Doxycycline: Difference between revisions

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<ref name="pmid17315050">{{cite journal |vauthors=Berman B, Perez OA, Zell D |title= Update on rosacea and anti-inflammatory-dose doxycycline|journal= Drugs of Today|volume= 43|issue= 1|date=January 2007|pages= 27–34|pmid=17315050 |doi=10.1358/dot.2007.43.1.1025697 |url=}}</ref>
<ref name="pmid17315050">{{cite journal |vauthors=Berman B, Perez OA, Zell D |title= Update on rosacea and anti-inflammatory-dose doxycycline|journal= Drugs of Today|volume= 43|issue= 1|date=January 2007|pages= 27–34|pmid=17315050 |doi=10.1358/dot.2007.43.1.1025697 |url=}}</ref>


Doxycycline is used to treat [[Acne|acne vulgaris]] and [[rosacea]].<ref name="pmid34812859">{{cite journal |vauthors=Eichenfield DZ, Sprague J, Eichenfield LF |title=Management of Acne Vulgaris: A Review |journal=JAMA |volume=326 |issue=20 |pages=2055–2067 |date=November 2021 |pmid=34812859 |doi=10.1001/jama.2021.17633 |s2cid=244490539 |url=}}</ref><ref name="pmid33133338">{{cite journal |vauthors=Baldwin H |title=Oral Antibiotic Treatment Options for Acne Vulgaris |journal=J Clin Aesthet Dermatol |volume=13 |issue=9 |pages=26–32 |date=September 2020 |pmid=33133338 |pmc=7577330 |doi= |url=}}</ref> However, there is no clear understanding of what contributes more: the bacteriostatic properties of doxycycline, which affect bacteria on the surface of sebaceous glands even in lower doses called "submicrobial"<ref name="pmid16146617">{{cite journal |vauthors=Parish LC, Parish JL, Routh HB, Witkowski JA |title=The treatment of acne vulgaris with low dosage doxycycline |journal=Acta Dermatovenerol Croat |volume=13 |issue=3 |pages=156–9 |date=2005 |pmid=16146617 |doi= |url=}}</ref><ref name="pmid27538054">{{cite journal |vauthors=Stein Gold LF |title=Acne: What's New |journal=Semin Cutan Med Surg |volume=35 |issue=6 Suppl |pages=S114–6 |date=June 2016 |pmid=27538054 |doi=10.12788/j.sder.2016.036 |url=}}</ref>or "subantimicrobial",<ref name="pmid36407641">{{cite journal |vauthors=Kontochristopoulos G, Tsiogka A, Agiasofitou E, Kapsiocha A, Soulaidopoulos S, Liakou AI, Gregoriou S, Rigopoulos D |title=Efficacy of Subantimicrobial, Modified-Release Doxycycline Compared to Regular-Release Doxycycline for the Treatment of Hidradenitis Suppurativa |journal=Skin Appendage Disord |volume=8 |issue=6 |pages=476–481 |date=November 2022 |pmid=36407641 |doi=10.1159/000524762 |pmc=9672876 |url= |pmc-embargo-date=November 1, 2023 }}</ref><ref name="pmid34161892">{{cite journal |vauthors=((Mello BSF)), ((Chaves Filho AJM)), Custódio CS, Rodrigues PA, Carletti JV, ((Vasconcelos SMM)), ((Sousa FCF)), ((Sanders LLO)), Macedo DS |title=Doxycycline at subantimicrobial dose combined with escitalopram reverses depressive-like behavior and neuroinflammatory hippocampal alterations in the lipopolysaccharide model of depression |journal=J Affect Disord |volume=292 |issue= |pages=733–745 |date=September 2021 |pmid=34161892 |doi=10.1016/j.jad.2021.05.083 |url=}}</ref><ref name="pmid14673277">{{cite journal |vauthors=Bikowski JB |title=Subantimicrobial dose doxycycline for acne and rosacea |journal=Skinmed |volume=2 |issue=4 |pages=234–45 |date=2003 |pmid=14673277 |doi=10.1111/j.1540-9740.2003.03014.x |url=}}</ref> or whether doxycycline's anti-inflammatory effects, which reduce inflammation in [[Acne|acne vulgaris]] and [[rosacea]], contribute more to its therapeutic effectiveness against these skin conditions.<ref name="pmid32401726">{{cite journal |vauthors=Navarro-Triviño FJ, Pérez-López I, Ruiz-Villaverde R |title=Doxycycline, an Antibiotic or an Anti-Inflammatory Agent? The Most Common Uses in Dermatology |journal=Actas Dermosifiliogr (Engl Ed) |volume=111 |issue=7 |pages=561–566 |date=September 2020 |pmid=32401726 |doi=10.1016/j.ad.2019.12.006 |s2cid=218635190 |url=}}</ref> Those lower, submicrobial, doses can still have a [[Bacteriostatic agent|bacteriostatic]] effect, especially when taken for extended periods, such as several months in treating acne and rosacea.<ref name="pmid37521754">{{cite journal |vauthors=Zolotarev O, Khakimova A, Rahim F, Senel E, Zatsman I, Gu D |title=Scientometric analysis of trends in global research on acne treatment |journal=Int J Womens Dermatol |volume=9 |issue=3 |pages=e082 |date=October 2023 |pmid=37521754 |pmc=10378739 |doi=10.1097/JW9.0000000000000082 |url=}}</ref> While the submicrobial doses of doxycycline are believed to have anti-inflammatory effects rather than solely antibacterial effects, such doses were proven to work by reducing inflammation associated with acne and rosacea. Still, the exact mechanisms have yet to be fully discovered.<ref name="pmid37820334">{{cite journal |vauthors=Shields A, Barbieri JS |title=From Breakouts to Bargains: Strategies for Patient-Centered, Cost-effective Acne Care |journal=Cutis |volume=112 |issue=2 |pages=E24–E29 |date=August 2023 |pmid=37820334 |doi=10.12788/cutis.0844 |s2cid=261786019 |url=}}</ref> 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 [[Reactive oxygen species|ROS]] by inflammatory cells; these ROS contribute towards exacerbating symptoms. Doxycycline may reduce ROS levels and induce antioxidant activity because it directly scavenges [[Hydroxyl radical|hydroxyl radicals]] and [[singlet oxygen]], helping minimize tissue damage caused by highly oxidative and inflammatory conditions.