposure to the sun or intense light is not recommended
- Cause drug-induced lupus, and hepatitis
- Cause microvesicular fatty liver
- Cause tinnitus
- Interfere with methotrexate by displacing it from the various protein binding sites
- Cause breathing complications, as well as anaphylactic shock, in some individuals
- Affect bone growth of the fetus, so should be avoided during pregnancy
Caution should be exercised in long-term use with breastfeeding. Short-term use is safe; bioavailability in milk is low to nil.[9] In 2010, the FDA added tetracycline to its Adverse Event Reporting System (AERS).[10] The AERS contains a list of medications under investigation by the FDA for potential safety issues. The list is published quarterly and available online. The AERS cites a potential link between the use of tetracycline products and Stevens–Johnson syndrome, toxic epidermal necrolysis and erythema multiforme.[10]
Indications
It is first-line therapy for Rocky Mountain spotted fever (Rickettsia), Lyme disease (B. burgdorferi), Q fever (Coxiella), psittacosis and lymphogranuloma venereum (Chlamydia), and to eradicate nasal carriage of meningococci. Tetracycline tablets were used in the plague outbreak in India in 1992.[11]
Other uses
Since tetracycline is absorbed into bone, it is used as a marker of bone growth for biopsies in humans. Tetracycline labeling is used to determine the amount of bone growth within a certain period of time, usually a period of approximately 21 days. Tetracycline is incorporated into mineralizing bone and can be detected by its fluorescence.[12] In "double tetracycline labeling", a second dose is given 11–14 days after the first dose, and the amount of bone formed during that interval can be calculated by measuring the distance between the two fluorescent labels.[13]
Tetracycline is also used as a biomarker in wildlife to detect consumption of medicine- or vaccine-containing baits.[14]
In genetic engineering, tetracycline is used in transcriptional activation. It is also one of the antibiotics used to treat ulcers caused by bacterial infections. In cancer research at Harvard Medical School, tetracycline has been used to switch off leukemia in genetically altered mice, and to do so reliably, when added to their drinking water.[15]
A technique being developed for the control of the mosquito species Aedes aegypti uses a genetically modified strain to require tetracycline to develop beyond the larval stage. Modified males raised in a laboratory will develop normally as they are supplied with this chemical and can be released into the wild. However, their subsequent offspring will find no tetracycline in their environment and will never develop into adults.[16]
Cell culture
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This section does not cite any references or sources. (January 2011) |
Tetracycline is used in cell biology as a selective agent in cell culture systems. It is toxic to prokaryotic and eukaryotic cells and selects for cells harboring the bacterial tetr gene, which encodes a 399-amino-acid, membrane-associated protein. This protein actively exports tetracycline from the cell, rendering cells harboring this gene more resistant to the drug. The yellow crystalline powder can be dissolved in water (20 mg/ml) or ethanol (5 mg/ml), and is routinely used at 10 mg/l in cell culture. In cell culture at 37°C (99°F), it is stable for days, with a half-life of approximately 24 hours.
Notes
- ^ Mehta, Akul (2011-05-27). "Mechanism of Action of Tetracyclines". Pharmaxchange.info. http://pharmaxchange.info/press/2011/05/mechanism-of-action-of-tetracyclines/. Retrieved 2012-06-07.
- ^ Klajn, Rafal, Chemistry and chemical biology of tetracyclines, retrieved 20 June 2007.
- ^ Jukes, Thomas H. Some historical notes on chlortetracycline. Reviews of Infectious Diseases 7(5):702-707 (1985).
- ^ "Coronagraph Mounts Done". The Science News 62 (6): 83. 1952. doi:10.2307/3931295. JSTOR 3931295.
- ^ "Scientists Discover Terramycin's Secret: Its Complex Structure". http://pqasb.pqarchiver.com/djreprints/access/107482962.html?dids=107482962:107482962&FMT=ABS&FMTS=ABS:AI&type=historic&date=Jul+28%2C+1952&author=&pub=Wall+Street+Journal&desc=Scientists+Discover+Terramycin's+Secret%3A+Its+Complex+Structure&pqatl=google.
