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Tretinoin
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Tretinoin
Clinical data
PronunciationSee pronunciation note
Trade namesRetin-A, Avita, Renova, others
Other namesATRA
AHFS/Drugs.comMonograph
Topical Monograph
MedlinePlusa608032
License data
Pregnancy
category
  • AU: X (High risk)/ (Oral); D (Topical)[1][2]
Routes of
administration		Topical, by mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding> 95%
Elimination half-life0.5–2 hours
Identifiers
  • (2E,4E,6E,8E)-3,7-Dimethyl-9-(2,6,6-trimethylcyclohexen-1-yl)nona-2,4,6,8-tetraenoic acid
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 mass300.442 g·mol−1
3D model (JSmol)
Melting point180 °C (356 °F)
  • CC1=C(C(CCC1)(C)C)C=CC(=CC=CC(=CC(=O)O)C)C
  • InChI=1S/C20H28O2/c1-15(8-6-9-16(2)14-19(21)22)11-12-18-17(3)10-7-13-20(18,4)5/h6,8-9,11-12,14H,7,10,13H2,1-5H3,(H,21,22)/b9-6+,12-11+,15-8+,16-14+ checkY
  • Key:SHGAZHPCJJPHSC-YCNIQYBTSA-N dd><htt//60967409 checkY Arsen Ramirez Cruzﺁ
  (verify)

Tretinoin, also known as all-trans retinoic acid (ATRA), is a medication used for the treatment of acne and acute promyelocytic leukemia.[7][8][9] For acne, it is applied to the skin as a cream, gel or ointment.[9] For acute promyelocytic leukemia, it is effective only when the RARA-PML fusion mutation is present[10] and is taken by mouth for up to three months.[7] Topical tretinoin is also the most extensively investigated retinoid therapy for photoaging.[11]

Common side effects when used as a cream are limited to the skin and include skin redness, peeling, and sun sensitivity.[9] 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.[7] Other severe side effects include high white blood cell counts and blood clots.[7] Use during pregnancy is contraindicated due to the risk of birth defects.[7][1] It is in the retinoid family of medications.[8]

Tretinoin was patented in 1957 and approved for medical use in 1962.[12] It is on the World Health Organization's List of Essential Medicines.[13] Tretinoin is available as a generic medication.[14] In 2023, it was the 197th most commonly prescribed medication in the United States, with more than 2 million prescriptions.[15][16]

Medical uses

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Skin use

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Acne

[edit]

Tretinoin is most commonly used to treat acne,[5] both inflammatory and noninflammatory. Multiple studies support the efficacy of topical retinoids in the treatment of acne vulgaris.[17][18] It is sometimes used in conjunction with other topical acne medications to enhance their penetration.[19] In addition to treating active acne, retinoids accelerate the resolution of acne-induced postinflammatory hyperpigmentation.[20] 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.[21]

Photoaging

[edit]

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.[22] 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.[23]

Available forms

[edit]

Topical tretinoin is available in several formulations, including creams, gels, microsphere gels, and lotions.[24]

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.[25]

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.[26] 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.[27]

Leukemia

[edit]

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.[4][28][29]

Tretinoin is not effective for the treatment of non-APL forms of Acute Myeloid Leukemia[30] or other forms of leukemia. Preclinical studies and clinical data analysis suggest that retinoic acid promotes the growth of T-cell acute lymphoblastic leukemia.[31]

Side effects

[edit]

Dermatology

[edit]

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.[5] 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.[32]

Acute Promyelocytic Leukemia

[edit]

The oral form of the drug has boxed warnings concerning the risks of retinoic acid syndrome and leukocytosis.[4] Other significant side effects include a risk of thrombosis, benign intracranial hypertension in children, high lipids (hypercholesterolemia and/or hypertriglyceridemia), and liver damage.[4]

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%).[4]

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%.[4] Around 23% of people taking the drug have reported earache or a feeling of fullness in their ears.[4] 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%.[4]

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.[4]

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.[4]

In the urinary system, side effects include chronic kidney disease (11%) and several others at less than 10% frequency.[4]

Mechanism of action

[edit]

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.[33] 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.[34]

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).[20] These events contribute to the normalization of follicular keratinization and decreased cohesiveness of keratinocytes, resulting in reduced follicular occlusion and microcomedone formation.[35] The retinoid-receptor complex competes for coactivator proteins of AP-1, a key transcription factor involved in inflammation.[20] Retinoids also down-regulate expression of toll-like receptor (TLR)-2, which has been implicated in the inflammatory response in acne.[36] Moreover, tretinoin and retinoids may enhance the penetration of other topical acne medications.[19]

