Doxycycline

Source: Wikipedia, the free encyclopedia.

Doxycycline
Clinical data
Pronunciation/ˌdɒksɪˈskln/
DOKS-iss-EYE-kleen
Trade namesDoxy, Doryx, Vibramycin, others
AHFS/Drugs.comMonograph
MedlinePlusa682063
License data
Pregnancy
category
  • AU: D
Routes of
administration
By mouth, intravenous[1]
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
Pharmacokinetic data
Bioavailability~100%
Protein binding80–90%
MetabolismNegligible
Elimination half-life10–22 hours
ExcretionMainly feces, 40% urine
Identifiers
  • (4S,4aR,5S,5aR,6R,12aS)-4-(Dimethylamino)-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide
JSmol)
  • CN(C)[C@@H]3C(\O)=C(\C(N)=O)C(=O)[C@@]4(O)C(/O)=C2/C(=O)c1c(cccc1O)[C@H](C)[C@H]2[C@H](O)[C@@H]34
  • InChI=1S/C22H24N2O8.H2O/c1-7-8-5-4-6-9(25)11(8)16(26)12-10(7)17(27)14-15(24(2)3)18(28)13(21(23)31)20(30)22(14,32)19(12)29;/h4-7,10,14-15,17,25,27-29,32H,1-3H3,(H2,23,31);1H2/t7-,10+,14+,15-,17-,22-;/m0./s1 checkY
  • Key:XQTWDDCIUJNLTR-CVHRZJFOSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Doxycycline is a

injection into a vein.[1]

Common side effects include

Doxycycline was patented in 1957 and came into commercial use in 1967.

generic medicine.[1][10] In 2021, it was the 82nd most commonly prescribed medication in the United States, with more than 8 million prescriptions.[11][12]

Medical uses

Generic 100 mg doxycycline capsules
A package of generic doxycycline

In addition to the general indications for all members of the

rickettsial infections.[18]

In Canada, in 2004, doxycycline was considered a first-line treatment for chlamydia and non-gonococcal urethritis and with cefixime for uncomplicated gonorrhea.[19]

Antibacterial

General indications

Doxycycline is a broad-spectrum antibiotic that is employed in the treatment of numerous bacterial infections. It is effective against bacteria such as Moraxella catarrhalis, Brucella melitensis, Chlamydia pneumoniae, and Mycoplasma pneumoniae. Additionally, doxycycline is used in the prevention and treatment of serious conditions like anthrax, leptospirosis, bubonic plague, and Lyme disease. However, some bacteria, including Haemophilus spp., Mycoplasma hominis, and Pseudomonas aeruginosa, have shown resistance to doxycycline.[20][21] It is also effective against Yersinia pestis (the infectious agent of bubonic plague), and is prescribed for the treatment of Lyme disease,[22][23][24][25] ehrlichiosis,[26][27] and Rocky Mountain spotted fever.[28]

Specifically, doxycycline is indicated for treatment of the following diseases:[28][29]

Gram-negative bacteria specific indications

When bacteriologic testing indicates appropriate susceptibility to the drug, doxycycline may be used to treat these infections caused by Gram-negative bacteria:[28][29]

Gram-positive bacteria specific indications

Some

S. faecalis specimens have developed resistance to the tetracycline group of antibiotics. Up to 57% of P. acnes strains developed resistance to doxycycline.[38] When bacteriologic testing indicates appropriate susceptibility to the drug, doxycycline may be used to treat these infections caused by Gram-positive bacteria:[28][29]

Specific applications of doxycycline when penicillin is contraindicated

When penicillin is contraindicated, doxycycline can be used to treat:[28][29]

Use as adjunctive therapy

Doxycycline may also be used as adjunctive therapy for severe acne.[39][28][29]