<ref name="pmid1357852">{{cite journal |vauthors=Akamatsu H, Asada M, Komura J, Asada Y, Niwa Y |title=Effect of doxycycline on the generation of reactive oxygen species: a possible mechanism of action of acne therapy with doxycycline |journal=Acta Derm Venereol |volume=72 |issue=3 |pages=178–9 |date=1992 |pmid=1357852 |doi= 10.2340/0001555572178179|s2cid=45726787 |url=}}</ref> Studies have shown that submicrobial doses of doxycycline can effectively improve acne and rosacea symptoms,<ref name="pmid26897386">{{cite journal |vauthors=Zaenglein AL, Pathy AL, Schlosser BJ, Alikhan A, Baldwin HE, Berson DS, Bowe WP, Graber EM, Harper JC, Kang S, Keri JE, Leyden JJ, Reynolds RV, Silverberg NB, Stein Gold LF, Tollefson MM, Weiss JS, Dolan NC, Sagan AA, Stern M, Boyer KM, Bhushan R |title=Guidelines of care for the management of acne vulgaris |journal=J Am Acad Dermatol |volume=74 |issue=5 |pages=945–73.e33 |date=May 2016 |pmid=26897386 |doi=10.1016/j.jaad.2015.12.037 |url=}}</ref> probably without inducing [[Antimicrobial resistance|antibiotic resistance]].<ref name="pmid18004018">{{cite journal |vauthors=Wise RD |title=Submicrobial doxycycline and rosacea |journal=Compr Ther |volume=33 |issue=2 |pages=78–81 |date=2007 |pmid=18004018 |doi=10.1007/s12019-007-8003-x |s2cid=28262106 |url=}}</ref> Therefore, 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 [[Periodontal disease|periodontitis]].<ref name="pmid12900822">{{cite journal |vauthors=Ahuja TS |title=Doxycycline decreases proteinuria in glomerulonephritis |journal=Am J Kidney Dis |volume=42 |issue=2 |pages=376–80 |date=August 2003 |pmid=12900822 |doi=10.1016/s0272-6386(03)00662-0 |url=}}</ref> 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.<ref name="pmid31955291">{{cite journal |vauthors=Patel A, Khande H, Periasamy H, Mokale S |title=Immunomodulatory Effect of Doxycycline Ameliorates Systemic and Pulmonary Inflammation in a Murine Polymicrobial Sepsis Model |journal=Inflammation |volume=43 |issue=3 |pages=1035–1043 |date=June 2020 |pmid=31955291 |doi=10.1007/s10753-020-01188-y |pmc=7224120 |url=}}</ref><ref name="pmid37759467">{{cite journal |vauthors=Martin V, Bettencourt AF, Santos C, Fernandes MH, Gomes PS |title=Unveiling the Osteogenic Potential of Tetracyclines: A Comparative Study in Human Mesenchymal Stem Cells |journal=Cells |volume=12 |issue=18 |date=September 2023 |page=2244 |pmid=37759467 |pmc=10526833 |doi=10.3390/cells12182244 |url= |doi-access=free }}</ref><ref name="pmid37751595">{{cite journal |vauthors=Waitayangkoon P, Moon SJ, Tirupur Ponnusamy JJ, Zeng L, Driban J, McAlindon T |title=Long-Term Safety Profiles Macrolides and Tetracyclines: A Systematic Review and Meta-analysis |journal=J Clin Pharmacol |volume= |issue= |pages= |date=September 2023 |pmid=37751595 |doi=10.1002/jcph.2358 |s2cid=263151406 |url=}}</ref> Doxycycline has been studied in various immunological disorders, including [[rheumatoid arthritis]], [[lupus]], and [[Periodontal disease|periodontitis]].<ref name="pmid35742496">{{cite journal |vauthors=Orylska-Ratynska M, Placek W, Owczarczyk-Saczonek A |title=Tetracyclines-An Important Therapeutic Tool for Dermatologists |journal=Int J Environ Res Public Health |volume=19 |issue=12 |date=June 2022 |page=7246 |pmid=35742496 |pmc=9224192 |doi=10.3390/ijerph19127246 |url= |doi-access=free }}</ref> IIn 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.<ref name="pmid33611055">{{cite journal |vauthors=Santos M, Gonçalves-Santos E, Gonçalves R, Santos E, Campos C, Bastos D, Marques M, Souza R, Novaes R |title=Doxycycline aggravates granulomatous inflammation and lung microstructural remodeling induced by Schistosoma mansoni infection |journal=Int Immunopharmacol |volume=94 |issue= |pages=107462 |date=May 2021 |pmid=33611055 |doi=10.1016/j.intimp.2021.107462 |s2cid=231988574 |url=}}</ref><ref name="pmid34899697">{{cite journal |vauthors=Florou DT, Mavropoulos A, Dardiotis E, Tsimourtou V, Siokas V, Aloizou AM, Liaskos C, Tsigalou C, Katsiari C, Sakkas LI, Hadjigeorgiou G, Bogdanos DP |title=Tetracyclines Diminish In Vitro IFN-γ and IL-17-Producing Adaptive and Innate Immune Cells in Multiple Sclerosis |journal=Front Immunol |volume=12 |issue= |pages=739186 |date=2021 |pmid=34899697 |pmc=8662812 |doi=10.3389/fimmu.2021.739186 |url= |doi-access=free }}</ref><ref name="pmid35294307">{{cite journal |vauthors=Garrido-Mesa J, Adams K, Galvez J, Garrido-Mesa N |title=Repurposing tetracyclines for acute respiratory distress syndrome (ARDS) and severe COVID-19: a critical discussion of recent publications |journal=Expert Opin Investig Drugs |volume=31 |issue=5 |pages=475–482 |date=May 2022 |pmid=35294307 |pmc=9115781 |doi=10.1080/13543784.2022.2054325 |url=}}</ref><ref name="pmid36869773">{{cite journal |vauthors=de Witte LD, Munk Laursen T, Corcoran CM, Kahn RS, Birnbaum R, Munk-Olsen T, Bergink V |title=A Sex-Dependent Association Between Doxycycline Use and Development of Schizophrenia |journal=Schizophr Bull |volume=49 |issue=4 |pages=953–961 |date=July 2023 |pmid=36869773 |doi=10.1093/schbul/sbad008 |pmc=10318877 |url= |pmc-embargo-date=March 3, 2024 }}</ref>
