tretinoin

Tretinoin is most commonly used to treat acne, both inflammatory and noninflammatory. Multiple studies support the efficacy of topical retinoids in the treatment of acne vulgaris.{{cite journal |vauthors=Leyden JJ, Shalita A, Thiboutot D, Washenik K, Webster G |title=Topical retinoids in inflammatory acne: a retrospective, investigator-blinded, vehicle-controlled, photographic assessment |journal=Clinical Therapeutics |volume=27 |issue=2 |pages=216–24 |date=February 2005 |pmid=15811485 |doi=10.1016/j.clinthera.2005.02.009}}{{cite journal |vauthors=Webster G, Cargill DI, Quiring J, Vogelson CT, Slade HB |title=A combined analysis of 2 randomized clinical studies of tretinoin gel 0.05% for the treatment of acne |journal=Cutis |volume=83 |issue=3 |pages=146–54 |date=March 2009 |pmid=19363908}} It is sometimes used in conjunction with other topical acne medications to enhance their penetration.{{cite journal |vauthors=Gollnick H, Cunliffe W, Berson D, Dreno B, Finlay A, Leyden JJ, Shalita AR, Thiboutot D |title=Management of acne: a report from a Global Alliance to Improve Outcomes in Acne |journal=Journal of the American Academy of Dermatology |volume=49 |issue=1 Suppl |pages=S1-37 |date=July 2003 |pmid=12833004 |doi=10.1067/mjd.2003.618 | collaboration = Global Alliance to Improve Outcomes in Acne}} In addition to treating active acne, retinoids accelerate the resolution of acne-induced postinflammatory hyperpigmentation.{{cite book | vauthors = Kang S, Voorhees JJ | chapter = Topical retinoids. | title = Fitzpatrick's Dermatology in General Medicine | edition = 7th | veditors = Wolff K, Goldsmith LA, Katz SI, etal | publisher = McGraw Hill | location = New York | date = 2008 | page = 2106 }} It is also useful as maintenance therapy for people who have responded well to their initial treatment, reducing the prolonged use of antibiotics for acne.{{cite journal | vauthors = Leyden J, Stein-Gold L, Weiss J | title = Why Topical Retinoids Are Mainstay of Therapy for Acne | journal = Dermatology and Therapy | volume = 7 | issue = 3 | pages = 293–304 | date = September 2017 | pmid = 28585191 | pmc = 5574737 | doi = 10.1007/s13555-017-0185-2 }}

Photoaging is premature skin aging resulting from prolonged and repeated exposure to solar radiation. Features of photoaging include fine and coarse wrinkles, changes in skin pigmentation, and loss of elasticity. In human skin, topical retinoids increase collagen production, induce epidermal hyperplasia, and decrease keratinocyte and melanocyte atypia. Topical tretinoin is the most extensively investigated retinoid therapy for photoaging.{{cite journal |vauthors=Han A, Chien AL, Kang S |title=Photoaging |journal=Dermatologic Clinics |volume=32 |issue=3 |pages=291–9, vii |date=July 2014 |pmid=24891052 |doi=10.1016/j.det.2014.03.015}} Topical tretinoin can be used for mild to severe photoaging in people of all skin types. Several weeks or months of use are typically required before improvement is appreciated. Although it has only been studied for up to two years, it may be continued indefinitely. A long-term maintenance regimen with a lower concentration or less frequent application may be an alternative to continued use.{{cite journal |vauthors=Kang S, Bergfeld W, Gottlieb AB, Hickman J, Humeniuk J, Kempers S, Lebwohl M, Lowe N, McMichael A, Milbauer J, Phillips T, Powers J, Rodriguez D, Savin R, Shavin J, Sherer D, Silvis N, Weinstein R, Weiss J, Hammerberg C, Fisher GJ, Nighland M, Grossman R, Nyirady J |title=Long-term efficacy and safety of tretinoin emollient cream 0.05% in the treatment of photodamaged facial skin: a two-year, randomized, placebo-controlled trial |journal=American Journal of Clinical Dermatology |volume=6 |issue=4 |pages=245–53 |date=2005 |pmid=16060712 |doi=10.2165/00128071-200506040-00005 |s2cid=40127961}}