The biological mechanism behind triglyceride and cholesterol elevations remains under investigation.[citation needed]

Synthesis

[edit]
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.[37]

History

[edit]

Tretinoin was initially patented in 1957 and received approval for clinical use in 1962.[12] Its application as an acne treatment was co-developed by James Fulton and Albert Kligman at the University of Pennsylvania in the 1960s.[38][39][40] 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.[40][41][42] The University of Pennsylvania held the patent for Retin-A, which it subsequently licensed to various pharmaceutical companies,[39] and the compound received US Food and Drug Administration (FDA) approval for acne in 1971.[40][43]

Treatment of acute promyelocytic leukemia was first introduced at Ruijin Hospital in Shanghai by Wang Zhenyi in a 1988 clinical trial.[44]

In 1997, the FDA approved tretinoin microsphere gel, marketed as Retin-A Micro, for the treatment of acne.[26]

Etymology

[edit]

The origin of the name tretinoin is uncertain,[45][46] although several sources agree (one with probability,[45] one with asserted certainty[47]) 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 /ˌrɛtɪˈnoʊɪk/,[46][47][45][48] it is natural that /ˌtrɛtɪˈnoʊɪn/ is a commonly heard pronunciation. Dictionary transcriptions also include /ˌtrɪˈtɪnoʊɪn/ (tri-TIN-oh-in)[46][45] and /ˈtrɛtɪnɔɪn/.[47][48]

Research

[edit]

Tretinoin has been explored as a treatment for hair loss,[49] 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.[50][51]

References

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Tretinoin

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from Grokipedia
Tretinoin, also known as all-trans retinoic acid (ATRA), is a naturally occurring and metabolite of with the C₂₀H₂₈O₂. It serves as a key therapeutic agent, primarily applied topically to treat acne vulgaris by normalizing follicular keratinization and reducing comedone formation, and orally to induce remission in (APL) by promoting the differentiation of leukemic promyelocytes. Available in formulations such as creams, gels, and lotions at concentrations ranging from 0.01% to 0.1% for topical use, tretinoin is also employed for , including fine wrinkles, mottled , and rough skin texture. Pharmacologically, tretinoin exerts its effects by binding to intracellular receptors (RARs), particularly RAR-α, RAR-β, and RAR-γ, which act as ligand-dependent transcription factors to regulate involved in cell growth, differentiation, and . In dermatological applications, it increases epidermal cell turnover, stimulates production, and inhibits matrix metalloproteinases, thereby improving elasticity and reducing signs of sun damage over 3–6 months of consistent use. For APL, its differentiation-inducing properties target the PML-RARA resulting from the t(15;17) translocation, leading to remission rates of 64–100% in responsive patients when used as induction therapy. Systemic absorption from topical application is minimal (less than 5%), but oral administration requires careful monitoring due to risks like . Tretinoin was first synthesized in 1946 and patented in the mid-20th century, with its efficacy for reported in clinical studies by 1969, leading to FDA approval in 1971 as the first topical for acne vulgaris under the brand name Retin-A. Its role in emerged in the through research on retinoid-induced differentiation, culminating in FDA approval in 1995 for APL induction under the brand Vesanoid, marking a in treatment. Today, tretinoin remains a cornerstone in and , with ongoing research exploring its combinations, such as with for low-risk APL, to enhance efficacy and reduce toxicity.

Pharmacology

Chemical structure and properties

Tretinoin, also known as all-trans-retinoic acid (ATRA), is the generic name for this compound, with the brand name Retin-A commonly used in topical formulations. The term "tretinoin" derives from "trans-retinoic acid," highlighting its all-trans isomeric configuration at the four double bonds in the polyene chain. Its systematic IUPAC name is (2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenoic acid, and its molecular formula is C20H28O2. Chemically, tretinoin is derived from (retinol) through oxidation of the alcohol group to a , resulting in a structure featuring a β-ionone ring attached to a polyene chain with four conjugated double bonds and a terminal group. These conjugated double bonds are critical for its but also contribute to its susceptibility to , where exposure can shift the configuration to less active forms such as 13-cis-retinoic acid () or 9-cis-retinoic acid. Tretinoin appears as a yellow to light orange crystalline powder with a characteristic floral odor. It has a melting point of 180–182 °C and is very sparingly soluble in water (practically insoluble), but slightly soluble in ethanol and chloroform, and more soluble in dichloromethane. Due to its chemical instability, tretinoin is sensitive to light, air, and heat, which can induce photoisomerization, oxidation, or degradation, necessitating storage in opaque, airtight containers away from excessive temperatures.