Subantimicrobial-dose doxycycline (SDD) is widely used as an adjunctive treatment to scaling and root planing for

periodontitis. Significant differences were observed for all investigated clinical parameters of periodontitis in favor of the scaling and root planing + SDD group where SDD dosage regimens is 20 mg twice daily for three months in a meta-analysis published in 2011.[40] SDD is also used to treat skin conditions such as acne and rosacea,[15][41][42] including ocular rosacea.[43] In ocular rosacea, treatment period is 2 to 3 months. After discontinuation of doxycycline, recurrences may occur within three months; therefore, many studies recommend either slow tapering or treatment with a lower dose over a longer period of time.[43]

Doxycycline is used as an adjunctive therapy for acute intestinal amebiasis.[44]

Doxycycline is also used as an adjunctive therapy for chancroid.[44]

As prophylaxis against sexually transmitted infections

As well as being used to treat some sexually transmitted infections, doxycycline can also be used as a preventative measure, i.e. as post-exposure prophylaxis (often referred to as "doxyPEP"). Three randomised controlled trials have demonstrated efficacy in the prevention of syphilis and chlamydia, and to a lesser extent gonorrhoea, in gay and bisexual men, as well as trans women.[45] A study conducted with heterosexual women in Kenya was unsuccessful, probably due to poor adherence.[46] Appropriate use of doxycycline in this way is supported by guidelines from the US Centers for Disease Control and Prevention (CDC)[47] and the Australasian Society for HIV Medicine.[48] The rapid uptake of "doxyPEP" among gay and bisexual men in San Francisco is credited with reducing the incidence of chlamydia and syphilis in 2023.[49]

Use in combination

The first-line treatment for brucellosis is a combination of doxycycline and streptomycin and the second-line is a combination of doxycycline and rifampicin (rifampin).[50]

Antimalarial

Doxycycline is active against the erythrocytic stages of Plasmodium falciparum but not against the gametocytes of P. falciparum.[51] It is used to prevent malaria.[52] It is not recommended alone for initial treatment of malaria, even when the parasite is doxycycline-sensitive, because the antimalarial effect of doxycycline is delayed.[53]

Doxycycline blocks protein production in apicoplast (an organelle) of P. falciparum—such blocking leads to two main effects: it disrupts the parasite's ability to produce fatty acids, which are essential for its growth, and it impairs the production of heme, a cofactor. These effects occur late in the parasite's life cycle when it is in the blood stage, causing the symptoms of malaria.[54] By blocking important processes in the parasite, doxycycline both inhibits the growth and prevents the multiplication of P. falciparum. It does not directly kill the living organisms of P. falciparum but creates conditions that prevent their growth and replication.[55]

The World Health Organization (WHO) guidelines state that the combination of doxycycline with either artesunate or quinine may be used for the treatment of uncomplicated malaria due to P. falciparum or following intravenous treatment of severe malaria.[56]

Antihelminthic

Doxycycline kills the

microfilariae.[58]

Spectrum of susceptibility

Doxycycline has been used successfully to treat sexually transmitted, respiratory, and ophthalmic infections. Representative pathogenic genera include Chlamydia, Streptococcus, Ureaplasma, Mycoplasma, and others. The following represents minimum inhibitory concentration susceptibility data for a few medically significant microorganisms.[59]

Sclerotherapy

Doxycycline is also used for

lymphatic malformations, as well as post-operative lymphoceles.[60]

Routes of administration

Doxycycline can be administered via oral or intravenous routes.[1]

The combination of doxycycline with dairy, antacids, calcium supplements, iron products, laxatives containing magnesium, or bile acid sequestrants is not inherently dangerous, but any of these foods and supplements may decrease absorption of doxycycline.[61][62]

Doxycycline has a high oral bioavailability, as it is almost completely absorbed in the stomach and proximal small intestine.[15] Unlike other tetracyclines, its absorption is not significantly affected by food or dairy intake.[15] However, co-administration of dairy products reduces the serum concentration of doxycycline by 20%.[15] Doxycycline absorption is also inhibited by divalent and trivalent cations, such as iron, bismuth, aluminum, calcium and magnesium.[15] Doxycycline forms unstable complexes with metal ions in the acidic gastric environment, which dissociate in the small intestine, allowing the drug to be absorbed. However, some doxycycline remains complexed with metal ions in the duodenum, resulting in a slight decrease in absorption.[15]