Topical tretinoin is available in several formulations, including creams, gels, microsphere gels, and lotions.{{cite web |vauthors=Ishver A |title=Tretinoin topical (Retin-A, Renova, and others) |website=WebMD |date=7 October 2024 |url=https://www.webmd.com/drugs/2/drug-3956/tretinoin-topical/details |access-date=2 April 2025}}

The chemical stability of tretinoin is significantly affected by light and oxidizing agents. When combined with 10% benzoyl peroxide and exposed to light, significant degradation occurs, with over 50% of the compound degrading within approximately two hours and up to 95% within 24 hours.{{cite journal | vauthors = Martin B, Meunier C, Montels D, Watts O | title = Chemical stability of adapalene and tretinoin when combined with benzoyl peroxide in presence and in absence of visible light and ultraviolet radiation | journal = The British Journal of Dermatology | volume = 139 | issue = Suppl 52 | pages = 8–11 | date = October 1998 | pmid = 9990414 | doi = 10.1046/j.1365-2133.1998.1390s2008.x | publisher = Wiley | s2cid = 43287596 }}

To address this instability, alternative formulations have been developed. The microsphere gel formulation utilizes microsponge technology, encapsulating tretinoin within an aqueous gel matrix to enhance stability and control the release of the active ingredient.{{cite journal |vauthors=Weiss JS, Shavin JS, Nighland M, Grossman R |title=Tretinoin microsphere gel 0.1% for photodamaged facial skin: a placebo-controlled trial |journal=Cutis |volume=78 |issue=6 |pages=426–32 |date=December 2006 |pmid=17243432 |doi= |url=https://cdn-uat.mdedge.com/files/s3fs-public/Document/September-2017/078060426.pdf}} When microencapsulated tretinoin is exposed to benzoyl peroxide and light, it exhibits improved stability, with only approximately 1% degradation after four hours and approximately 13% after 24 hours.{{cite journal |vauthors=Nyirady J, Lucas C, Yusuf M, Mignone P, Wisniewski S |title=The stability of tretinoin in tretinoin gel microsphere 0.1% |journal=Cutis |volume=70 |issue=5 |pages=295–8 |date=November 2002 |pmid=12469785 |url=https://www.mdedge.com/dermatology/article/66872/acne/stability-tretinoin-tretinoin-gel-microsphere-01}}

Tretinoin is used to induce remission in people with acute promyelocytic leukemia (APL) who have a mutation (the t(15;17) translocation that gives rise to the PML::RARα fusion gene). It is not used for maintenance therapy.{{cite web |title=Tretinoin capsule |website=DailyMed |date=12 December 2018 |url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=264138c1-9e5f-45ef-be87-79ca97c989d9 |access-date=16 January 2020}}{{cite journal |vauthors=Huang ME, Ye YC, Chen SR, Chai JR, Lu JX, Zhoa L, Gu LJ, Wang ZY |title=Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia |journal=Blood |volume=72 |issue=2 |pages=567–72 |date=August 1988 |pmid=3165295 |doi=10.1182/blood.V72.2.567.567 |url=http://www.bloodjournal.org/cgi/reprint/72/2/567.pdf|doi-access=free }}{{cite journal |vauthors=Castaigne S, Chomienne C, Daniel MT, Ballerini P, Berger R, Fenaux P, Degos L |title=All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. I. Clinical results |journal=Blood |volume=76 |issue=9 |pages=1704–9 |date=November 1990 |pmid=2224119 |doi=10.1182/blood.V76.9.1704.1704 |url=http://www.bloodjournal.org/cgi/reprint/76/9/1704.pdf|doi-access=free }}

