Tetracycline

Last updated
Tetracycline
Tetracycline skeletal.svg
Clinical data
Pronunciation /ˌtɛtrəˈskln/
Trade names Sumycin, others
AHFS/Drugs.com Monograph
MedlinePlus a682098
License data
Pregnancy
category
  • AU: D
  • US: D (Evidence of risk)
    Routes of
    administration
    By mouth
    ATC code
    Legal status
    Legal status
    • In general: ℞ (Prescription only)
    Pharmacokinetic data
    Bioavailability 80%
    Metabolism Not metabolized
    Elimination half-life 8–11 hours, 57–108 hours (kidney impairment)
    Excretion Urine (>60%), feces
    Identifiers
    CAS Number
    PubChem CID
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    PDB ligand
    ECHA InfoCard 100.000.438 Blue pencil.svg
    Chemical and physical data
    Formula C22H24N2O8
    Molar mass 444.435 g/mol g·mol−1
    3D model (JSmol)
       (verify)

    Tetracycline, sold under the brand name Sumycin among others, is an antibiotic used to treat a number of infections. [1] This includes acne, cholera, brucellosis, plague, malaria, and syphilis. [1] It is taken by mouth. [1]

    Antibiotic drug used in the treatment and prevention of bacterial infections

    An antibiotic is a type of antimicrobial substance active against bacteria and is the most important type of antibacterial agent for fighting bacterial infections. Antibiotic medications are widely used in the treatment and prevention of such infections. They may either kill or inhibit the growth of bacteria. A limited number of antibiotics also possess antiprotozoal activity. Antibiotics are not effective against viruses such as the common cold or influenza; drugs which inhibit viruses are termed antiviral drugs or antivirals rather than antibiotics.

    Cholera Bacterial infection of the small intestine

    Cholera is an infection of the small intestine by some strains of the bacterium Vibrio cholerae. Symptoms may range from none, to mild, to severe. The classic symptom is large amounts of watery diarrhea that lasts a few days. Vomiting and muscle cramps may also occur. Diarrhea can be so severe that it leads within hours to severe dehydration and electrolyte imbalance. This may result in sunken eyes, cold skin, decreased skin elasticity, and wrinkling of the hands and feet. Dehydration can cause the skin to turn bluish. Symptoms start two hours to five days after exposure.

    Brucellosis Human disease

    Brucellosis is a highly contagious zoonosis caused by ingestion of unpasteurized milk or undercooked meat from infected animals, or close contact with their secretions. It is also known as undulant fever, Malta fever, and Mediterranean fever.

    Contents

    Common side effects include vomiting, diarrhea, rash, and loss of appetite. [1] Other side effects include poor tooth development if used by children less than eight years of age, kidney problems, and sunburning easily. [1] Use during pregnancy may harm the baby. [1] Tetracycline is in the tetracyclines family of medications. [1] It works by blocking the ability of bacteria to make proteins. [1]

    Diarrhea Loose or liquid bowel movements

    Diarrhea is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin with loss of the normal stretchiness of the skin and irritable behaviour. This can progress to decreased urination, loss of skin color, a fast heart rate, and a decrease in responsiveness as it becomes more severe. Loose but non-watery stools in babies who are exclusively breastfed, however, are normal.

    Tooth hard, calcified structure found in the jaws (or mouths) of many vertebrates and used to break down food

    A tooth is a hard, calcified structure found in the jaws of many vertebrates and used to break down food. Some animals, particularly carnivores, also use teeth for hunting or for defensive purposes. The roots of teeth are covered by gums. Teeth are not made of bone, but rather of multiple tissues of varying density and hardness. The cellular tissues that ultimately become teeth originate from the embryonic germ layer, the ectoderm.

    Sunburn burning of the skin by the suns radiation

    Sunburn is a form of radiation burn that affects living tissue, such as skin, that results from an overexposure to ultraviolet (UV) radiation, commonly from the sun. Common symptoms in humans and other animals include red or reddish skin that is hot to the touch, pain, general fatigue, and mild dizziness. An excess of UV radiation can be life-threatening in extreme cases. Excessive UV radiation is the leading cause of primarily non-malignant skin tumors.