Contraindications

Severe

intracranial hypertension (increased pressure around the brain) in rare cases.[61]

Pregnancy and lactation

Doxycycline is categorized by the

rickettsial diseases in young children and others advocate for its use in malaria.[66]

Adverse effects

Adverse effects are similar to those of other members of the

An

erythematous rash in sun-exposed parts of the body has been reported to occur in 7.3–21.2% of persons taking doxycycline for malaria prophylaxis. One study examined the tolerability of various malaria prophylactic regimens and found doxycycline did not cause a significantly higher percentage of all skin events (photosensitivity not specified) when compared with other antimalarials. The rash resolves upon discontinuation of the drug.[71]

Unlike some other members of the tetracycline group, it may be used in those with renal impairment.[72]

Doxycycline use has been associated with increased risk of inflammatory bowel disease.[73] In one large retrospective study, patients who were prescribed doxycycline for their acne had a 2.25-fold greater risk of developing Crohn's disease.[74]

Interactions

Previously, doxycycline was believed to impair the effectiveness of many types of hormonal contraception due to CYP450 induction. Research has shown no significant loss of effectiveness in oral contraceptives while using most tetracycline antibiotics (including doxycycline), although many physicians still recommend the use of barrier contraception for people taking the drug to prevent unwanted pregnancy.[75][72][76]

Pharmacology

Doxycycline, like other tetracycline antibiotics, is bacteriostatic. It works by preventing bacteria from reproducing through the inhibition of protein synthesis.[77]

Doxycycline is highly lipophilic, so it can easily enter cells, meaning the drug is easily absorbed after oral administration and has a large volume of distribution. It can also be re-absorbed in the renal tubules and gastrointestinal tract due to its high lipophilicity, giving it a long elimination half-life, and it is also prevented from accumulating in the kidneys of patients with kidney failure due to the compensatory excretion in faeces.[68][78] Doxycycline–metal ion complexes are unstable at acid pH, therefore more doxycycline enters the duodenum for absorption than the earlier tetracycline compounds. In addition, food has less effect on absorption than on absorption of earlier drugs with doxycycline serum concentrations being reduced by about 20% by test meals compared with 50% for tetracycline.[79]

Mechanism of action

Doxycycline is a broad-spectrum bacteriostatic antibiotic. It inhibits the synthesis of bacterial proteins by binding to the 30S ribosomal subunit, which is only found in bacteria.[67][78] This prevents the binding of transfer RNA to messenger RNA at the ribosomal subunit meaning amino acids cannot be added to polypeptide chains and new proteins cannot be made. This stops bacterial growth giving the immune system time to kill and remove the bacteria.[80]

Pharmacokinetics

The substance is almost completely absorbed from the upper part of the

aqueous humor, cerebrospinal fluid (CSF), and especially in inflamed meninges.[61][81][82] By comparison, the tetracycline antibiotic minocycline penetrates significantly better into the CSF and meninges.[83]

Doxycycline

end-stage kidney disease. The biological half-life is 18 to 22 hours (16 ± 6 hours according to another source[81]) in healthy people, slightly longer in those with end-stage kidney disease, and significantly longer in those with liver disease.[61][81][82]

Chemistry

Expired tetracyclines or tetracyclines allowed to stand at a pH less than 2 are reported to be nephrotoxic due to the formation of a degradation product, anhydro-4-epitetracycline[84][85] causing Fanconi syndrome.[86] In the case of doxycycline, the absence of a hydroxyl group in C-6 prevents the formation of the nephrotoxic compound.[85] Nevertheless, tetracyclines and doxycycline itself have to be taken with caution in patients with kidney injury, as they can worsen azotemia due to catabolic effects.[86]

