Tretinoin

Tretinoin, also known as all-trans retinoic acid (ATRA), is a medication used for the treatment of acne and acute promyelocytic leukemia.<ref name="AHFS2016" /><ref name="Tiv2016">Template:Cite book</ref><ref name="BNF69">Template:Cite book</ref> For acne, it is applied to the skin as a cream, gel or ointment.<ref name="BNF69" /> For acute promyelocytic leukemia, it is effective only when the RARA-PML fusion mutation is present<ref>Template:Cite journal</ref> and is taken by mouth for up to three months.<ref name="AHFS2016">Template:Cite web</ref> Topical tretinoin is also the most extensively investigated retinoid therapy for photoaging.<ref>Template:Cite web</ref>

Common side effects when used as a cream are limited to the skin and include skin redness, peeling, and sun sensitivity.<ref name="BNF69" /> When taken by mouth, side effects include hypertriglyceridemia, hypercholesterolemia, shortness of breath, headache, numbness, depression, skin dryness, itchiness, hair loss, vomiting, muscle pains, and vision changes.<ref name="AHFS2016" /> Other severe side effects include high white blood cell counts and blood clots.<ref name="AHFS2016" /> Use during pregnancy is contraindicated due to the risk of birth defects.<ref name="AHFS2016" /><ref name="Drugs.com oral pregnancy" /> It is in the retinoid family of medications.<ref name="Tiv2016" />

Tretinoin was patented in 1957 and approved for medical use in 1962.<ref name="Fis2006">Template:Cite book</ref> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO21st">Template:Cite book</ref> Tretinoin is available as a generic medication.<ref name="AHFS2016B">Template:Cite web</ref> In 2023, it was the 197th most commonly prescribed medication in the United States, with more than 2Template:Nbspmillion prescriptions.<ref name="Top 300">Template:Cite web</ref><ref>Template:Cite web</ref>

Medical uses

Skin use

Acne

Tretinoin is most commonly used to treat acne,<ref name="TopicalLabel" /> both inflammatory and noninflammatory. Multiple studies support the efficacy of topical retinoids in the treatment of acne vulgaris.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> It is sometimes used in conjunction with other topical acne medications to enhance their penetration.<ref name="pmid12833004">Template:Cite journal</ref> In addition to treating active acne, retinoids accelerate the resolution of acne-induced postinflammatory hyperpigmentation.<ref name="Kang S 2008">Template:Cite book</ref> 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.<ref>Template:Cite journal</ref>

Photoaging

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.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>

Available forms

Topical tretinoin is available in several formulations, including creams, gels, microsphere gels, and lotions.<ref name="Ishver">Template:Cite web</ref>

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.<ref name="Wiley 1998 pp. 8–11">Template:Cite journal</ref>

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.<ref name="pmid17243432">Template:Cite journal</ref> 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.<ref name="pmid12469785">Template:Cite journal</ref>

Leukemia

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.<ref name="OralLabel">Template:Cite web</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Tretinoin is not effective for the treatment of non-APL forms of Acute Myeloid Leukemia<ref>Template:Cite journal</ref> or other forms of leukemia. Preclinical studies and clinical data analysis suggest that retinoic acid promotes the growth of T-cell acute lymphoblastic leukemia.<ref>Template:Cite journal</ref>

Side effects

Dermatology

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.<ref name="TopicalLabel">Template:Cite web</ref> 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.<ref>Template:Cite journal</ref>

Acute Promyelocytic Leukemia

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

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%).<ref name="OralLabel" />

Respiratory side effects usually signify retinoic acid syndrome (also called differentiation 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%.<ref name="OralLabel" /> Around 23% of people taking the drug have reported earache or a feeling of fullness in their ears.<ref name="OralLabel" /> 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%.<ref name="OralLabel" />

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.<ref name="OralLabel" />

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.<ref name="OralLabel" />

In the urinary system, side effects include chronic kidney disease (11%) and several others at less than 10% frequency.<ref name="OralLabel" />

Mechanism of action

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.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>

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).<ref name="Kang S 2008" /> These events contribute to the normalization of follicular keratinization and decreased cohesiveness of keratinocytes, resulting in reduced follicular occlusion and microcomedone formation.<ref>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.</ref> The retinoid-receptor complex competes for coactivator proteins of AP-1, a key transcription factor involved in inflammation.<ref name="Kang S 2008" /> Retinoids also down-regulate expression of toll-like receptor (TLR)-2, which has been implicated in the inflammatory response in acne.<ref>Template:Cite journal</ref> Moreover, tretinoin and retinoids may enhance the penetration of other topical acne medications.<ref name="pmid12833004" />

The biological mechanism behind triglyceride and cholesterol elevations remains under investigation.Template:Citation needed

Synthesis

File:Tretinon.png

Biosynthetic pathway of tretinon

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.<ref>Template:Cite web</ref>

History

Tretinoin was initially patented in 1957 and received approval for clinical use in 1962.<ref name="Fis2006"/> Its application as an acne treatment was co-developed by James Fulton and Albert Kligman at the University of Pennsylvania in the 1960s.<ref name="FultonObit">Template:Cite web</ref><ref name="KligmanObit">Template:Cite web</ref><ref name="Kelly 2025">Template:Cite web</ref> 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.<ref name="Kelly 2025"/><ref>Template:Cite book</ref><ref>Template:Cite book</ref> The University of Pennsylvania held the patent for Retin-A, which it subsequently licensed to various pharmaceutical companies,<ref name="KligmanObit" /> and the compound received US Food and Drug Administration (FDA) approval for acne in 1971.<ref name="Kelly 2025"/><ref name="pmid33871811">Template:Cite journal</ref>

Treatment of acute promyelocytic leukemia was first introduced at Ruijin Hospital in Shanghai by Wang Zhenyi in a 1988 clinical trial.<ref>Template:Cite journal</ref>

In 1997, the FDA approved tretinoin microsphere gel, marketed as Retin-A Micro, for the treatment of acne.<ref name="pmid17243432"/>

Etymology

The origin of the name tretinoin is uncertain,<ref name="MW_Medical" /><ref name="OxfordDictionaries">Template:Citation</ref> although several sources agree (one with probability,<ref name="MW_Medical" /> one with asserted certainty<ref name="AHD">Template:Citation</ref>) 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 Template:IPAc-en,<ref name="OxfordDictionaries" /><ref name="AHD" /><ref name="MW_Medical">Template:Citation</ref><ref name="Dorlands">Template:CitationTemplate:Dead link</ref> it is natural that Template:IPAc-en is a commonly heard pronunciation. Dictionary transcriptions also include Template:IPAc-en (Template:Respell)<ref name="OxfordDictionaries" /><ref name="MW_Medical" /> and Template:IPAc-en.<ref name="AHD" /><ref name="Dorlands" />

Research

Tretinoin has been explored as a treatment for hair loss,<ref name="pmid34984080">Template:Cite journal</ref> 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.<ref>Template:Cite book</ref><ref>Template:Cite journal</ref>

External links

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