    Tetracycline was patented in 1953 and came into commercial use in 1978. [2] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. [3] Tetracycline is available as a generic medication. [1] The wholesale cost in the developing world is about 0.35 to 1.78 USD for a course of treatment. [4] In the United States a course of treatment typically costs less than 25 USD. [5] Tetracycline was originally made from bacteria of the Streptomyces type. [1]

    A health system, also sometimes referred to as health care system or as healthcare system, is the organization of people, institutions, and resources that deliver health care services to meet the health needs of target populations.

    United States dollar Currency of the United States of America

    The United States dollar is the official currency of the United States and its territories per the United States Constitution since 1792. In practice, the dollar is divided into 100 smaller cent (¢) units, but is occasionally divided into 1000 mills (₥) for accounting. The circulating paper money consists of Federal Reserve Notes that are denominated in United States dollars.

    <i>Streptomyces</i> genus of Actinobacteria

    Streptomyces is the largest genus of Actinobacteria and the type genus of the family Streptomycetaceae. Over 500 species of Streptomyces bacteria have been described. As with the other Actinobacteria, streptomycetes are gram-positive, and have genomes with high GC content. Found predominantly in soil and decaying vegetation, most streptomycetes produce spores, and are noted for their distinct "earthy" odor that results from production of a volatile metabolite, geosmin.

    Medical uses

    It is first-line therapy for Rocky Mountain spotted fever (Rickettsia), Lyme disease (B. burgdorferi), Q fever (Coxiella), psittacosis, and Mycoplasma pneumoniae and to eradicate nasal carriage of meningococci. Tetracycline tablets were used in the plague outbreak in India in 1994. [6]

    Rocky Mountain spotted fever human disease

    Rocky Mountain spotted fever (RMSF) is a bacterial disease spread by ticks. It typically begins with a fever and headache, which is followed a few days later with the development of a rash. The rash is generally made up of small spots of bleeding and starts on the wrists and ankles. Other symptoms may include muscle pains and vomiting. Long-term complications following recovery may include hearing loss or loss of part of an arm or leg.

    Lyme disease infectious disease caused by Borrelia bacteria, spread by ticks

    Lyme disease, also known as Lyme borreliosis, is an infectious disease caused by a bacterium named Borrelia spread by ticks. The most common sign of infection is an expanding area of redness on the skin, known as erythema migrans, that appears at the site of the tick bite about a week after it occurred. The rash is typically neither itchy nor painful. Approximately 70–80% of infected people develop a rash. Other early symptoms may include fever, headache and tiredness. If untreated, symptoms may include loss of the ability to move one or both sides of the face, joint pains, severe headaches with neck stiffness, or heart palpitations, among others. Months to years later, repeated episodes of joint pain and swelling may occur. Occasionally, people develop shooting pains or tingling in their arms and legs. Despite appropriate treatment, about 10 to 20% of people develop joint pains, memory problems, and tiredness for at least six months.

    Q fever disease caused by infection with Coxiella burnetii, a bacterium that affects humans and other animals; the most common manifestation is flu-like symptoms; the name Q stands for “query”, so named when the pathogen was unknown

    Q fever is a disease caused by infection with Coxiella burnetii, a bacterium that affects humans and other animals. This organism is uncommon, but may be found in cattle, sheep, goats, and other domestic mammals, including cats and dogs. The infection results from inhalation of a spore-like small-cell variant, and from contact with the milk, urine, feces, vaginal mucus, or semen of infected animals. Rarely, the disease is tick-borne. The incubation period is 9–40 days. Humans are vulnerable to Q fever, and infection can result from even a few organisms. The bacterium is an obligate intracellular pathogenic parasite.

    Spectrum of bacterial susceptibility

    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. The following represents MIC susceptibility data for a few medically significant microorganisms:

    Gram-positive bacteria bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their cell wall

    Gram-positive bacteria are bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their cell wall.

    Gram-negative bacteria group of bacteria that do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation

    Gram-negative bacteria are bacteria that do not retain the crystal violet stain used in the gram-staining method of bacterial differentiation. They are characterized by their cell envelopes, which are composed of a thin peptidoglycan cell wall sandwiched between an inner cytoplasmic cell membrane and a bacterial outer membrane.

    <i>Pseudomonas aeruginosa</i> common bacterium

    Pseudomonas aeruginosa is a common encapsulated, Gram-negative, rod-shaped bacterium that can cause disease in plants and animals, including humans. A species of considerable medical importance, P. aeruginosa is a multidrug resistant pathogen recognized for its ubiquity, its intrinsically advanced antibiotic resistance mechanisms, and its association with serious illnesses – hospital-acquired infections such as ventilator-associated pneumonia and various sepsis syndromes.