Chemical properties

Doxycycline, doxycycline

aqueous solution has a pH of 2–3, and the specific rotation
is  −110° cm3/dm·g in 0.01 

Solubility[81]
Solubility in Doxycycline Doxycycline monohydrate Doxycycline hyclate
Water very slightly very slightly freely
Ethanol very slightly very slightly sparingly
Aqueous acids freely freely
Alkali hydroxyde solutions freely freely
Chloroform very slightly practically insoluble practically insoluble
Diethyl ether insoluble practically insoluble practically insoluble

History

After

tetracycline class of antibiotics.[4] Shortly thereafter, scientists at Pfizer discovered oxytetracycline and it was brought to market. Both compounds, like penicillin, were natural products and it was commonly believed that nature had perfected them, and further chemical changes could only degrade their effectiveness. Scientists at Pfizer led by Lloyd Conover modified these compounds, which led to the invention of tetracycline itself, the first semi-synthetic antibiotic. Charlie Stephens' group at Pfizer worked on further analogs and created one with greatly improved stability and pharmacological efficacy: doxycycline. It was clinically developed in the early 1960s and approved by the FDA in 1967.[4]

As its patent grew near to expiring in the early 1970s, the patent became the subject of lawsuit between Pfizer and International Rectifier[87] that was not resolved until 1983; at the time it was the largest litigated patent case in US history.[88] Instead of a cash payment for infringement, Pfizer took the veterinary and feed-additive businesses of International Rectifier's subsidiary, Rachelle Laboratories.[88]

In January 2013, the FDA reported shortages of some, but not all, forms of doxycycline "caused by increased demand and manufacturing issues".

Teva (which ceased production in May 2013), Mylan, Actavis, and Hikma Pharmaceuticals.[90][91] The shortage came at a particularly bad time, since there were also shortages of an alternative antibiotic, tetracycline, at the same time.[92] The market price for doxycycline dramatically increased in the United States in 2013 and early 2014 (from $20 to over $1800 for a bottle of 500 tablets),[93][94][95] before decreasing again.[96][97]

Society and culture

Doxycycline is available worldwide under many brand names.[98] Doxycycline is available as a generic medicine.[1][10]

Research

Research areas have included:

Tet-ON inducible shRNA system

Anti-inflammatory agent

Some studies show doxycycline as a potential agent to possess anti-inflammatory properties acting by inhibiting proinflammatory cytokines such as

nuclear factor-kappa B (NF-κB) pathway, which is responsible for upregulating several inflammatory mediators in various cells, including neurons; therefore, it is studied as a potential agent for treating neuroinflammation.[101][102][103]

A potential explanation of doxycycline's anti-inflammatory properties is its inhibition of matrix metalloproteinases (MMPs), which are a group of proteases known to regulate the turnover of extracellular matrix (ECM) and thus are suggested to be important in the process of several diseases associated with tissue remodeling and inflammation.[104][105][106][107] Doxycycline has been shown to inhibit MMPs, including matrilysin (MMP7), by interacting with the structural zinc atom and/or calcium atoms within the structural metal center of the protein.[108][109][110]

Doxycycline is used to treat acne vulgaris and rosacea.[111][112][15] However, there is no clear understanding of what contributes more: the bacteriostatic properties of doxycycline, which affect bacteria (such as Propionibacterium acnes[15]) on the surface of sebaceous glands even in lower doses called "submicrobial"[113][114] or "subantimicrobial",[115][116][117][15] or whether doxycycline's anti-inflammatory effects, which reduce inflammation in acne vulgaris and rosacea, including ocular rosacea,[43] contribute more to its therapeutic effectiveness against these skin conditions.[118] Subantimicrobial-dose doxycycline (SDD) can still have a bacteriostatic effect, especially when taken for extended periods, such as several months in treating acne and rosacea.[119] While the SDD is believed to have anti-inflammatory effects rather than solely antibacterial effects, SDD was proven to work by reducing inflammation associated with acne and rosacea. Still, the exact mechanisms have yet to be fully discovered.[120] One probable mechanism is doxycycline's ability to decrease the amount of reactive oxygen species (ROS). Inflammation in rosacea may be associated with increased production of ROS by inflammatory cells; these ROS contribute toward exacerbating symptoms. Doxycycline may reduce ROS levels and induce antioxidant activity because it directly scavenges hydroxyl radicals and singlet oxygen, helping minimize tissue damage caused by highly oxidative and inflammatory conditions.[121] Studies have shown that SDD can effectively improve acne and rosacea symptoms,[122] probably without inducing antibiotic resistance.[123]