Doxycycline is used to treat [[Acne|acne vulgaris]] and [[rosacea]].<ref name="pmid34812859">{{cite journal |vauthors=Eichenfield DZ, Sprague J, Eichenfield LF |title=Management of Acne Vulgaris: A Review |journal=JAMA |volume=326 |issue=20 |pages=2055–2067 |date=November 2021 |pmid=34812859 |doi=10.1001/jama.2021.17633 |s2cid=244490539 |url=}}</ref><ref name="pmid33133338">{{cite journal |vauthors=Baldwin H |title=Oral Antibiotic Treatment Options for Acne Vulgaris |journal=J Clin Aesthet Dermatol |volume=13 |issue=9 |pages=26–32 |date=September 2020 |pmid=33133338 |pmc=7577330 |doi= |url=}}</ref> However, there is no clear understanding of what contributes more: the bacteriostatic properties of doxycycline, which affect bacteria on the surface of sebaceous glands even in lower doses called "submicrobial"<ref name="pmid16146617">{{cite journal |vauthors=Parish LC, Parish JL, Routh HB, Witkowski JA |title=The treatment of acne vulgaris with low dosage doxycycline |journal=Acta Dermatovenerol Croat |volume=13 |issue=3 |pages=156–9 |date=2005 |pmid=16146617 |doi= |url=}}</ref><ref name="pmid27538054">{{cite journal |vauthors=Stein Gold LF |title=Acne: What's New |journal=Semin Cutan Med Surg |volume=35 |issue=6 Suppl |pages=S114–6 |date=June 2016 |pmid=27538054 |doi=10.12788/j.sder.2016.036 |url=}}</ref>or "subantimicrobial",<ref name="pmid36407641">{{cite journal |vauthors=Kontochristopoulos G, Tsiogka A, Agiasofitou E, Kapsiocha A, Soulaidopoulos S, Liakou AI, Gregoriou S, Rigopoulos D |title=Efficacy of Subantimicrobial, Modified-Release Doxycycline Compared to Regular-Release Doxycycline for the Treatment of Hidradenitis Suppurativa |journal=Skin Appendage Disord |volume=8 |issue=6 |pages=476–481 |date=November 2022 |pmid=36407641 |doi=10.1159/000524762 |pmc=9672876 |url= |pmc-embargo-date=November 1, 2023 }}</ref><ref name="pmid34161892">{{cite journal |vauthors=((Mello BSF)), ((Chaves Filho AJM)), Custódio CS, Rodrigues PA, Carletti JV, ((Vasconcelos SMM)), ((Sousa FCF)), ((Sanders LLO)), Macedo DS |title=Doxycycline at subantimicrobial dose combined with escitalopram reverses depressive-like behavior and neuroinflammatory hippocampal alterations in the lipopolysaccharide model of depression |journal=J Affect Disord |volume=292 |issue= |pages=733–745 |date=September 2021 |pmid=34161892 |doi=10.1016/j.jad.2021.05.083 |url=}}</ref><ref name="pmid14673277">{{cite journal |vauthors=Bikowski JB |title=Subantimicrobial dose doxycycline for acne and rosacea |journal=Skinmed |volume=2 |issue=4 |pages=234–45 |date=2003 |pmid=14673277 |doi=10.1111/j.1540-9740.2003.03014.x |url=}}</ref> or whether doxycycline's anti-inflammatory effects, which reduce inflammation in [[Acne|acne vulgaris]] and [[rosacea]], contribute more to its therapeutic effectiveness against these skin conditions.<ref name="pmid32401726">{{cite journal |vauthors=Navarro-Triviño FJ, Pérez-López I, Ruiz-Villaverde R |title=Doxycycline, an Antibiotic or an Anti-Inflammatory Agent? The Most Common Uses in Dermatology |journal=Actas Dermosifiliogr (Engl Ed) |volume=111 |issue=7 |pages=561–566 |date=September 2020 |pmid=32401726 |doi=10.1016/j.ad.2019.12.006 |s2cid=218635190 |url=}}</ref> Those lower, submicrobial, doses can still have a [[Bacteriostatic agent|bacteriostatic]] effect, especially when taken for extended periods, such as several months in treating acne and rosacea.<ref name="pmid37521754">{{cite journal |vauthors=Zolotarev O, Khakimova A, Rahim F, Senel E, Zatsman I, Gu D |title=Scientometric analysis of trends in global research on acne treatment |journal=Int J Womens Dermatol |volume=9 |issue=3 |pages=e082 |date=October 2023 |pmid=37521754 |pmc=10378739 |doi=10.1097/JW9.0000000000000082 |url=}}</ref> While the submicrobial doses of doxycycline are believed to have anti-inflammatory effects rather than solely antibacterial effects, such doses were proven to work by reducing inflammation associated with acne and rosacea. Still, the exact mechanisms have yet to be fully discovered.<ref name="pmid37820334">{{cite journal |vauthors=Shields A, Barbieri JS |title=From Breakouts to Bargains: Strategies for Patient-Centered, Cost-effective Acne Care |journal=Cutis |volume=112 |issue=2 |pages=E24–E29 |date=August 2023 |pmid=37820334 |doi=10.12788/cutis.0844 |s2cid=261786019 |url=}}</ref> 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 [[Reactive oxygen species|ROS]] by inflammatory cells; these ROS contribute towards exacerbating symptoms. Doxycycline may reduce ROS levels and induce antioxidant activity because it directly scavenges [[Hydroxyl radical|hydroxyl radicals]] and [[singlet oxygen]], helping minimize tissue damage caused by highly oxidative and inflammatory conditions.