- ^ Prior to 1952, neither the molecular structure of Terramycin nor that of Aureomycin was known. In the spring of 1952, the Pfizer team succeeded in ascertaining the structures of both Terramycin and Aureomycin. Shortly thereafter, L.H. Conover discovered that another antibiotic, tetracycline, could be produced by the deschlorination of Aureomycin. Pfizer filed the application for a product and process patent on tetracycline in October 1952, and in March 1953 Cyanamid filed its Boothe-Morton application for a similar patent. In addition to these two applications, in September 1953, Heyden Chemical Corporation filed for a patent on tetracycline and the fermentation process for producing it in the name of P. Paul Minieri, and in October 1953, Bristol filed a similar application under the name of Heinemann. Because of an agreement among the major drug companies to cross-license tetracyline, Fair Trade Practices litigation was initiated which was not resolved until 1982. The Federal Trade Commission argued that Pfizer, American Cyanamid (successor to Heyden), Bristol-Myers and others had conspired to fix prices for the new antibiotic. The FTC had argued because tetracycline was produced through fermentation, rather than synthetically, it was not patentable, and its distribution was subject to pricing fixing challenge. The FTC also argued tetracycline was not patentable because of its production through fermentation. Hochstein, F. A.; Stephens, C. R.; Conover, L. H.; Regna, P. P.; Pasternack, R.; Gordon, P. N.; Pilgrim, F. J.; Brunings, K. J. et al. (November 1953). "The structure of terramycin". Journal of the American Chemical Society 75 (22): 5455–75. doi:10.1021/ja01118a001.
- ^ Patented February 7, 1956
- ^ George Armelagos (May 2000). "Take Two Beers and Call Me in 1,600 Years - use of tetracycline by Nubians and Ancient Egyptians". American Museum of Natural History. http://www.findarticles.com/p/articles/mi_m1134/is_4_109/ai_62324477. Retrieved 2007-12-19.
- ^ Riordan,Jan."Breastfeeding & Human Lactation",Jones & Bartlett,2010 p.179
- ^ a b FDA Adverse Events Reporting System Retrieved on January 14, 2011
- ^ Lippincott's Illustrated Reviews: Pharmacology, 4th ed. Harvery RA, Champe, PC. Lippincott, Williams & Wilkins, 2009
- ^ Mayton CA. Tetracycline labeling of bone
- ^ The Johns Hopkins Medical Institutions. > Tetracycline Labeling Last updated January 8, 2001.
- ^ Olson CA, Mitchell KD, Werner PA (October 2000). "Bait ingestion by free-ranging raccoons and nontarget species in an oral rabies vaccine field trial in Florida". J. Wildl. Dis. 36 (4): 734–43. PMID 11085436. http://www.jwildlifedis.org/cgi/reprint/36/4/734.
- ^ William J. Cromie (February 10, 2000). "Researchers Switch Cancer Off and On -- In Mice". Harvard Gazette. http://news.harvard.edu/gazette/2000/02.10/leukemia.html. Retrieved 2008-10-25.
- ^ Conal Urquhart (15 July 2012). "Can GM mosquitoes rid the world of a major killer?". The Observer. http://www.guardian.co.uk/environment/2012/jul/15/gm-mosquitoes-dengue-fever-feature. Retrieved 2012-07-15.