Doxycycline's dual benefits as an antibacterial and anti-inflammatory make it a helpful treatment option for diseases involving inflammation not only of the skin, such as rosacea and acne, but also in conditions such as osteoarthritis or periodontitis.[124] Nevertheless, current results are inconclusive, and evidence of doxycycline's anti-inflammatory properties needs to be improved, considering conflicting reports from animal models so far.[125][126][127] Doxycycline has been studied in various immunological disorders, including rheumatoid arthritis, lupus, and periodontitis.[128] In these conditions, doxycycline has been researched to determine anti-inflammatory and immunomodulatory effects that could be beneficial in treating these conditions. However, a solid conclusion still needs to be provided.[129][130][131][132]

Doxycycline is also studied for its neuroprotective properties which are associated with antioxidant, anti-apoptotic, and anti-inflammatory mechanisms. In this context, it is important to note that doxycycline is able to cross the blood-brain barrier. Several studies have shown that doxycycline inhibits dopaminergic neurodegeneration through the upregulation of axonal and synaptic proteins.[133][134] Axonal degeneration and synaptic loss are key events at the early stages of neurodegeneration and precede neuronal death in neurodegenerative diseases, including Parkinson's disease (PD). Therefore, the regeneration of the axonal and synaptic network might be beneficial in PD.[135] It has been demonstrated that doxycycline mimics nerve growth factor (NGF) signaling in PC12 cells. However, the involvement of this mechanism in the neuroprotective effect of doxycycline is unknown. Doxycycline is also studied in reverting inflammatory changes related to depression.[116] While there is some research on the use of doxycycline for treating major depressive disorder, the results are mixed.[116][136][137]

After a large-scale trial showed no benefit of using doxycycline in treating COVID‑19, the UK's National Institute for Health and Care Excellence (NICE) updated its guidance to not recommend the medication for the treatment of COVID‑19.[138][139] Doxycycline was expected to possess anti-inflammatory properties that could lessen the cytokine storm associated with a SARS-CoV-2 infection, but the trials did not demonstrate the expected benefit.[140] Researchers also believed that doxycycline possesses anti-inflammatory and immunomodulatory effects that could reduce the production of cytokines in COVID-19, but these supposed effects failed to improve the outcome of COVID-19 treatment.[141][142]

Research reagent

Doxycycline and other members of the

matrix metalloproteases, and has been used in various experimental systems for this purpose, such as for recalcitrant recurrent corneal erosions.[146]