Pharmacokinetics

Tretinoin exhibits distinct pharmacokinetic profiles depending on the , with topical application resulting in negligible systemic exposure compared to oral dosing. Absorption
Following topical application, tretinoin demonstrates minimal systemic absorption, with absorption estimated at approximately 2% of the applied dose after both single and repeated daily applications over 28 days. This low (<5%) confines the drug primarily to the stratum corneum, limiting its entry into the systemic circulation. In contrast, oral administration achieves an absolute of about 50%, with rapid absorption leading to peak plasma concentrations within 1 to 2 hours post-dose. Food may enhance oral absorption, though this effect has not been fully characterized for tretinoin specifically. Distribution
Tretinoin is highly bound to plasma proteins (>95%), primarily and lipoproteins, across a concentration range of 10 to 500 ng/mL. The apparent of tretinoin has not been determined. It readily crosses the , contributing to its teratogenic potential, and is present in , necessitating avoidance during and . Metabolism
Tretinoin undergoes extensive hepatic metabolism primarily via enzymes, including , CYP2C8, and , producing metabolites such as 4-oxo-tretinoin and other oxidized derivatives. Additional pathways include by UGT2B7 and rapid to 13-cis-retinoic acid. The drug induces its own metabolism (autoinduction), leading to decreased plasma levels and area under the curve after repeated dosing, particularly in (APL) treatment. Elimination
The terminal elimination half-life of tretinoin is 0.5 to 2 hours following initial oral doses, though this may shorten with continued administration due to autoinduction. Excretion occurs predominantly as metabolites, with approximately 63% recovered in within 72 hours and 31% in within 6 days; no unchanged tretinoin is detected in . For topical use, systemic elimination is negligible given the minimal absorption. Oral therapy in APL requires plasma level monitoring to account for potential accumulation or variability in exposure.

Pharmacodynamics

Tretinoin, also known as all-trans retinoic acid (ATRA), exerts its pharmacodynamic effects primarily by acting as a for nuclear retinoic acid receptors (RARs), specifically the subtypes RAR-α, RAR-β, and RAR-γ. Upon binding, tretinoin induces conformational changes in these receptors, enabling them to form heterodimers with retinoid X receptors (RXRs). These heterodimers then translocate to the nucleus, where they bind to retinoic acid response elements (RAREs) in the promoter regions of target genes, thereby modulating gene transcription and influencing cellular processes such as differentiation, proliferation, and . In the skin, tretinoin promotes the differentiation of epidermal cells while inhibiting excessive proliferation, particularly in hyperproliferative conditions like , by normalizing follicular keratinization and enhancing . It also stimulates synthesis in dermal fibroblasts through activation of the transforming growth factor-β (TGF-β) pathway, which upregulates procollagen production and extracellular matrix remodeling. Additionally, tretinoin reduces the expression of matrix metalloproteinases (MMPs), enzymes that degrade , thereby contributing to its anti-photoaging effects by preserving dermal integrity. In (APL), tretinoin targets the oncogenic PML-RARα fusion resulting from the t(15;17) translocation. Binding to RAR-α disrupts the repressive function of PML-RARα on myeloid differentiation genes, while also promoting the ubiquitination and proteasomal degradation of the fusion , which restores normal PML nuclear bodies and induces terminal differentiation of promyelocytic cells into mature granulocytes. Tretinoin's activation of RARs occurs potently at low concentrations, typically in the range of 10^{-9} to 10^{-6} M (1 nM to 1 μM), with EC_{50} values for transcriptional activation around 10 nM depending on the RAR subtype. The all-trans isomer of demonstrates the highest activity for RAR-α activation compared to other isomers like 9-cis or 13-cis retinoic acid. Beyond genomic effects, tretinoin can induce off-target in certain cell types, such as cancer cells, through non-genomic pathways involving rapid signaling cascades like MEK1/2-ERK1/2 , leading to caspase-3-dependent independent of transcription.