    <i>Escherichia coli</i> species of Gram-negative, rod-shaped bacterium

    Escherichia coli, also known as E. coli, is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus Escherichia that is commonly found in the lower intestine of warm-blooded organisms (endotherms). Most E. coli strains are harmless, but some serotypes can cause serious food poisoning in their hosts, and are occasionally responsible for product recalls due to food contamination. The harmless strains are part of the normal microbiota of the gut, and can benefit their hosts by producing vitamin K2, and preventing colonization of the intestine with pathogenic bacteria, having a symbiotic relationship. E. coli is expelled into the environment within fecal matter. The bacterium grows massively in fresh fecal matter under aerobic conditions for 3 days, but its numbers decline slowly afterwards.

    <i>Shigella</i> genus of bacteria

    Shigella is a genus of Gram-negative, facultative aerobic, non-spore-forming, nonmotile, rod-shaped bacteria genetically closely related to E. coli. The genus is named after Kiyoshi Shiga, who first discovered it in 1897.

    Mechanisms of resistance

    Bacteria usually acquire resistance to tetracycline from horizontal transfer of a gene that either encodes an efflux pump or a ribosomal protection protein. Efflux pumps actively eject tetracycline from the cell, preventing the buildup of an inhibitory concentration of tetracycline in the cytoplasm. [8] Ribosomal protection proteins interact with the ribosome and dislodge tetracycline from the ribosome, allowing for translation to continue. [9]

    Precautions

    Use of the tetracycline antibiotics group can: [10]

    Caution should be exercised in long-term use when breastfeeding. Short-term use is safe; bioavailability in milk is low to nil. [11] According to the U.S. Food and Drug Administration (FDA), cases of Stevens–Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme associated with doxycyline use have been reported, but a causative role has not been established. [12]

    Other uses

    Tetracycline hydrochloride is available as yellow crystalline powder. Tetracycline-HCl substance photo.jpg
    Tetracycline hydrochloride is available as yellow crystalline powder.

    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 around 21 days. Tetracycline is incorporated into mineralizing bone and can be detected by its fluorescence. [13] 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. [14]

    Tetracycline is also used as a biomarker in wildlife to detect consumption of medicine- or vaccine-containing baits. [15]

    In genetic engineering, tetracycline is used in transcriptional activation. It is also one of a group of antibiotics which together may be used to treat peptic ulcers caused by bacterial infections. The mechanism of action for the antibacterial effect of tetracyclines relies on disrupting protein translation in bacteria, thereby damaging the ability of microbes to grow and repair; however, protein translation is also disrupted in eukaryotic mitochondria leading to effects that may confound experimental results. [16] [17]

    Tetracycline has been used as an engineered "control switch" in chronic myelogenous leukemia models in mice. Engineers were able to develop a retrovirus that induced a particular type of leukemia in mice, and could then "switch" the cancer on and off through tetracycline administration. This could be used to grow the cancer in mice and then halt it at a particular stage to allow for further experimentation or study. [18]

    A technique being developed for the control of the mosquito species Aedes aegypti uses a strain that is genetically modified to require tetracycline to develop beyond the larval stage. Modified males raised in a laboratory develop normally as they are supplied with this chemical and can be released into the wild. Their subsequent offspring inherit this trait, but find no tetracycline in their environments, so never develop into adults. [19]

    Mechanism of action

    Tetracycline inhibits protein synthesis by blocking the attachment of charged aminoacyl-tRNA to the A site on the ribosome. Tetracycline binds to the 30S subunit of microbial ribosomes. Thus, it prevents introduction of new amino acids to the nascent peptide chain. [20] The action is usually inhibitory and reversible upon withdrawal of the drug. Mammalian cells are less vulnerable to the effect of tetracyclines, despite the fact that tetracycline binds to the small ribosomal subunit of both prokaryotes and eukaryotes (30S and 40S, respectively). This is because bacteria actively pump tetracycline into their cytoplasm, even against a concentration gradient, whereas mammalian cells do not. This accounts for the relatively small off-site effect of tetracycline on human cells. [21]