External links
- Tetracycline bound to proteins in the PDB
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Stomatological preparations (A01)
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| Caries prophylactic agents |
- Dectaflur
- Olaflur
- Sodium fluoride
- Sodium monofluorophosphate
- Stannous fluoride
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| Anti-infectives and antiseptics |
- Amphotericin B
- Benzoxonium chloride
- Chlorhexidine
- Chlortetracycline
- Clotrimazole
- Domiphen bromide
- Doxycycline
- Eugenol
- Hexetidine
- Hydrogen peroxide
- Mepartricin
- Metronidazole
- Miconazole
- Minocycline
- Natamycin
- Neomycin
- Oxyquinoline
- Polynoxylin
- Sodium perborate
- Tetracycline
- Tibezonium iodide
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| Corticosteroids (Glucocorticoids) |
- Dexamethasone
- Hydrocortisone
- Triamcinolone
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| Other |
- Amlexanox
- Acetylsalicylic acid
- Becaplermin
- Benzydamine
- Epinephrine/Adrenalone
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noco/cofa(c)/cogi/tumr, sysi
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Antibiotics and chemotherapeutics for dermatological use (D06)
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| Antibiotics |
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Tetracycline and derivatives
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- Demeclocycline
- Chlortetracycline
- Oxytetracycline
- Tetracycline
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Others
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- Amphenicol: Chloramphenicol
- Aminoglycosides: Neomycin
- Gentamicin
- Amikacin
- Streptogramin: Virginiamycin
- other: Fusidic acid
- Bacitracin
- Tyrothricin
- Mupirocin
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| Chemotherapeutics |
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Sulfonamides
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- Silver sulfadiazine
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Antivirals
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Docosanol
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Other
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noco(i/b/d/q/u/r/p/m/k/v/f)/cong/tumr(n/e/d), sysi/epon
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proc, drug (D2/3/4/5/8/11)
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Acne-treating agents (D10)
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| Antibacterial |
- Azelaic acid
- Benzoyl peroxide#
- Hydroxyquinoline
- Blue light therapy
- Tea tree oil
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| Keratolytic |
- Glycolic acid
- Salicylic acid#
- Sulfur
- Benzoyl peroxide#
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| Anti-inflammatory |
- Nicotinamide
- Ibuprofen
- Aspirin
- Red light therapy
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| Antibiotics |
- Clindamycin
- Dapsone
- Erythromycin
- Sulfacetamide
- Tetracyclines (Lymecycline
- Minocycline
- Doxycycline)
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| Hormonal |
- Antiandrogens
- Contraceptives
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| Retinoids |
- Adapalene
- Isotretinoin
- Motretinide
- Tazarotene
- Tretinoin
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| Other |
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| Combinations |
- Adapalene/benzoyl peroxide
- Benzoyl peroxide/clindamycin
- Clindamycin/tretinoin
- Erythromycin/isotretinoin
- Sulfacetamide/sulfur
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- #WHO-EM
- ‡Withdrawn from market
- Clinical trials:
- †Phase III
- §Never to phase III
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noco/cong/tumr, sysi/epon
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Antibacterials: protein synthesis inhibitors (J01A, J01B, J01F, J01G, QJ01XQ)
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| 30S |
Aminoglycosides
(initiation inhibitors) |
| -mycin (Streptomyces) |
- Streptomycin#
- Dihydrostreptomycin
- Neomycin#
- Framycetin
- Paromomycin
- Ribostamycin
- Kanamycin#
- Amikacin
- Arbekacin
- Bekanamycin
- Dibekacin
- Tobramycin
- Spectinomycin#
- Hygromycin B
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| -micin (Micromonospora) |
- Gentamicin#
- Netilmicin
- Sisomicin
- Isepamicin
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Tetracycline antibiotics
(tRNA binding) |
| Tetracyclines |
- Doxycycline#
- Chlortetracycline
- Clomocycline
- Demeclocycline
- Lymecycline
- Meclocycline
- Metacycline
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- Oxytetracycline
- Penimepicycline
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| Glycylcyclines |
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| 50S |
Oxazolidinone
(initiation inhibitors) |
- Linezolid
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| Lincosamides |
- Clindamycin#
- Lincomycin
- Pirlimycin
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| Streptogramins |
- Pristinamycin
- Quinupristin/dalfopristin
- Virginiamycin
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| EF-G |
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- #WHO-EM
- ‡Withdrawn from market
- Clinical trials:
- †Phase III
- §Never to phase III
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gr+f/gr+a(t)/gr-p(c)/gr-o
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Otologicals (S02)
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| Anti-infectives |
- Acetic acid
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- Rifamycin
- Tetracycline
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| Corticosteroids |
- Betamethasone
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- Hydrocortisone
- Prednisolone
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| Analgesics and anesthetics |
- Lidocaine
- Cocaine
- Phenazone
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