<ref name="pmid1357852">{{cite journal |vauthors=Akamatsu H, Asada M, Komura J, Asada Y, Niwa Y |title=Effect of doxycycline on the generation of reactive oxygen species: a possible mechanism of action of acne therapy with doxycycline |journal=Acta Derm Venereol |volume=72 |issue=3 |pages=178–9 |date=1992 |pmid=1357852 |doi= 10.2340/0001555572178179|s2cid=45726787 |url=}}</ref> Studies have shown that submicrobial doses of doxycycline can effectively improve acne and rosacea symptoms,<ref name="pmid26897386">{{cite journal |vauthors=Zaenglein AL, Pathy AL, Schlosser BJ, Alikhan A, Baldwin HE, Berson DS, Bowe WP, Graber EM, Harper JC, Kang S, Keri JE, Leyden JJ, Reynolds RV, Silverberg NB, Stein Gold LF, Tollefson MM, Weiss JS, Dolan NC, Sagan AA, Stern M, Boyer KM, Bhushan R |title=Guidelines of care for the management of acne vulgaris |journal=J Am Acad Dermatol |volume=74 |issue=5 |pages=945–73.e33 |date=May 2016 |pmid=26897386 |doi=10.1016/j.jaad.2015.12.037 |url=}}</ref> probably without inducing [[Antimicrobial resistance|antibiotic resistance]].<ref name="pmid18004018">{{cite journal |vauthors=Wise RD |title=Submicrobial doxycycline and rosacea |journal=Compr Ther |volume=33 |issue=2 |pages=78–81 |date=2007 |pmid=18004018 |doi=10.1007/s12019-007-8003-x |s2cid=28262106 |url=}}</ref>
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 [[Periodontal disease|periodontitis]].<ref name="pmid12900822">{{cite journal |vauthors=Ahuja TS |title=Doxycycline decreases proteinuria in glomerulonephritis |journal=Am J Kidney Dis |volume=42 |issue=2 |pages=376–80 |date=August 2003 |pmid=12900822 |doi=10.1016/s0272-6386(03)00662-0 |url=}}</ref> 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.<ref name="pmid31955291">{{cite journal |vauthors=Patel A, Khande H, Periasamy H, Mokale S |title=Immunomodulatory Effect of Doxycycline Ameliorates Systemic and Pulmonary Inflammation in a Murine Polymicrobial Sepsis Model |journal=Inflammation |volume=43 |issue=3 |pages=1035–1043 |date=June 2020 |pmid=31955291 |doi=10.1007/s10753-020-01188-y |pmc=7224120 |url=}}</ref><ref name="pmid37759467">{{cite journal |vauthors=Martin V, Bettencourt AF, Santos C, Fernandes MH, Gomes PS |title=Unveiling the Osteogenic Potential of Tetracyclines: A Comparative Study in Human Mesenchymal Stem Cells |journal=Cells |volume=12 |issue=18 |date=September 2023 |page=2244 |pmid=37759467 |pmc=10526833 |doi=10.3390/cells12182244 |url= |doi-access=free }}</ref><ref name="pmid37751595">{{cite journal |vauthors=Waitayangkoon P, Moon SJ, Tirupur Ponnusamy JJ, Zeng L, Driban J, McAlindon T |title=Long-Term Safety Profiles Macrolides and Tetracyclines: A Systematic Review and Meta-analysis |journal=J Clin Pharmacol |volume= |issue= |pages= |date=September 2023 |pmid=37751595 |doi=10.1002/jcph.2358 |s2cid=263151406 |url=}}</ref> Doxycycline has been studied in various immunological disorders, including [[rheumatoid arthritis]], [[lupus]], and [[Periodontal disease|periodontitis]].<ref name="pmid35742496">{{cite journal |vauthors=Orylska-Ratynska M, Placek W, Owczarczyk-Saczonek A |title=Tetracyclines-An Important Therapeutic Tool for Dermatologists |journal=Int J Environ Res Public Health |volume=19 |issue=12 |date=June 2022 |page=7246 |pmid=35742496 |pmc=9224192 |doi=10.3390/ijerph19127246 |url= |doi-access=free }}</ref> IIn 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.<ref name="pmid33611055">{{cite journal |vauthors=Santos M, Gonçalves-Santos E, Gonçalves R, Santos E, Campos C, Bastos D, Marques M, Souza R, Novaes R |title=Doxycycline aggravates granulomatous inflammation and lung microstructural remodeling induced by Schistosoma mansoni infection |journal=Int Immunopharmacol |volume=94 |issue= |pages=107462 |date=May 2021 |pmid=33611055 |doi=10.1016/j.intimp.2021.107462 |s2cid=231988574 |url=}}</ref><ref name="pmid34899697">{{cite journal |vauthors=Florou DT, Mavropoulos A, Dardiotis E, Tsimourtou V, Siokas V, Aloizou AM, Liaskos C, Tsigalou C, Katsiari C, Sakkas LI, Hadjigeorgiou G, Bogdanos DP |title=Tetracyclines Diminish In Vitro IFN-γ and IL-17-Producing Adaptive and Innate Immune Cells in Multiple Sclerosis |journal=Front Immunol |volume=12 |issue= |pages=739186 |date=2021 |pmid=34899697 |pmc=8662812 |doi=10.3389/fimmu.2021.739186 |url= |doi-access=free }}</ref><ref name="pmid35294307">{{cite journal |vauthors=Garrido-Mesa J, Adams K, Galvez J, Garrido-Mesa N |title=Repurposing tetracyclines for acute respiratory distress syndrome (ARDS) and severe COVID-19: a critical discussion of recent publications |journal=Expert Opin Investig Drugs |volume=31 |issue=5 |pages=475–482 |date=May 2022 |pmid=35294307 |pmc=9115781 |doi=10.1080/13543784.2022.2054325 |url=}}</ref><ref name="pmid36869773">{{cite journal |vauthors=de Witte LD, Munk Laursen T, Corcoran CM, Kahn RS, Birnbaum R, Munk-Olsen T, Bergink V |title=A Sex-Dependent Association Between Doxycycline Use and Development of Schizophrenia |journal=Schizophr Bull |volume=49 |issue=4 |pages=953–961 |date=July 2023 |pmid=36869773 |doi=10.1093/schbul/sbad008 |pmc=10318877 |url= |pmc-embargo-date=March 3, 2024 }}</ref>