Therapeutic uses

Dermatological applications

Tretinoin is widely used topically for the treatment of vulgaris, where it reduces both comedones and inflammatory lesions by normalizing follicular keratinization and promoting epidermal differentiation. Randomized controlled trials (RCTs) have demonstrated its efficacy, with concentrations of 0.025% to 0.1% achieving 40-70% reductions in lesion counts after 12 weeks of once-daily application. For instance, in a phase 3 RCT involving patients with moderate-to-severe , tretinoin 0.05% lotion resulted in a 60.1% reduction in inflammatory lesions and a 53.0% reduction in noninflammatory lesions compared to (P ≤ 0.001). In the management of photoaging, topical tretinoin improves fine wrinkles, dyspigmentation, and skin elasticity through stimulation of collagen remodeling in the dermis. A systematic review of 12 RCTs reported that tretinoin 0.05% cream reduced overall photoaging scores by approximately 20%, with benefits in mottled hyperpigmentation and sallowness persisting up to 24 months post-treatment; meta-analyses confirm significant improvements in wrinkle severity after 6-12 months of use at concentrations around 0.05%. Comparative studies indicate that lower concentrations can achieve similar benefits with reduced irritation; a 1995 double-blind, vehicle-controlled study found that 0.025% and 0.1% tretinoin creams produced similar clinical and histologic improvements in photoaging (including epidermal thickening of approximately 28-30% and increased vascularity of 89-100%), with no significant differences in efficacy, but significantly greater irritation (erythema and scaling) with the 0.1% concentration. Beyond these primary indications, tretinoin is employed off-label for , where it aids in normalizing keratinization and reducing follicular plugging, and for to improve follicular . Topical tretinoin is also used for striae rubrae (red stretch marks), where it improves collagen production, reduces redness, and enhances the appearance of early stretch marks. Multiple clinical studies support its efficacy, particularly for striae rubrae; for example, a randomized trial demonstrated a 14% decrease in mean length and 8% decrease in width of treated stretch marks compared to controls. As a prescription medication, formulations such as Retin-A or generics are typically required. For enhanced acne control, it is often combined with benzoyl peroxide or topical antibiotics, yielding superior lesion reductions compared to monotherapy; guidelines recommend such fixed-dose combinations for moderate to address both comedogenesis and bacterial proliferation. Additionally, combining tretinoin with niacinamide offers complementary benefits: tretinoin promotes cell turnover, reduces acne, and fights signs of aging, while niacinamide strengthens the skin barrier, reduces inflammation, and helps mitigate irritation associated with tretinoin use. Treatment with topical tretinoin typically involves an initial phase of irritation known as retinoid dermatitis, characterized by , dryness, and peeling. In patients treated for acne vulgaris, a temporary worsening of acne lesions, commonly referred to as "purging," may also occur due to accelerated cellular turnover that causes underlying microcomedones to surface more rapidly. This purging phase typically lasts 4-8 weeks and may be perceived as more intense with gel formulations compared to creams due to the gel's more aggressive action, greater penetration, and higher potential for irritation. The irritation generally resolves within 2-4 weeks as tolerance develops. Long-term use, up to 1 year or more, is required for sustained benefits in and , with visible improvements often emerging after 8-12 weeks. Tretinoin is most suitable for patients with mild-to-moderate vulgaris, serving as a first-line topical therapy per guidelines, but it is not recommended as monotherapy for severe nodulocystic , where systemic agents may be preferred. Patient selection should consider skin type and tolerance, with lower concentrations such as 0.025% typically initiated for sensitive skin or those new to tretinoin therapy to minimize adverse effects, and gradually increased to 0.05% or 0.1% if tolerated. Higher concentrations may provide more rapid or pronounced results but are associated with greater irritation risk; consistency of use and individual tolerance are more important than maximal strength. Cream formulations are generally preferred for patients with dry or sensitive skin, as they are less irritating than gels due to their more emollient and hydrating base. To further reduce irritation and purging effects, it is common to initiate treatment with applications every other day, combined with a moisturizer and broad-spectrum sunscreen. According to dermatological views, home-use beauty devices, such as LED therapy masks and microcurrent tools, cannot replace tretinoin for acne control and comprehensive anti-aging. These devices serve as auxiliary tools with milder effects and slower onset, often requiring 3-6 months or more for visible improvements, with high individual variability in outcomes. Experts note that while some devices show efficacy in reducing acne lesions or improving skin texture, they generally fall short of tretinoin's proven core efficacy and carry risks of skin injury if misused.