Tretinoin is not effective for the treatment of non-APL forms of Acute Myeloid Leukemia{{cite journal |vauthors=Küley-Bagheri Y, Kreuzer KA, Monsef I, Lübbert M, Skoetz N |title=Effects of all-trans retinoic acid (ATRA) in addition to chemotherapy for adults with acute myeloid leukaemia (AML) (non-acute promyelocytic leukaemia (non-APL)) |journal=The Cochrane Database of Systematic Reviews |volume=2018 |pages=CD011960 |date=August 2018 |issue=8 |pmid=30080246 |pmc=6513628 |doi=10.1002/14651858.CD011960.pub2 | collaboration = Cochrane Haematological Malignancies Group}} or other forms of leukemia. Preclinical studies and clinical data analysis suggest that retinoic acid promotes the growth of T-cell acute lymphoblastic leukemia.{{cite journal | vauthors = Ono Y, Fukuhara N, Yoshie O | title = TAL1 and LIM-only proteins synergistically induce retinaldehyde dehydrogenase 2 expression in T-cell acute lymphoblastic leukemia by acting as cofactors for GATA3 | journal = Molecular and Cellular Biology | volume = 18 | issue = 12 | pages = 6939–6950 | date = December 1998 | pmid = 9819382 | pmc = 109277 | doi = 10.1128/MCB.18.12.6939 }}

Topical tretinoin is for use only on the skin and should not be applied to eyes or mucosal tissues. Common side effects include skin irritation, redness, swelling, and blistering.{{cite web |title=Tretinoin Cream- tretinoin cream |website=DailyMed |date=1 December 2018 |url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=745cc3ce-60b4-4479-a055-316817567949 |access-date=16 January 2020}} If irritation is a problem, a decrease in the frequency of application to every other or every third night can be considered, and the frequency of application can be increased as tolerance improves. The fine skin flaking that is often seen can be gently exfoliated with a washcloth. A non-comedogenic facial moisturizer can also be applied if needed. Delaying the application of the retinoid for at least 20 minutes after washing and drying the face may also be helpful. Topical retinoids are not true photosensitizing drugs, but people using topical retinoids have described symptoms of increased sun sensitivity. This is thought to be due to the thinning of the stratum corneum leading to a decreased barrier against ultraviolet light exposure, as well as an enhanced sensitivity due to the presence of cutaneous irritation.{{cite journal |vauthors=Zaenglein AL |title=Topical retinoids in the treatment of acne vulgaris |journal=Seminars in Cutaneous Medicine and Surgery |volume=27 |issue=3 |pages=177–82 |date=September 2008 |pmid=18786495 |doi=10.1016/j.sder.2008.06.001|doi-broken-date=17 February 2025 }}

The oral form of the drug has boxed warnings concerning the risks of retinoic acid syndrome and leukocytosis. Other significant side effects include a risk of thrombosis, benign intracranial hypertension in children, high lipids (hypercholesterolemia and/or hypertriglyceridemia), and liver damage.

There are many significant side effects from this drug that include malaise (66%), shivering (63%), hemorrhage (60%), infections (58%), peripheral edema (52%), pain (37%), chest discomfort (32%), edema (29%), disseminated intravascular coagulation (26%), weight increase (23%), injection site reactions (17%), anorexia (17%), weight decrease (17%), and myalgia (14%).

Respiratory side effects usually signify retinoic acid syndrome, and include upper respiratory tract disorders (63%), dyspnea (60%), respiratory insufficiency (26%), pleural effusion (20%), pneumonia (14%), rales (14%), and expiratory wheezing (14%), and many others at less than 10%. Around 23% of people taking the drug have reported earache or a feeling of fullness in their ears. Gastrointestinal disorders include bleeding (34%), abdominal pain (31%), diarrhea (23%), constipation (17%), dyspepsia (14%), and swollen belly (11%) and many others at less than 10%.