Doxycycline is also studied for its neuroprotective properties which are associated with antioxidant, anti-apoptotic, and anti-inflammatory mechanisms. Doxycycline is also able to cross the blood-brain barrier. Several studies have shown that doxycycline inhibits dopaminergic neurodegeneration through the upregulation of axonal and synaptic proteins.<ref name="pmid30798507">{{cite journal |vauthors=Santa-Cecília FV, Leite CA, Del-Bel E, Raisman-Vozari R |title=The Neuroprotective Effect of Doxycycline on Neurodegenerative Diseases |journal=Neurotox Res |volume=35 |issue=4 |pages=981–986 |date=May 2019 |pmid=30798507 |doi=10.1007/s12640-019-00015-z |s2cid=71147889 |url=}}</ref><ref name="pmid31879858">{{cite journal |vauthors=Paldino E, Balducci C, La Vitola P, Artioli L, D'Angelo V, Giampà C, Artuso V, Forloni G, Fusco FR |title=Neuroprotective Effects of Doxycycline in the R6/2 Mouse Model of Huntington's Disease |journal=Mol Neurobiol |volume=57 |issue=4 |pages=1889–1903 |date=April 2020 |pmid=31879858 |pmc=7118056 |doi=10.1007/s12035-019-01847-8 |url=}}</ref><ref name="pmid30798507">{{cite journal |vauthors=Santa-Cecília FV, Leite CA, Del-Bel E, Raisman-Vozari R |title=The Neuroprotective Effect of Doxycycline on Neurodegenerative Diseases |journal=Neurotox Res |volume=35 |issue=4 |pages=981–986 |date=May 2019 |pmid=30798507 |doi=10.1007/s12640-019-00015-z |s2cid=71147889 |url=}}</ref> 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. Therefore, the regeneration of the axonal and synaptic network might be beneficial in PD.<ref name="pmid36843128">{{cite journal |vauthors=do Amaral L, Dos Santos NAG, Sisti FM, Del Bel E, Dos Santos AC |title=Doxycycline inhibits dopaminergic neurodegeneration through upregulation of axonal and synaptic proteins |journal=Naunyn Schmiedebergs Arch Pharmacol |volume=396 |issue=8 |pages=1787–1796 |date=August 2023 |pmid=36843128 |doi=10.1007/s00210-023-02435-3 |s2cid=257218181 |url=}}</ref> 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.<ref name="pmid34161892">{{cite journal |vauthors=Mello BSF, Chaves Filho AJM, Custódio CS, Rodrigues PA, Carletti JV, Vasconcelos SMM, Sousa FCF, Sanders LLO, Macedo DS |title=Doxycycline at subantimicrobial dose combined with escitalopram reverses depressive-like behavior and neuroinflammatory hippocampal alterations in the lipopolysaccharide model of depression |journal=J Affect Disord |volume=292 |issue= |pages=733–745 |date=September 2021 |pmid=34161892 |doi=10.1016/j.jad.2021.05.083 |url=}}</ref>While there is some research on the use of doxycycline for treating depression, the results are mixed.<ref name="pmid34161892"/><ref name="pmid34711196">{{cite journal |vauthors=Lee JW, Lee H, Kang HY |title=Association between depression and antibiotic use: analysis of population-based National Health Insurance claims data |journal=BMC Psychiatry |volume=21 |issue=1 |pages=536 |date=October 2021 |pmid=34711196 |pmc=8554858 |doi=10.1186/s12888-021-03550-2 |url= |doi-access=free }}</ref><ref name="pmid36343696">{{cite journal |vauthors=Leyder E, Suresh P, Jun R, Overbey K, Banerjee T, Melnikova T, Savonenko A |title=Depression-related phenotypes at early stages of Aβ and tau accumulation in inducible Alzheimer's disease mouse model: Task-oriented and concept-driven interpretations |journal=Behav Brain Res |volume=438 |issue= |pages=114187 |date=February 2023 |pmid=36343696 |doi=10.1016/j.bbr.2022.114187 |s2cid=253300844 |url=}}</ref>