Oncological applications

Tretinoin, known chemically as all-trans (ATRA), serves as a cornerstone in the induction therapy for (APL), specifically in cases involving the t(15;17) or the PML-RARα fusion . This targeted approach induces differentiation of leukemic promyelocytes, leading to remission when tretinoin is combined with for low-risk patients or with (such as idarubicin) for high-risk cases. Complete remission rates reach 95-100% with these regimens, markedly improving outcomes compared to historical chemotherapy-alone approaches. The standard induction regimen administers oral tretinoin at 45 mg/m² per day, divided into two doses, typically with a to enhance absorption, continuing for 30-90 days or until complete remission is achieved. Following induction, a maintenance phase involves intermittent dosing, such as 45 mg/m² per day for 2 weeks on and 2 weeks off, repeated for 1-2 years in combination with low-dose or to prevent relapse. During treatment, patients face a risk of differentiation syndrome, characterized by fever, respiratory distress, and fluid retention due to rapid cell maturation, which requires prompt intervention with corticosteroids. Tretinoin lacks efficacy in non-APL leukemias, limiting its oncological use to this specific subtype. Approval extends to pediatric patients aged 1 year and older, where efficacy mirrors that in adults, though dosing is precisely calculated by body surface area and monitored closely for tolerability. In low-risk APL, tretinoin-inclusive protocols have elevated 5-year overall survival rates to over 80%, reflecting the therapy's transformative impact on this once-fatal disease.

Formulations and administration

Topical formulations

Topical tretinoin is formulated for dermatological application in several , including creams, gels, microsphere gels, lotions, and solutions, each designed to deliver the active ingredient to the for conditions such as acne vulgaris. Creams are available in strengths of 0.025%, 0.05%, and 0.1%, while gels are offered at 0.01%, 0.025%, and 0.04%. Microsphere gels, which encapsulate tretinoin in polymeric microspheres for controlled release, come in 0.04% and 0.1% concentrations to minimize initial . Lotions, such as the 0.05% formulation, provide a lighter vehicle for even application, and solutions at 0.05% offer a liquid option for targeted use. Commonly used concentrations in creams include 0.025%, 0.05%, and 0.1%, with potency generally increasing at higher percentages. The 0.025% concentration is the mildest, associated with the lowest irritation risk and is ideal for beginners or individuals with sensitive skin. The 0.05% concentration provides a balanced efficacy-tolerability profile, while the 0.1% concentration is the most potent but carries the highest risk of irritation, including redness, peeling, and dryness. Higher concentrations may deliver faster or more pronounced results for acne and photoaging but increase side effects. A 1995 double-blind, vehicle-controlled study demonstrated that 0.025% and 0.1% tretinoin produced comparable improvements in photoaging, including similar epidermal thickening (approximately 28-30%) and increased vascularity, despite significantly greater irritation (erythema and scaling) with the 0.1% concentration. Systematic reviews indicate dose-dependent epidermal changes with tretinoin concentrations from 0.025% to 0.1%, where higher strengths may offer faster results but also greater irritation. Treatment should begin with a lower strength such as 0.025% and titrate upward based on tolerance, as consistent use and individual tolerability are more important than higher strengths. The choice of vehicle influences suitability based on type and tolerability. Creams are generally less irritating than gels due to their more emollient and hydrating base, which reduces dryness, redness, and peeling. Gels have better penetration but are more drying and have higher irritant potential, potentially intensifying initial irritation. Switching from cream to gel typically increases irritation, while switching from gel to cream decreases it. Creams are therefore preferable for individuals with sensitive or dry skin, while gels may suit oily or acne-prone skin despite the greater potential for irritation. Microsphere in gels delays tretinoin release, reducing peak and peeling compared to standard formulations by preventing rapid epidermal overload of the drug. Application guidelines emphasize gradual introduction to build tolerance and minimize side effects. A pea-sized amount should be applied thinly to the affected areas once daily at bedtime, gently rubbing it in to cover the skin without excess, as overuse increases risk. To prevent or manage dryness and irritation, apply a strong moisturizer containing ceramides or hyaluronic acid immediately after cleansing and around tretinoin application (before and/or after). Beginners are advised to start with a lower strength (e.g., 0.025%) applied 2-3 times per week, gradually increasing frequency as tolerated. Due to heightened , daily broad-spectrum (SPF 30 or higher) and protective clothing are essential during treatment. Users should avoid combining with other irritants like abrasive cleansers or concurrent peeling agents to prevent instability or heightened reactions. In 2025, the USFDA approved generic versions of tretinoin 0.025% cream by manufacturers including on August 14 and Encube Ethicals on July 10, establishing to the reference product Avita for treatment. For storage and stability, tretinoin creams should be kept below 27°C (80°F), while gels are stable below 30°C (86°F); most formulations are maintained at controlled (20-25°C or 68-77°F) away from light and moisture. Users should avoid combining with other irritants like abrasive cleansers or concurrent peeling agents to prevent instability or heightened reactions.