    History

    The tetracyclines, a large family of antibiotics, were discovered by Benjamin Minge Duggar in 1945 as natural products, and first prescribed in 1948. [22] Benjamin Duggar, working under Yellapragada Subbarow at Lederle Laboratories, discovered the first tetracycline antibiotic, chlortetracycline (Aureomycin), in 1945. [23]

    In 1950, Harvard University professor R.B. Woodward determined the chemical structure of the related substance, oxytetracycline (Terramycin); [24] the patent protection for its fermentation and production was also first issued in that year. [25] Chemist Lloyd Conover, in a research team of eight scientists at Pfizer, collaborated with Woodward over a two-year period, leading to tetracycline's discovery. [26] [27] [28]

    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. [29] [ full citation needed ][ non-primary source needed ] This resulted in tetracycline litigation in which the winner would have to prove beyond reasonable doubt of priority invention and tetracycline's natural state.[ clarification needed ][ needs update ] [30]

    Evidence in antiquity

    Nubian mummies studied in the 1990s were found to contain significant levels of tetracycline; the beer brewed at the time was conjectured to have been the source. [31]

    Society and culture

    Price

    According to data from EvaluatePharma and published in the Boston Globe , the price of tetracycline rose from $0.06 per 250-mg pill in 2013 to $4.06 a pill in 2015. [32] The Globe described the "big price hikes of some generic drugs" as a "relatively new phenomenon" which has left most pharmacists "grappling" with large upswings" in the "costs of generics, with 'overnight' price changes sometimes exceeding 1,000%." [32]

    Names

    It 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.

    Related Research Articles

    Erythromycin chemical compound

    Erythromycin is an antibiotic used for the treatment of a number of bacterial infections. This includes respiratory tract infections, skin infections, chlamydia infections, pelvic inflammatory disease, and syphilis. It may also be used during pregnancy to prevent Group B streptococcal infection in the newborn, as well as to improve delayed stomach emptying. It can be given intravenously and by mouth. An eye ointment is routinely recommended after delivery to prevent eye infections in the newborn.

    Streptomycin An antibiotic effective against various gram-positive and gram-negative bacteria

    Streptomycin is an antibiotic used to treat a number of bacterial infections. This includes tuberculosis, Mycobacterium avium complex, endocarditis, brucellosis, Burkholderia infection, plague, tularemia, and rat bite fever. For active tuberculosis it is often given together with isoniazid, rifampicin, and pyrazinamide. It is given by injection into a vein or muscle.

    Gentamicin chemical compound

    Gentamicin, sold under brand name Garamycin among others, is an antibiotic used to treat several types of bacterial infections. This may include bone infections, endocarditis, pelvic inflammatory disease, meningitis, pneumonia, urinary tract infections, and sepsis among others. It is not effective for gonorrhea or chlamydia infections. It can be given intravenously, by injection into a muscle, or topically. Topical formulations may be used in burns or for infections of the outside of the eye. In the developed world, it is often only used for two days until bacterial cultures determine what specific antibiotics the infection is sensitive to. The dose required should be monitored by blood testing.

    Oxytetracycline second of the broad-spectrum tetracycline group of antibiotics to be discovered

    Oxytetracycline was the second of the broad-spectrum tetracycline group of antibiotics to be discovered.

    Aminoglycoside molecule or a portion of a molecule composed of amino-modified sugars

    Aminoglycoside is a medicinal and bacteriologic category of traditional Gram-negative antibacterial medications that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside (sugar). The term can also refer more generally to any organic molecule that contains amino sugar substructures. Aminoglycoside antibiotics display bactericidal activity against Gram-negative aerobes and some anaerobic bacilli where resistance has not yet arisen but generally not against Gram-positive and anaerobic Gram-negative bacteria.

    Clindamycin chemical compound

    Clindamycin is an antibiotic useful for the treatment of a number of bacterial infections. This includes middle ear infections, bone or joint infections, pelvic inflammatory disease, strep throat, pneumonia, and endocarditis among others. It can be useful against some cases of methicillin-resistant Staphylococcus aureus (MRSA). It may also be used for acne and in addition to quinine for malaria. It is available by mouth, intravenously, and as a cream to be applied to the skin or in the vagina.