After a large-scale trial showed no benefit of using doxycycline in treating [[COVID-19|COVID{{nbhyph}}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{{nbhyph}}19.<ref>{{Cite journal |date=31 May 2022 |title=Platform trial rules out treatments for COVID-19 |url=https://evidence.nihr.ac.uk/alert/platform-trial-rules-out-covid-treatments/ |journal=NIHR Evidence |doi=10.3310/nihrevidence_50873 |access-date=1 June 2022 |archive-date=1 June 2022 |archive-url=https://web.archive.org/web/20220601095141/https://evidence.nihr.ac.uk/alert/platform-trial-rules-out-covid-treatments/ |url-status=live }}</ref><ref>{{cite journal | vauthors = Butler CC, Yu LM, Dorward J, Gbinigie O, Hayward G, Saville BR, Van Hecke O, Berry N, Detry MA, Saunders C, Fitzgerald M, Harris V, Djukanovic R, Gadola S, Kirkpatrick J, de Lusignan S, Ogburn E, Evans PH, Thomas NP, Patel MG, Hobbs FD | display-authors = 6 | title = Doxycycline for community treatment of suspected COVID-19 in people at high risk of adverse outcomes in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial | journal = The Lancet. Respiratory Medicine | volume = 9 | issue = 9 | pages = 1010–1020 | date = September 2021 | pmid = 34329624 | pmc = 8315758 | doi = 10.1016/S2213-2600(21)00310-6 }}</ref> 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.<ref name="pmid35462191">{{cite journal |vauthors=Sharma S, Bhatt P, Asdaq S, Alshammari M, Alanazi A, Alrasheedi N, Alrashdi B, Alyami S, Alhazmi B, Alam P, Sharma P, Tomar R, Arora M, Imran M |title=Combined therapy with ivermectin and doxycycline can effectively alleviate the cytokine storm of COVID-19 infection amid vaccination drive: A narrative review |journal=J Infect Public Health |volume=15 |issue=5 |pages=566–572 |date=May 2022 |pmid=35462191 |pmc=8964533 |doi=10.1016/j.jiph.2022.03.014 |url=}}</ref> 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.<ref name="pmid35227056">{{cite journal |vauthors=Ohe M |title=Multi-drug Treatment for COVID-19-induced Acute Respiratory Distress Syndrome |journal=Turk J Pharm Sci |volume=19 |issue=1 |pages=101–103 |date=February 2022 |pmid=35227056 |pmc=8892560 |doi=10.4274/tjps.galenos.2021.63060 |url=}}</ref><ref name="pmid34584416">{{cite journal |vauthors=Dorobisz K, Dorobisz T, Janczak D, Zatoński T |title=Doxycycline in the Coronavirus Disease 2019 Therapy |journal=Ther Clin Risk Manag |volume=17 |issue= |pages=1023–1026 |date=2021 |pmid=34584416 |pmc=8464303 |doi=10.2147/TCRM.S314923 |url= |doi-access=free }}</ref>
After a large-scale trial showed no benefit of using doxycycline in treating [[COVID-19|COVID{{nbhyph}}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{{nbhyph}}19.<ref>{{Cite journal |date=31 May 2022 |title=Platform trial rules out treatments for COVID-19 |url=https://evidence.nihr.ac.uk/alert/platform-trial-rules-out-covid-treatments/ |journal=NIHR Evidence |doi=10.3310/nihrevidence_50873 |access-date=1 June 2022 |archive-date=1 June 2022 |archive-url=https://web.archive.org/web/20220601095141/https://evidence.nihr.ac.uk/alert/platform-trial-rules-out-covid-treatments/ |url-status=live }}</ref><ref>{{cite journal | vauthors = Butler CC, Yu LM, Dorward J, Gbinigie O, Hayward G, Saville BR, Van Hecke O, Berry N, Detry MA, Saunders C, Fitzgerald M, Harris V, Djukanovic R, Gadola S, Kirkpatrick J, de Lusignan S, Ogburn E, Evans PH, Thomas NP, Patel MG, Hobbs FD | display-authors = 6 | title = Doxycycline for community treatment of suspected COVID-19 in people at high risk of adverse outcomes in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial | journal = The Lancet. Respiratory Medicine | volume = 9 | issue = 9 | pages = 1010–1020 | date = September 2021 | pmid = 34329624 | pmc = 8315758 | doi = 10.1016/S2213-2600(21)00310-6 }}</ref> 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.<ref name="pmid35462191">{{cite journal |vauthors=Sharma S, Bhatt P, Asdaq S, Alshammari M, Alanazi A, Alrasheedi N, Alrashdi B, Alyami S, Alhazmi B, Alam P, Sharma P, Tomar R, Arora M, Imran M |title=Combined therapy with ivermectin and doxycycline can effectively alleviate the cytokine storm of COVID-19 infection amid vaccination drive: A narrative review |journal=J Infect Public Health |volume=15 |issue=5 |pages=566–572 |date=May 2022 |pmid=35462191 |pmc=8964533 |doi=10.1016/j.jiph.2022.03.014 |url=}}</ref> 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.<ref name="pmid35227056">{{cite journal |vauthors=Ohe M |title=Multi-drug Treatment for COVID-19-induced Acute Respiratory Distress Syndrome |journal=Turk J Pharm Sci |volume=19 |issue=1 |pages=101–103 |date=February 2022 |pmid=35227056 |pmc=8892560 |doi=10.4274/tjps.galenos.2021.63060 |url=}}</ref><ref name="pmid34584416">{{cite journal |vauthors=Dorobisz K, Dorobisz T, Janczak D, Zatoński T |title=Doxycycline in the Coronavirus Disease 2019 Therapy |journal=Ther Clin Risk Manag |volume=17 |issue= |pages=1023–1026 |date=2021 |pmid=34584416 |pmc=8464303 |doi=10.2147/TCRM.S314923 |url= |doi-access=free }}</ref>