Cardiovascular side effects include arrhythmias (23%), flushing (23%), hypotension (14%), hypertension (11%), phlebitis (11%), and cardiac failure (6%) and for 3% of patients: cardiac arrest, myocardial infarction, enlarged heart, heart murmur, ischemia, stroke, myocarditis, pericarditis, pulmonary hypertension, secondary cardiomyopathy.

In the nervous system, side effects include dizziness (20%), paresthesias (17%), anxiety (17%), insomnia (14%), depression (14%), confusion (11%), and many others at less than 10% frequency.

In the urinary system, side effects include chronic kidney disease (11%) and several others at less than 10% frequency.

For its use in Acute Promyelocytic Leukemia, tretinoin causes the RARA:PML fusion oncogene to degrade, resulting in the loss of the key driver oncogene.{{cite journal | vauthors = Yoshida H, Kitamura K, Tanaka K, Omura S, Miyazaki T, Hachiya T, Ohno R, Naoe T | title = Accelerated degradation of PML-retinoic acid receptor alpha (PML-RARA) oncoprotein by all-trans-retinoic acid in acute promyelocytic leukemia: possible role of the proteasome pathway | journal = Cancer Research | volume = 56 | issue = 13 | pages = 2945–2948 | date = July 1996 | pmid = 8674046 | url = https://pubmed.ncbi.nlm.nih.gov/8674046/ }} This degradation allows the blasts to mature and results in dramatic responses. This response is typically short-lived as Cyp26 genes are rapidly upregulated to degrade tretinoin. The RARA:PML oncogene is not present in other cancer types, thus explaining why tretinoin and other retinoids have not been effective across hundreds of different trials.{{cite journal | vauthors = Esposito M, Amory JK, Kang Y | title = The pathogenic role of retinoid nuclear receptor signaling in cancer and metabolic syndromes | journal = The Journal of Experimental Medicine | volume = 221 | issue = 9 | date = September 2024 | pmid = 39133222 | doi = 10.1084/jem.20240519 | doi-access = free | pmc = 11318670 }}

For its use in acne, tretinoin (along with other retinoids) are vitamin A derivatives that act by binding to two nuclear receptor families within keratinocytes: the retinoic acid receptors (RAR) and the retinoid X receptors (RXR). These events contribute to the normalization of follicular keratinization and decreased cohesiveness of keratinocytes, resulting in reduced follicular occlusion and microcomedone formation.Fernandez [Graber] EM, Zaenglein A, Thiboutot D. Acne Treatment Methodologies. In: Cosmetic Formulation of Skin Care Products, Taylor and Francis Group, New York 2006. p.273. The retinoid-receptor complex competes for coactivator proteins of AP-1, a key transcription factor involved in inflammation. Retinoids also down-regulate expression of toll-like receptor (TLR)-2, which has been implicated in the inflammatory response in acne.{{cite journal |vauthors=Liu PT, Krutzik SR, Kim J, Modlin RL |title=Cutting edge: all-trans retinoic acid down-regulates TLR2 expression and function |journal=Journal of Immunology |volume=174 |issue=5 |pages=2467–70 |date=March 2005 |pmid=15728448 |doi=10.4049/jimmunol.174.5.2467 |s2cid=20740543 |doi-access=free}} Moreover, tretinoin and retinoids may enhance the penetration of other topical acne medications.