    Doxycycline chemical compound

    Doxycycline is an antibiotic that is used in the treatment of infections caused by bacteria and certain other parasites. It is useful for bacterial pneumonia, acne, chlamydia infections, early Lyme disease, cholera and syphilis. It is also useful for the treatment of malaria when used with quinine and for the prevention of malaria. Doxycycline can be used either by mouth or intravenously.

    Bacitracin mixture of related cyclic peptides

    Bacitracin is a mixture of related cyclic peptides produced by organisms of the licheniformis group of Bacillus subtilisvar Tracy, first isolated in 1945. These peptides disrupt Gram-positive bacteria by interfering with cell wall and peptidoglycan synthesis.

    Cycloheximide chemical compound

    Cycloheximide is a eukaryote protein synthesis inhibitor, produced by the bacterium Streptomyces griseus. Cycloheximide exerts its effect by interfering with the translocation step in protein synthesis, thus blocking translational elongation. Cycloheximide is widely used in biomedical research to inhibit protein synthesis in eukaryotic cells studied in vitro. It is inexpensive and works rapidly. Its effects are rapidly reversed by simply removing it from the culture medium.

    Kanamycin A chemical compound

    Kanamycin A, often referred to simply as kanamycin, is an antibiotic used to treat severe bacterial infections and tuberculosis. It is not a first line treatment. It is used by mouth, injection into a vein, or injection into a muscle. Kanamycin is recommended for short-term use only, usually from 7 to 10 days. As with most antibiotics, it is ineffective in viral infections.

    Tigecycline chemical compound

    Tigecycline is an antibiotic for a number of bacterial infections. It is a glycylcycline administered intravenously. It was developed in response to the growing rate of antibiotic resistant bacteria such as Staphylococcus aureus, Acinetobacter baumannii, and E. coli. As a tetracycline derivative antibiotic, its structural modifications has expanded its therapeutic activity to include Gram-positive and Gram-negative organisms, including those of multi-drug resistance.

    Tobramycin chemical compound

    Tobramycin is an aminoglycoside antibiotic derived from Streptomyces tenebrarius that is used to treat various types of bacterial infections, particularly Gram-negative infections. It is especially effective against species of Pseudomonas.

    Glycylcyclines are a class of antibiotics derived from tetracycline. These tetracycline analogues are specifically designed to overcome two common mechanisms of tetracycline resistance, namely resistance mediated by acquired efflux pumps and/or ribosomal protection. Presently, tigecycline is the only glycylcycline approved for antibiotic use.

    Dicloxacillin chemical compound

    Dicloxacillin is a narrow-spectrum β-lactam antibiotic of the penicillin class. It is used to treat infections caused by susceptible (non-resistant) Gram-positive bacteria. It is active against beta-lactamase-producing organisms such as Staphylococcus aureus, which would otherwise be resistant to most penicillins. Dicloxacillin is available under a variety of trade names including Diclocil (BMS).

    Tetracycline antibiotics type of broad-spectrum antibiotic

    Tetracyclines are a group of broad-spectrum antibiotic compounds that have a common basic structure and are either isolated directly from several species of Streptomyces bacteria or produced semi-synthetically from those isolated compounds. Tetracycline molecules comprise a linear fused tetracyclic nucleus to which a variety of functional groups are attached. Tetracyclines are named for their four ("tetra-") hydrocarbon rings ("-cycl-") derivation ("-ine"). They are defined as a subclass of polyketides, having an octahydrotetracene-2-carboxamide skeleton and are known as derivatives of polycyclic naphthacene carboxamide. While all tetracyclines have a common structure, they differ from each other by the presence of chloride, methyl, and hydroxyl groups. These modifications do not change their broad antibacterial activity, but do affect pharmacological properties such as half-life and binding to proteins in serum.

    Lloyd Hillyard Conover was an American chemist and the inventor of tetracycline. For this invention, he was inducted into the National Inventors Hall of Fame. Conover was the first to make an antibiotic by chemically modifying a naturally produced drug. He had close to 300 patents to his name.

    Oleandomycin chemical compound

    Oleandomycin is a macrolide antibiotic. It is synthesized from strains of Streptomyces antibioticus. It is weaker than erythromycin.

    Protein synthesis inhibitor compounds which inhibit the synthesis of proteins. They are usually anti-bacterial agents or toxins

    A protein synthesis inhibitor is a substance that stops or slows the growth or proliferation of cells by disrupting the processes that lead directly to the generation of new proteins.