Revision as of 12:39, 15 October 2023

Doxycycline
Clinical data
Pronunciation/ˌdɒksɪˈsaɪkliːn/
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
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.008.429 Edit this at Wikidata
Chemical and physical data
FormulaC22H24N2O8
Molar mass444.440 g·mol−1
3D model (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 broad-spectrum antibiotic of the tetracycline class used in the treatment of infections caused by bacteria and certain parasites.[1] It is used to treat bacterial pneumonia, acne, chlamydia infections, Lyme disease, cholera, typhus, and syphilis.[1] It is also used to prevent malaria in combination with quinine.[1] Doxycycline may be taken by mouth or by injection into a vein.[1]

Common side effects include diarrhea, nausea, vomiting, abdominal pain, and an increased risk of sunburn.[1] Use during pregnancy is not recommended.[1] Like other agents of the tetracycline class, it either slows or kills bacteria by inhibiting protein production.[1][2] It kills malaria by targeting a plastid organelle, the apicoplast.[3][4]

Doxycycline was patented in 1957 and came into commercial use in 1967.[5][6] It is on the World Health Organization's List of Essential Medicines.[7] Doxycycline is available as a generic medicine.[1][8] In 2020, it was the 79th most commonly prescribed medication in the United States, with more than 9 million prescriptions.[9][10]

Medical use

Generic 100 mg doxycycline capsules
Doxycycline package

In addition to the general indications for all members of the tetracycline antibiotics group, doxycycline is frequently used to treat Lyme disease, chronic prostatitis, sinusitis, pelvic inflammatory disease,[11][12] acne, rosacea,[13][14] and rickettsial infections.[15]

In Canada, in 2004, doxycycline was considered a first-line treatment for chlamydia and non-gonococcal urethritis and with cefixime for uncomplicated gonorrhea.[16]

Antibacterial

Moraxella catarrhalis, Brucella melitensis, Chlamydia pneumoniae, and Mycoplasma pneumoniae are generally susceptible to doxycycline, while some Haemophilus spp., Mycoplasma hominis, and Pseudomonas aeruginosa have developed resistance to varying degrees.[17]

It is used in the treatment and prophylaxis of anthrax and Leptospirosis.[18] It is also effective against Yersinia pestis (the infectious agent of bubonic plague), and is prescribed for the treatment of Lyme disease,[19][20][21][22] ehrlichiosis,[23][24] and Rocky Mountain spotted fever.[25]

Doxycycline is indicated for treatment of:[25][26]

When bacteriologic testing indicates appropriate susceptibility to the drug, doxycycline may be used to treat these infections caused by Gram-negative bacteria:[25][26]

Some Gram-positive bacteria have developed resistance to doxycycline. Up to 44% of Streptococcus pyogenes and up to 74% of S. faecalis specimens have developed resistance to the tetracycline group of antibiotics. Up to 57% of P. acnes strains developed resistance to doxycycline.[30] When bacteriologic testing indicates appropriate susceptibility to the drug, doxycycline may be used to treat these infections caused by Gram-positive bacteria:[25][26]

When penicillin is contraindicated, doxycycline can be used to treat:[25][26]

  • Syphilis caused by Treponema pallidum
  • Yaws caused by Treponema pertenue
  • Listeriosis due to Listeria monocytogenes
  • Vincent's infection caused by Fusobacterium fusiforme
  • Actinomycosis caused by Actinomyces israelii
  • Infections caused by Clostridium species

Doxycycline may also be used as adjunctive therapy for severe acne.[25][26]

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).[31]

Antimalarial

Doxycycline is active against the erythrocytic stages of Plasmodium falciparum but not against the gametocytes of P. falciparum.[32] It is used to prevent malaria.[33] 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.[34]

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.[35]

Antihelminthic

Doxycycline kills the symbiotic Wolbachia bacteria in the reproductive tracts of parasitic filarial nematodes, making the nematodes sterile, and thus reducing transmission of diseases such as onchocerciasis and elephantiasis.[36] Field trials in 2005 showed an eight-week course of doxycycline almost eliminates the release of microfilariae.[37]

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 MIC susceptibility data for a few medically significant microorganisms.[38]

  • Chlamydia psittaci: 0.03 μg/mL
  • Mycoplasma pneumoniae: 0.016–2 μg/mL
  • Streptococcus pneumoniae: 0.06–32 μg/mL

Sclerotherapy

Doxycycline is also used for sclerotherapy in slow-flow vascular malformations, namely venous and lymphatic malformations, as well as post-operative lymphoceles.[39]

Others

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]

Contraindications

Pregnancy and lactation

Doxycycline is categorized by the FDA as a class D drug in pregnancy. Doxycycline crosses into breastmilk.[41] Other tetracycline antibiotics are contraindicated in pregnancy and up to eight years of age, due to the potential for disrupting bone and tooth development.[42] They include a class warning about staining of teeth and decreased development of dental enamel in children exposed to tetracyclines in utero, during breastfeeding or during young childhood.[43] However, the FDA has acknowledged that the actual risk of dental staining of primary teeth is undetermined for doxycycline specifically. The best available evidence indicates that doxycycline has little or no effect on hypoplasia of dental enamel or on staining of teeth and the CDC recommends the use of doxycycline for treatment of Q fever and also for tick-borne rickettsial diseases in young children and others advocate for its use in malaria.[44]

Other

Other contraindications are severe liver disease and concomitant use of isotretinoin or other retinoids, as both tetracyclines and retinoids can cause intracranial hypertension (increased pressure around the brain) in rare cases.[45]

Adverse effects

Adverse effects are similar to those of other members of the tetracycline antibiotic group. Doxycycline can cause gastrointestinal upset.[46][47] Oral doxycycline can cause pill esophagitis, particularly when it is swallowed without adequate fluid, or by persons with difficulty swallowing or impaired mobility.[48] Doxycycline is less likely than other antibiotic drugs to cause Clostridium difficile colitis.[49]

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.[50]

Unlike some other members of the tetracycline group, it may be used in those with renal impairment.[51]

Doxycycline use has been associated with increased risk of inflammatory bowel disease.[52] 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.[53]

Interactions

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 doxycycline's effectiveness.[45][54]

Breakfast was observed to reduce doxycycline absorption significantly. Absorption of tetracycline occurs in the stomach and the upper small intestine. Absorption of tetracyclines has been reported to be impaired by milk products, aluminum hydroxide gels, sodium bicarbonate, calcium and magnesium salts, laxatives containing magnesium and iron preparations. The mechanisms responsible for decreased absorption appear to be chelation and an increase in gastric pH. ... In view of these results, it is advisable to instruct the patients to take doxycycline on an empty stomach.[55]

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.[56][57][58]

Pharmacology

See also: Tetracycline antibiotics § Mechanism of action

Doxycycline, like other tetracycline antibiotics, is bacteriostatic. It works by preventing bacteria from reproducing through the inhibition of protein synthesis.[59]