References

  1. ^ a b c d e f g h i j "Doxycycline calcium". The American Society of Health-System Pharmacists. Archived from the original on 23 September 2015. Retrieved 18 August 2015.
  2. ^ "Malaria". Fit for Travel. Public Health Scotland. Chemoprophylaxis. Archived from the original on 4 December 2023. Retrieved 4 December 2023.
  3. ^ "Choosing a Drug to Prevent Malaria". Centers for Disease Control and Prevention. February 2023. Doxycycline. Archived from the original on 13 November 2016. Retrieved 4 December 2023.
  4. ^
    S2CID 34647314
    .
  5. .
  6. .
  7. .
  8. from the original on 14 January 2023. Retrieved 9 September 2017.
  9. . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  10. ^ .
  11. ^ "The Top 300 of 2021". ClinCalc. Archived from the original on 15 January 2024. Retrieved 14 January 2024.
  12. ^ "Doxycycline - Drug Usage Statistics". ClinCalc. Archived from the original on 8 July 2020. Retrieved 14 January 2024.
  13. PMID 3162653
    .
  14. .
  15. ^ .
  16. .
  17. .
  18. .
  19. ^ Rekart ML (December 2004). "Doxycycline:" New" treatment of choice for genital chlamydia infections". British Columbia Medical Journal. 46 (10): 503. Archived from the original on 2 February 2017.
  20. ^ "Doxycycline spectrum of bacterial susceptibility and Resistance" (PDF). Archived from the original (PDF) on 1 February 2014. Retrieved 4 May 2012.
  21. ^ Stoddard RA, Galloway RL, Guerra MA (10 July 2015). "Leptospirosis". Yellow Book. Atlanta, GA: Centers for Disease Control and Prevention. Archived from the original on 9 April 2017. Retrieved 16 April 2017.
  22. S2CID 23358315
    .
  23. .
  24. .
  25. .
  26. .
  27. .
  28. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag "Doxycycline, ANDA no. 065055 Label" (PDF). U.S. Food and Drug Administration. 14 December 2012. Archived from the original (PDF) on 19 April 2014.
  29. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af "Doxycycline, ANDA no. 065454 Label" (PDF). U.S. Food and Drug Administration. 16 July 2008. Archived from the original (PDF) on 19 October 2013.
  30. PMID 38110855
    .
  31. from the original on 19 April 2014.
  32. from the original on 28 January 2023. Retrieved 5 February 2024.
  33. from the original on 5 February 2024. Retrieved 5 February 2024.
  34. ^ "Spotted fever group rickettsial disease | DermNet". Archived from the original on 5 February 2024. Retrieved 5 February 2024.
  35. PMID 22972867
    .
  36. ^ "Lyme disease. Treatment". 21 December 2018. Archived from the original on 10 June 2016.
  37. PMID 38167816
    .
  38. .
  39. .
  40. .
  41. .
  42. .
  43. ^ .
  44. ^ a b "Doxycycline Dosage Guide + Max Dose, Adjustments". Archived from the original on 5 February 2024. Retrieved 5 February 2024.
  45. ^ Samuel K (26 May 2023). "Using antibiotics to prevent STIs". Aidsmap. Retrieved 10 March 2024.
  46. PMID 38118022
    . Retrieved 10 March 2024.
  47. ^ "Guidelines for the Use of Doxycycline Post-Exposure Prophylaxis for Bacterial STI Prevention". CDC. 29 September 2023. Retrieved 10 March 2024.
  48. ^ "2023 Consensus Statement on doxycycline prophylaxis (Doxy-PEP) for the prevention of syphilis, chlamydia and gonorrhoea among gay, bisexual, and other men who have sex with men in Australia". Australasian Society for HIV Medicine. Retrieved 10 March 2024.
  49. ^ Highleyman L (5 March 2024). "Sexually transmitted infections in San Francisco have fallen since doxyPEP roll-out". Aidsmap. Retrieved 10 March 2024.
  50. from the original on 28 August 2021. Retrieved 23 August 2014.
  51. ^ "Doryx- doxycycline hyclate tablet, delayed release". DailyMed. 23 October 2020. Archived from the original on 3 January 2022. Retrieved 5 March 2022.
  52. ^ "Malaria - Chapter 3 - 2018 Yellow Book | Travelers' Health | CDC". CDC. Archived from the original on 3 December 2018. Retrieved 4 December 2018.