The biological mechanism behind triglyceride and cholesterol elevations remains under investigation.{{cn|date=January 2025}}

File:Tretinon.png

All-trans retinoic acid is produced by the body from dietary factors including retinol, retinyl esters or beta-carotene. The beta-carotene is first cleaved by beta-carotene 15-15'-monooxygenase to retinol which is subsequently oxidized by RDH and ALDH enzymes to produce all-trans retinoic acid (see retinoic acid). Tretinoin is produced synthetically using standard industrial practices.{{Cite web |title=WIPO - Search International and National Patent Collections |url=https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2012155796 |access-date=15 August 2024 |website=patentscope.wipo.int}}

Tretinoin was initially patented in 1957 and received approval for clinical use in 1962. Its application as an acne treatment was co-developed by James Fulton and Albert Kligman at the University of Pennsylvania in the 1960s.{{cite web | work = Vivant Pharmaceuticals, LLC Press Release | date = 10 July 2013 | url = http://vivantskin.blogspot.com/2013/07/vivant-skin-care-co-founder-james-e.html | title = Vivant Skin Care Co-founder James E. Fulton, MD, Loses Colon Cancer Battle | archive-url = https://web.archive.org/web/20160418081737/http://vivantskin.blogspot.com/2013/07/vivant-skin-care-co-founder-james-e.html | archive-date = 18 April 2016 }}{{cite web | vauthors = Gellene D |work=The New York Times |date=22 February 2010 |url=https://www.nytimes.com/2010/02/23/us/23kligman.html?_r=0 |title=Dr. Albert M. Kligman, Dermatologist, Dies at 93}}{{cite web |last=Kelly |first=Kim |title=The Horrifying History Behind a Beloved Skin-Care Ingredient |website=Teen Vogue |date=26 February 2025 |url=https://www.teenvogue.com/story/retinol-skincare-ingredient-history |access-date=8 April 2025}} Phase I trials, the first conducted on human subjects, were performed on inmates at Holmesburg Prison during a long-running regime of non-therapeutic testing on prison inmates at Holmesburg.{{cite book | vauthors = Washington HA |url=https://www.worldcat.org/oclc/61131882 |title=Medical apartheid : the dark history of medical experimentation on Black Americans from colonial times to the present |date=2006 |publisher=Doubleday |isbn=0-385-50993-6 |location=New York |oclc=61131882}}{{cite book | vauthors = Hornblum AM |url=https://www.worldcat.org/oclc/37884781 |title=Acres of skin : human experiments at Holmesburg Prison : a story of abuse and exploitation in the name of medical science |date=1998 |publisher=Routledge |isbn=0-415-91990-8 |location=New York |oclc=37884781}} The University of Pennsylvania held the patent for Retin-A, which it subsequently licensed to various pharmaceutical companies, and the compound received US Food and Drug Administration (FDA) approval for acne in 1971.{{cite journal |vauthors=Baldwin H, Webster G, Stein Gold L, Callender V, Cook-Bolden FE, Guenin E |title=50 Years of Topical Retinoids for Acne: Evolution of Treatment |journal=American Journal of Clinical Dermatology |volume=22 |issue=3 |pages=315–327 |date=May 2021 |pmid=33871811 |doi=10.1007/s40257-021-00594-8}}

Treatment of acute promyelocytic leukemia was first introduced at Ruijin Hospital in Shanghai by Wang Zhenyi in a 1988 clinical trial.{{cite journal |vauthors=Huang ME, Ye YC, Chen SR, Chai JR, Lu JX, Zhoa L, Gu LJ, Wang ZY |title=Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia |journal=Blood |volume=72 |issue=2 |pages=567–72 |date=August 1988 |pmid=3165295 |doi=10.1182/blood.V72.2.567.567 |doi-access=free}}

In 1997, the FDA approved tretinoin microsphere gel, marketed as Retin-A Micro, for the treatment of acne.