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.[47][60] 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.[61]

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.[46][60] 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.[62]

Pharmacokinetics

The substance is almost completely absorbed from the upper part of the small intestine. It reaches highest concentrations in the blood plasma after one to two hours and has a high plasma protein binding rate of about 80–90%. Doxycycline penetrates into almost all tissues and body fluids. Very high concentrations are found in the gallbladder, liver, kidneys, lung, breast milk, bone and genitals; low ones in saliva, aqueous humour, cerebrospinal fluid (CSF), and especially in inflamed meninges.[45][63][64] By comparison, the tetracycline antibiotic minocycline penetrates significantly better into the CSF and meninges.[65]

Doxycycline metabolism is negligible. It is actively excreted into the gut (in part via the gallbladder, in part directly from blood vessels), where some of it is inactivated by forming chelates. About 40% are eliminated via the kidneys, much less in people with end-stage kidney disease. The biological half-life is 18 to 22 hours (16±6 hours according to another source[63]) in healthy people, slightly longer in those with end-stage kidney disease, and significantly longer in those with liver disease.[45][63][64]

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[66][67] causing Fanconi syndrome.[68] In the case of doxycycline, the absence of a hydroxyl group in C-6 prevents the formation of the nephrotoxic compound.[67] 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.[68]

Chemical properties

Doxycycline, doxycycline monohydrate and doxycycline hyclate are yellow, crystalline powders with a bitter taste. The latter smells faintly of ethanol, a 1% aqueous solution has a pH of 2–3, and the specific rotation is −110° cm3/dm·g in 0.01 N methanolic hydrochloric acid.[63]

Solubility[63]
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 penicillin revolutionized the treatment of bacterial infections in WWII, many chemical companies moved into the field of discovering antibiotics by bioprospecting. American Cyanamid was one of these, and in the late 1940s chemists there discovered chlortetracycline, the first member of the tetracycline class of antibiotics.[2] 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.[2]

As its patent grew near to expiring in the early 1970s, the patent became the subject of lawsuit between Pfizer and International Rectifier[69] that was not resolved until 1983; at the time it was the largest litigated patent case in US history.[70] Instead of a cash payment for infringement, Pfizer took the veterinary and feed-additive businesses of International Rectifier's subsidiary, Rachelle Laboratories.[70]

In January 2013, the FDA reported shortages of some, but not all, forms of doxycycline "caused by increased demand and manufacturing issues".[71] Companies involved included an unnamed major generics manufacturer that ceased production in February 2013, Teva (which ceased production in May 2013), Mylan, Actavis, and Hikma Pharmaceuticals.[72][73] The shortage came at a particularly bad time, since there were also shortages of an alternative antibiotic, tetracycline, at the same time.[74] 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),[75][76][77] before decreasing again.[78][79]

Society and culture

Doxycycline is available worldwide under many brand names.[80] Doxycycline is available as a generic medicine.[1][8]

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 interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and matrix metalloproteinases (MMPs) while increasing the production of anti-inflammatory cytokines such as interleukin-10 (IL-10). Cytokines are small proteins that are secreted by immune cells and play a key role in the immune response. Some studies suggest that doxycycline can also suppress the activation of the 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.[83] [84] [85]

Doxycycline is used to treat acne vulgaris and rosacea.[86][87] However, there is no clear understanding of what contributes more: the bacteriostatic properties of doxycycline, which affect bacteria on the surface of sebaceous glands even in lower doses called "submicrobial"[88][89]or "subantimicrobial",[90][91][92] or whether doxycycline's anti-inflammatory effects, which reduce inflammation in acne vulgaris and rosacea, contribute more to its therapeutic effectiveness against these skin conditions.[93] Those lower, submicrobial, doses can still have a bacteriostatic effect, especially when taken for extended periods, such as several months in treating acne and rosacea.[94] While the submicrobial doses of doxycycline are believed to have anti-inflammatory effects rather than solely antibacterial effects, such doses were proven to work by reducing inflammation associated with acne and rosacea. Still, the exact mechanisms have yet to be fully discovered.[95] 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 towards 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.[96] Studies have shown that submicrobial doses of doxycycline can effectively improve acne and rosacea symptoms,[97] probably without inducing antibiotic resistance.[98]

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.[99] 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.[100][101][102] Doxycycline has been studied in various immunological disorders, including rheumatoid arthritis, lupus, and periodontitis.[103] IIn 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.[104][105][106][107]


Doxycycline is also studied for its neuroprotective properties which are associated with antioxidant, anti-apoptotic, and anti-inflammatory mechanisms. Doxycycline is also able to cross the blood-brain barrier. Several studies have shown that doxycycline inhibits dopaminergic neurodegeneration through the upregulation of axonal and synaptic proteins.[108][109][108] 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. Therefore, the regeneration of the axonal and synaptic network might be beneficial in PD.[110] 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.[91]While there is some research on the use of doxycycline for treating depression, the results are mixed.[91][111][112]

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.[113][114] 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.[115] 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.[116][117]

Research reagent

Doxycycline and other members of the tetracycline class of antibiotics are often used as research reagents in in vitro and in vivo biomedical research experiments involving bacteria as well in experiments in eukaryotic cells and organisms with inducible protein expression systems using tetracycline-controlled transcriptional activation. 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 impairing metabolism and leading to effects that can confound experimental results.[118][119] Doxycycline is also used in "tet-on" (gene expression activated by doxycycline) and "tet-off" (gene expression inactivated by doxycycline) tetracycline-controlled transcriptional activation to regulate transgene expression in organisms and cell cultures.[120] Doxycycline is more stable than tetracycline for this purpose.[120] At subantimicrobial doses, doxycycline is an inhibitor of matrix metalloproteases, and has been used in various experimental systems for this purpose, such as for recalcitrant recurrent corneal erosions.[121]

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External links

  • "Doxycycline". Drug Information Portal. U.S. National Library of Medicine.
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