    The discovery of tetracycline engendered an enormous amount of litigation. In late 1958, the U.S. government charged Pfizer and American Cyanamid with price fixing in connection with tetracycline. That and other related litigation lasted until 1982. Often, the series of cases is referred to as the “antibiotics litigation.”

    Carbomycin chemical compound

    Carbomycin, also known as magnamycin, is a colorless, optically active crystalline macrolide antibiotic with the molecular formula C42H67NO16. It is derived from the bacterium Streptomyces halstedii and active in inhibiting the growth of Gram-positive bacteria and "certain Mycoplasma strains." Its structure was first proposed by Robert Woodward in 1957 and was subsequently corrected in 1965.

    References

    1. 1 2 3 4 5 6 7 8 9 10 "Tetracycline". The American Society of Health-System Pharmacists. Archived from the original on 28 December 2016. Retrieved 8 December 2016.
    2. Fischer, Janos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 489. ISBN   9783527607495. Archived from the original on 2016-12-20.
    3. "WHO Model List of Essential Medicines (19th List)" (PDF). World Health Organization. April 2015. Archived (PDF) from the original on 13 December 2016. Retrieved 8 December 2016.
    4. "Tetracycline HCL". International Drug Price Indicator Guide. Archived from the original on 10 May 2017. Retrieved 8 December 2016.
    5. Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 107. ISBN   9781284057560.
    6. Lippincott's Illustrated Reviews: Pharmacology, 4th ed. Harvery RA, Champe, PC. Lippincott, Williams & Wilkins, 2009
    7. http://www.toku-e.com/Assets/MIC/Tetracycline%20hydrochloride.pdf
    8. Chopra I, Roberts M; Roberts (June 2001). "Tetracycline Antibiotics: Mode of Action, Applications, Molecular Biology, and Epidemiology of Bacterial Resistance". Microbiol. Mol. Biol. Rev. 65 (2): 232–260. doi:10.1128/MMBR.65.2.232-260.2001. PMC   99026 . PMID   11381101.
    9. Connell SR, Tracz DM, Nierhaus KH, Taylor DE (December 2003). "Ribosomal Protection Proteins and Their Mechanism of Tetracycline Resistance". Antimicrob. Agents Chemother. 47 (12): 3675–3681. doi:10.1128/AAC.47.12.3675-3681.2003. PMC   296194 . PMID   14638464.
    10. "Tetracycline: MedlinePlus Drug Information". medlineplus.gov. Archived from the original on 2017-05-10. Retrieved 2017-05-19.
    11. Riordan, Jan."Breastfeeding & Human Lactation", Jones & Bartlett,2010 p.179
    12. FDA Adverse Events Reporting System Archived 2011-01-17 at the Wayback Machine Retrieved on January 14, 2011
    13. Mayton CA. Tetracycline labeling of bone Archived 2007-03-12 at the Wayback Machine
    14. The Johns Hopkins Medical Institutions. > Tetracycline Labeling Archived 2012-12-15 at Archive.today Last updated January 8, 2001.
    15. 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. doi:10.7589/0090-3558-36.4.734. PMID   11085436. Archived from the original on 2013-04-15.
    16. Moullan N, Mouchiroud L, Wang X, Ryu D, Williams EG, Mottis A, Jovaisaite V, Frochaux MV, Quiros PM, Deplancke B, Houtkooper RH, Auwerx J (2015). "Tetracyclines Disturb Mitochondrial Function across Eukaryotic Models: A Call for Caution in Biomedical Research". Cell Reports. 10 (10): 1681–91. doi:10.1016/j.celrep.2015.02.034. PMC   4565776 . PMID   25772356.
    17. Chatzispyrou IA, Held NM, Mouchiroud L, Auwerx J, Houtkooper RH (2015). "Tetracycline antibiotics impair mitochondrial function and its experimental use confounds research". Cancer Research. 75 (21): 4446–9. doi:10.1158/0008-5472.CAN-15-1626. PMC   4631686 . PMID   26475870.
    18. A Dugray, JF Geay, A Foudi, ML Bonnet, W Vainchenker, F Wendling, F Louache & AG Turhan. "Rapid generation of a tetracycline-inducible BCR-ABL defective retrovirus using a single autoregulatory retroviral cassette".CS1 maint: Multiple names: authors list (link)