The origin of the name tretinoin is uncertain,{{Citation| title = Tretinoin |work = Oxford Dictionaries Online |publisher=Oxford University Press |url=https://www.oxfordreference.com/display/10.1093/oi/authority.20110803105624146 }} although several sources agree (one with probability, one with asserted certainty{{Citation |author=Houghton Mifflin Harcourt |title=The American Heritage Dictionary of the English Language |publisher=Houghton Mifflin Harcourt |url=https://ahdictionary.com/ |postscript=. |url-status=dead |archive-url=https://web.archive.org/web/20150925104737/https://ahdictionary.com/ |archive-date=25 September 2015 |access-date=24 January 2015}}) that it probably comes from trans- + retinoic [acid] + -in, which is plausible given that tretinoin is the all-trans isomer of retinoic acid. The name isotretinoin is the same root tretinoin plus the prefix iso-. Regarding pronunciation, the following variants apply equally to both tretinoin and isotretinoin. Given that retinoic is pronounced {{IPAc-en|ˌ|r|ɛ|t|ɪ|ˈ|n|oʊ|ɪ|k}},{{Citation |title= Tretinoin | work = Merriam-Webster's Medical Dictionary | date = 30 January 2025 |publisher=Merriam-Webster |url=https://www.merriam-webster.com/dictionary/tretinoin |postscript=.}}{{Citation |title= Tretinoin |work = Dorland's Illustrated Medical Dictionary |publisher=Elsevier |url=https://www.dorlandsonline.com/dorland/definition?id=50812 |postscript=.}} it is natural that {{IPAc-en|ˌ|t|r|ɛ|t|ɪ|ˈ|n|oʊ|ɪ|n}} is a commonly heard pronunciation. Dictionary transcriptions also include {{IPAc-en|ˌ|t|r|ɪ|ˈ|t|ɪ|n|oʊ|ɪ|n}} ({{respell|tri|TIN|oh|in}}) and {{IPAc-en|ˈ|t|r|ɛ|t|ɪ|n|ɔɪ|n}}.

Tretinoin has been explored as a treatment for hair loss,{{cite journal |vauthors=Sattur SS, Sattur IS |title=Pharmacological Management of Pattern Hair Loss |journal=Indian Journal of Plastic Surgery : Official Publication of the Association of Plastic Surgeons of India |volume=54 |issue=4 |pages=422–434 |date=October 2021 |pmid=34984080 |pmc=8719956 |doi=10.1055/s-0041-1739254}} potentially as a way to increase the ability of minoxidil (by acting as an enzyme and accelerating the production of minoxidil sulfate) to penetrate the scalp, but the evidence is weak and contradictory.{{cite book | vauthors = Trüeb RM | chapter = Diagnosis and Treatment |title=The Difficult Hair Loss Patient: Guide to Successful Management of Alopecia and Related Conditions. |date=2015 |publisher=Springer |location=Cham |isbn=978-3-319-19701-2 | chapter-url = https://books.google.com/books?id=0ue5BAAAQBAJ&pg=PA95 | archive-url= https://web.archive.org/web/20171105200032/https://books.google.com/books?id=0ue5BAAAQBAJ&pg=PA95 | archive-date=5 November 2017}}{{cite journal |vauthors=Rogers NE, Avram MR |title=Medical treatments for male and female pattern hair loss |journal=Journal of the American Academy of Dermatology |volume=59 |issue=4 |pages=547–66; quiz 567–8 |date=October 2008 |pmid=18793935 |doi=10.1016/j.jaad.2008.07.001}}

{{Reflist}}

• {{cite web |title=Tretinoin Topical |website=MedlinePlus |url=https://medlineplus.gov/druginfo/meds/a682437.html}}

{{Clear}}

{{Acne Agents}}

{{Chemotherapeutic agents}}

{{Vitamin}}

{{Carotenoids}}

{{Retinoid receptor modulators}}

{{Portal bar|Medicine}}

{{Authority control}}

Category:Anti-acne preparations

Category:Antineoplastic drugs

Category:Aromatase inhibitors

Category:Carboxylic acids

Category:Carotenoids

Category:Cyclohexenes

Category:Drugs developed by Hoffmann-La Roche

Category:Retinoids

Category:Wikipedia medicine articles ready to translate

Category:World Health Organization essential medicines

Category:Vitamin A