Tretinoin

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Tretinoin
Tretinoin structure.svg
Clinical data
PronunciationSee pronunciation note
Trade namesVesanoid, Avita, Renova, Retin-a, others
AHFS/Drugs.comMonograph
MedlinePlusa682437
License data
Pregnancy
category
  • AU: X (High risk)
  • US: D (Evidence of risk)
Routes of
administration
topical, by mouth
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
Pharmacokinetic data
Protein binding> 95%
Elimination half-life0.5-2 hours
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.005.573 Edit this at Wikidata
Chemical and physical data
FormulaC20H28O2
Molar mass300.4412 g/mol g·mol−1
3D model (JSmol)
Melting point180 °C (356 °F)
  (verify)

Tretinoin, also known as all-trans retinoic acid (ATRA), is medication used for the treatment of acne and acute promyelocytic leukemia.[1][2][3] For acne, it is applied to the skin as a cream or ointment.[3] For leukemia, it is taken by mouth for up to three months.[1]

Common side effects when used by mouth include shortness of breath, headache, numbness, depression, skin dryness, itchiness, hair loss, vomiting, muscle pains, and vision changes.[1] Other severe side effects include high white blood cell counts and blood clots.[1] When used as a cream, side effects include skin redness, peeling, and sun sensitivity.[3] Use during pregnancy is contraindicated due to the risk of birth defects.[1] It is in the retinoid family of medications.[2]

Tretinoin was patented in 1957 and approved for medical use in 1962.[4] It is on the World Health Organization's List of Essential Medicines, which lists the safest and most effective medicines needed in a health system.[5] Tretinoin is available as a generic medication.[6] In the United Kingdom the cream together with erythromycin costs the NHS about £7.05 per 25 mL while the pills are £1.61 per 10 mg.[3] In 2016 it was the 297th most prescribed medication in the United States with more than a million prescriptions.[7]

Medical uses[edit]

Skin use[edit]

Tretinoin is most commonly used to treat acne.[8] In topical form, this drug is pregnancy category C and should not be used by pregnant women.[8]

People using the topical form should not also use any cream or lotion that has a strong drying effect, contains alcohol, astringents, spices, lime, sulfur, resorcinol, or aspirin, as these may interact with tretinoin or exacerbate its side effects.[8]

Leukemia[edit]

Tretinoin is used to induce remission in people with acute promyelocytic leukemia who have a mutation (the t(15;17) translocation 160 and/or the presence of the PML/RARα gene) and who don't respond to anthracyclines or can't take that class of drug. It is not used for maintenance therapy.[9][10][11]

By mouth, this drug is pregnancy category D and should not be used by pregnant women as it may harm the fetus.[9]

Side effects[edit]

Skin use[edit]

Topical tretinoin is only for use on skin and it should not be applied to eyes or mucosal tissues. Common side effects include skin irritation, redness, swelling, and blistering.[8]

Leukemia use[edit]

The oral form of the drug has boxed warnings concerning the risks of retinoic acid syndrome and leukocytosis.[9]

Other significant side effects include a risk of thrombosis, benign intracranial hypertension in children, high lipids (hypercholesterolemia and/or hypertriglyceridemia), and liver damage.[9]

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%).[9]

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%.[9]

Around 23% of people taking the drug have reported earache or a feeling of fullness in their ears.[9]

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%.[9]

In the cardiovascular system, 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.[9]

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.[9]

In the urinary system, side effects include chronic kidney disease (11%) and several others at less than 10% frequency.[9]

Mechanism of action[edit]

For its use in cancer, its mechanism of action is unknown, but on a cellular level, laboratory test show that tretinoin forces APL cells to differentiate and stops them from proliferating; in people there is evidence that it forces the primary cancerous promyelocytes to differentiate into their final form, allowing normal cells to take over the bone marrow.[9] Recent study shows that ATRA inhibits and degrades active PIN1.[12]

For its use in acne, the mechanism is unknown, but again on a cellular level there is evidence that it decreases the ability of epithelial cells in hair follicles to stick together, leading to fewer blackheads; it also seems to make the epithelial cells divide faster, causing the blackheads to be pushed out.[citation needed]

Biosynthesis[edit]

Biosynthetic pathway of tretinon

Tretinoin is synthesized from Beta-carotene. The Beta-carotene is firstly cleaved into Beta-carotene 15-15'-monooxygenase through site 1 double bond oxidized to epoxide. The epoxide is attacked by water to form diol in site 1. NADH, as a reduction agent, reduce the alcohol group to aldehydes.[13]

History[edit]

Tretinoin was co-developed for its use in acne by James Fulton and Albert Kligman when they were at University of Pennsylvania in the late 1960s.[14][15] The University of Pennsylvania held the patent for Retin-A, which it licensed to pharmaceutical companies.[15]

Etymology[edit]