  53. PMID 16940111
    .
  54. .
  55. .
  56. .
  57. .
  58. .
  59. ^ a b c d "Doxycycline hyclate Susceptibility and Minimum Inhibitory Concentration (MIC) Data" (PDF). toku-e.com. Archived (PDF) from the original on 24 February 2015. Retrieved 16 April 2017.
  60. OCLC 853455295
    .
  61. ^ a b c d Haberfeld H, ed. (2020). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag. Doxycyclin Genericon 200 mg lösliche Tabletten.
  62. U.S. National Library of Medicine. Archived from the original
    on 11 November 2013. Retrieved 16 July 2016.
  63. .
  64. .
  65. ^ "Bioterrorism and Drug Preparedness - Doxycycline Use by Pregnant and Lactating Women". FDA. 3 November 2018. Archived from the original on 8 February 2019. Retrieved 9 December 2018.
  66. PMID 28407772
    .
  67. ^ .
  68. ^ .
  69. .
  70. .
  71. .
  72. ^ ]
  73. .
  74. .
  75. .
  76. .
  77. .
  78. ^ .
  79. .
  80. ^ "Doxycycline". www.drugbank.ca. Archived from the original on 10 November 2008. Retrieved 23 January 2019.
  81. ^ .
  82. ^ a b Doxycycline Professional Drug Facts. Accessed 5 August 2020.
  83. ^ Haberfeld H, ed. (2020). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag. Minostad 50 mg-Kapseln.
  84. ISSN 0250-863X. Archived from the original
    on 10 May 2011.
  85. ^ .
  86. ^ a b Brunton LL, Chabner BA, Knollmann BC (eds.). Goodman & Gilman's The Pharmacological Basis of Therapeutics (12th ed.).
  87. ^ "Pfizer, Inc. v. International Rectifier Corp., 545 F. Supp. 486 (C.D. Cal. 1980)". Justia Law. Archived from the original on 24 February 2015.
  88. ^ a b "Pfizer to Get Rachelle Units". The New York Times. The Associated Press. 6 July 1983. Archived from the original on 6 March 2016.
  89. ^ "Nationwide Shortage of Doxycycline: Resources for Providers and Recommendations for Patient Care". CDC Health Alert Network. 12 June 2013. Archived from the original on 15 February 2015.
  90. ^ "Doxycycline Capsules and Tablets". American Society of Health-System Pharmacists. 12 December 2014. Archived from the original on 1 January 2015.
  91. ^ "Doxycycline Hyclate Injection". American Society of Health-System Pharmacists. 12 November 2014. Archived from the original on 1 January 2015.
  92. ^ "FDA reports shortage of doxycycline antibiotic. What are your options?". Consumer Reports News. 4 February 2013. Archived from the original on 1 January 2015.
  93. ^ "Sudden increase in cost of common drug concerns many". WSMV-TV. 12 March 2013. Archived from the original on 31 December 2014.
  94. ^ Rosenthal E (7 October 2014). "Officials Question the Rising Costs of Generic Drugs". The New York Times. Archived from the original on 23 February 2017.
  95. ^ Palmer E (13 March 2014). "Hikma hits the jackpot with doxycycline shortage". FiercePharmaManufacturing. Archived from the original on 1 January 2015.
  96. ^ "Costco Drug Information". Archived from the original on 4 March 2016. Retrieved 31 July 2016.
  97. ^ "Doxycycline Hyclate Prices and Doxycycline Hyclate Coupons". GoodRx. Archived from the original on 28 July 2016. Retrieved 31 July 2016.
  98. ^ "International availability for doxycycline". drugs.com. Archived from the original on 16 May 2015. Retrieved 29 April 2015.
  99. S2CID 26680094
    .
  100. .
  101. from the original on 2 February 2024. Retrieved 2 February 2024.
  102. .
  103. .
  104. .
  105. .
  106. .
  107. .
  108. .
  109. .
  110. .
  111. .
  112. .
  113. .
  114. .
  115. .
  116. ^ .
  117. .
  118. .
  119. .
  120. .
  121. .
  122. .
  123. .
  124. .
  125. .
  126. .
  127. .
  128. .
  129. .
  130. .
  131. .
  132. .
  133. .
  134. .
  135. .
  136. .
  137. .
  138. from the original on 1 June 2022. Retrieved 1 June 2022.
  139. .
  140. .
  141. .
  142. .
  143. .
  144. .
  145. ^ .
  146. .

External links