    19. Conal Urquhart (15 July 2012). "Can GM mosquitoes rid the world of a major killer?". The Observer. Archived from the original on 5 December 2013. Retrieved 2012-07-15.
    20. Mehta, Akul (2011-05-27). "Mechanism of Action of Tetracyclines". Pharmaxchange.info. Archived from the original on 2012-06-05. Retrieved 2012-06-07.
    21. Kenneth Todar, Antimicrobial Agents in the Treatment of Infectious Disease. Online Textbook of Bacteriology. 2012. "Archived copy". Archived from the original on 2013-10-08. Retrieved 2013-08-27.CS1 maint: Archived copy as title (link)
    22. Klajn, Rafal, Chemistry and chemical biology of tetracyclines Archived 2007-06-17 at the Wayback Machine , retrieved 20 June 2007.[ better source needed ]
    23. Jukes, Thomas H. (1985). "Some Historical Notes on Chlortetracycline". Reviews of Infectious Diseases. 7 (5, Sep.–Oct): 702–707. doi:10.1093/clinids/7.5.702. JSTOR   4453725.
    24. Hochstein, F. A.; Stephens, C. R.; Conover, L. H.; Regna, P. P.; Pasternack, R.; Gordon, P. N.; Pilgrim, F. J.; Brunings, K. J.; Woodward, R. B. (November 1953). "The structure of terramycin". Journal of the American Chemical Society . 75 (22): 5455–75. doi:10.1021/ja01118a001.[ non-primary source needed ]
    25. https://patents.google.com/patent/US2516080A/en
    26. The team included K.J. Brunings, Francis A. Hochstein, Frederick J. Pilgrim, C.R. Stephens, Lloyd Conover, Abraham Bavley, Richard Pasternack, and Peter P. Regna.[ citation needed ]
    27. TSNL Staff (August 9, 1952). "Coronagraph Mounts Done". The Science News-Letter. 62 (6): 83. doi:10.2307/3931295. JSTOR   3931295.
    28. WSJ Staff (July 28, 1952). "Scientists Discover Terramycin's Secret: Its Complex Structure". The Wall Street Journal. Archived from the original on March 14, 2017. Retrieved March 13, 2017. (Subscription required (help)). [Quote:] Laboratory Work May Lead to Manufacture of Non-Toxic Antibiotic Drugs
    29. Patented February 7, 1956 [ full citation needed ][ non-primary source needed ]
    30. Prior to 1952, neither the molecular structure of Terramycin nor that of Aureomycin was known.[ citation needed ] In the spring of 1952, the Pfizer team succeeded in ascertaining the structures of both Terramycin (see Hochstein et al., op. cit.) and Aureomycin.[ citation needed ] Shortly thereafter, Lloyd Conover produced another antibiotic, tetracycline, that he discovered to be the result of dechlorination of Aureomycin.[ citation needed ] Pfizer filed the application for a product and process patent on tetracycline in October 1952.[ citation needed ] In March 1953, Cyanamid filed its Boothe-Morton application for a similar patent.[ citation needed ] In September 1953, Heyden Chemicals filed for a patent on tetracycline and the fermentation process for producing it in the name of P. Paul Minieri (see the Minieri patent cited in the main body, op. cit.). In October 1953, Bristol filed a similar application under the name of "Heinemann".[ citation needed ] Because of an agreement among the major drug companies to cross-license tetracyline, the Federal Trade Commission (FTC) initiated Fair Trade Practices litigation that remained unresolved until 1982.[ citation needed ] The FTC argued that tetracycline was not patentable because of its production through fermentation, [ citation needed ] that Pfizer, American Cyanamid (successor to Heyden), Bristol-Myers and others had conspired to fix prices for the new antibiotic,[ citation needed ] and that distribution of such fermented, nonsynthetic products, because not patentable, was subject to the FTC price-fixing challenge.[ citation needed ]
    31. Armelagos, George (2000). "Take Two Beers and Call Me in 1,600 Years: Use of Tetracycline by Nubians and Ancient Egyptians" (PDF). Natural History (5, May): 50–53. Retrieved March 13, 2017.
    32. 1 2 McCluskey, Priyanka Dayal (6 November 2015). "As competition wanes, prices for generics skyrocket". Boston Globe. Archived from the original on 19 November 2015. Retrieved 18 November 2015.