The origin of the name tretinoin is uncertain,[16][17] although several sources agree (one with probability,[16] one with asserted certainty[18]) 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 /ˌrɛtɪˈnɪk/,[17][18][19][20] it is natural that /ˌtrɛtɪˈnɪn/ is a commonly heard pronunciation. Dictionary transcriptions also include /ˌtrɪˈtɪnɪn/ (tri-TIN-oh-in)[17][19] and /ˈtrɛtɪnɔɪn/.[18][20]

Research[edit]

Tretinoin has been explored as a treatment for hair loss, potentially as a way to increase the ability of minoxidil to penetrate the scalp, but the evidence is weak and contradictory.[21][22]

It has been used off-label to treat and reduce the appearance of stretch marks.[23] It has also been studied in skin ageing.[24]

See also[edit]

References[edit]

  1. ^ a b c d e "Tretinoin". The American Society of Health-System Pharmacists. Archived from the original on 30 November 2016. Retrieved 8 December 2016.
  2. ^ a b Tivnan A (2016). Resistance to Targeted Therapies Against Adult Brain Cancers. Springer. p. 123. ISBN 9783319465050. Archived from the original on 2017-11-05.
  3. ^ a b c d British national formulary : BNF 69 (69 ed.). British Medical Association. 2015. pp. 627, 821–822. ISBN 9780857111562.
  4. ^ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 476. ISBN 9783527607495. Archived from the original on 2017-11-05.
  5. ^ "World Health Organization model list of essential medicines: 21st list 2019". 2019. hdl:10665/325771. Cite journal requires |journal= (help)
  6. ^ "Tretinoin topical". The American Society of Health-System Pharmacists. Archived from the original on 16 May 2016. Retrieved 8 December 2016.
  7. ^ "The Top 300 of 2019". clincalc.com. Retrieved 22 December 2018.
  8. ^ a b c d e Topical Cream Gel Liquid Label Archived 2011-12-29 at the Wayback Machine
  9. ^ a b c d e f g h i j k l Oral Label Archived 2016-05-08 at the Wayback Machine
  10. ^ Huang ME, Ye YC, Chen SR, Chai JR, Lu JX, Zhoa L, et al. (August 1988). "Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia" (PDF). Blood. 72 (2): 567–72. PMID 3165295.
  11. ^ Castaigne S, Chomienne C, Daniel MT, Ballerini P, Berger R, Fenaux P, Degos L (November 1990). "All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. I. Clinical results" (PDF). Blood. 76 (9): 1704–9. PMID 2224119.
  12. ^ Wei S, Kozono S, Kats L, Nechama M, Li W, Guarnerio J, et al. (May 2015). "Active Pin1 is a key target of all-trans retinoic acid in acute promyelocytic leukemia and breast cancer". Nature Medicine. 21 (5): 457–66. doi:10.1038/nm.3839. PMC 4425616. PMID 25849135.
  13. ^ Woggon W (2009). "Oxidative cleavage of carotenoids catalyzed by enzyme models and beta-carotene 15,15´-monooxygenase". Pure and Applied Chemistry. 74 (8): 1397–1408. doi:10.1351/pac200274081397. ISSN 1365-3075.
  14. ^ Vivant Pharmaceuticals, LLC Press Release. July 10, 2013, Vivant Skin Care Co-founder James E. Fulton, MD, Loses Colon Cancer Battle
  15. ^ a b Gellene D (22 February 2010). "Dr. Albert M. Kligman, Dermatologist, Dies at 93". The New York Times.}
  16. ^ a b Merriam-Webster, Merriam-Webster's Unabridged Dictionary, Merriam-Webster.
  17. ^ a b c Oxford Dictionaries, Oxford Dictionaries Online, Oxford University Press, archived from the original on 2014-10-22.
  18. ^ a b c Houghton Mifflin Harcourt, The American Heritage Dictionary of the English Language, Houghton Mifflin Harcourt, archived from the original on 2015-09-25.
  19. ^ a b Merriam-Webster, Merriam-Webster's Medical Dictionary, Merriam-Webster.
  20. ^ a b Elsevier, Dorland's Illustrated Medical Dictionary, Elsevier.
  21. ^ Ralph M. Trüeb. The Difficult Hair Loss Patient: Guide to Successful Management of Alopecia and Related Conditions. Springer, 2015. ISBN 9783319197012 Pg. 95 Archived 2017-11-05 at the Wayback Machine
  22. ^ Rogers NE, Avram MR (October 2008). "Medical treatments for male and female pattern hair loss". Journal of the American Academy of Dermatology. 59 (4): 547–66, quiz 567–8. doi:10.1016/j.jaad.2008.07.001. PMID 18793935.
  23. ^ Arthur W. Perry (2007). Straight talk about cosmetic surgery. Yale University Press. p. 63. ISBN 978-0-300-12104-9.
  24. ^ Mukherjee S, Date A, Patravale V, Korting HC, Roeder A, Weindl G (December 2006). "Retinoids in the treatment of skin aging: an overview of clinical efficacy and safety". Clinical Interventions in Aging. 1 (4): 327–48. doi:10.2147/ciia.2006.1.4.327. PMC 2699641. PMID 18046911.

External links[edit]