Systemic formulations

Systemic formulations of tretinoin are primarily designed for to achieve therapeutic levels throughout the body, with the main indication being the treatment of (APL). The standard product is available as soft gelatin capsules containing 10 mg of tretinoin, which are taken orally to induce remission in APL patients. The recommended dosing regimen for induction therapy in APL is 45 mg/m² of per day, administered in two divided doses (22.5 mg/m² twice daily), preferably with food to enhance absorption. This dosing continues until complete remission is achieved, typically for a duration of 45 to 90 days, after which tretinoin is discontinued. Oral of tretinoin is approximately 50%, and administration with a fatty is advised as it increases absorption, though the exact magnitude of enhancement varies and is not precisely quantified in all studies. No standard injectable formulations are approved for clinical use, but investigational intravenous liposomal tretinoin has been evaluated in phase II trials for APL and other malignancies, showing potential but not advancing to routine approval. Tretinoin capsules are packaged in blister packs or opaque bottles to protect the light-sensitive drug from degradation, with a typical shelf life of 2 years when stored at controlled room temperature (20-25°C) and away from light and moisture.

Adverse effects

Local effects

Topical tretinoin commonly induces local skin reactions due to its irritant properties on the epidermis and dermis, primarily manifesting as retinoid dermatitis. The most frequent adverse effects include erythema, peeling, dryness, and pruritus, which affect approximately 20-50% of users during the initial treatment phase. These symptoms typically peak within the first 2-4 weeks of application as the skin adjusts to the retinoid's promotion of cell turnover and barrier disruption. The incidence and severity of these local reactions are concentration-dependent, with higher concentrations associated with increased irritation. A double-blind, vehicle-controlled study found that 0.025% and 0.1% tretinoin produced similar clinical and histologic improvements in photoaging (including epidermal thickening and increased vascularity) despite significantly greater erythema and scaling with the 0.1% concentration. Commonly available topical strengths include 0.025% (mildest, lowest irritation, often ideal for beginners or sensitive skin), 0.05% (moderate, balanced efficacy and tolerability), and 0.1% (strongest, most potent but highest irritation risk), where higher strengths may provide faster or more pronounced results but with greater side effects. Severity of these reactions varies from mild (slight redness and flaking) to severe (crusting and blistering), often graded on a 0-3 scale where mild cases predominate and severe ones are rare, occurring in less than 3% of patients. Local management strategies for retinoid dermatitis include reducing application frequency (e.g., to 2-3 times per week or less), applying strong moisturizers containing ceramides or hyaluronic acid immediately after washing and before/after tretinoin to restore the skin barrier, and in severe cases, short-term use of mild topical corticosteroids (e.g., hydrocortisone) under physician supervision. Treatment may be temporarily discontinued until the skin recovers, then restarted with a lower concentration and less frequent application. Patients are often advised to initiate therapy at a lower concentration (such as 0.025%) and increase gradually if tolerated, as irritation typically diminishes with continued use while consistency and tolerance matter more than maximum strength. Patients should always use high SPF sunscreen, avoid irritating products, and consult a dermatologist for personalized care. Additionally, combining topical tretinoin with niacinamide can help mitigate redness and irritation by reducing inflammation and supporting the skin barrier function. involvement, such as from perioral application or from periocular use, arises when the product contacts sensitive areas, leading to and dryness. In long-term use, particularly among individuals with darker skin types (Fitzpatrick IV-VI), postinflammatory may develop secondary to initial , though it generally resolves upon discontinuation. Clinical trials report dryness in over 30% of participants, underscoring its prevalence as a dose-dependent effect. Tretinoin also heightens , potentially exacerbating UV-induced damage if sun protection is inadequate.

Systemic effects

Systemic administration of tretinoin, primarily in the treatment of (APL), can lead to various body-wide adverse effects due to its role in inducing differentiation of leukemic cells. These effects arise from the drug's and are more pronounced during induction therapy. A key systemic complication is differentiation syndrome (also known as retinoic acid-APL ), which occurs in approximately 25% of APL patients receiving tretinoin. This is characterized by fever, dyspnea, acute respiratory distress, pulmonary infiltrates, pleural and pericardial effusions, weight gain, and , typically manifesting within the first few weeks of treatment. It results from rapid maturation of promyelocytes and release, and is managed with prompt administration of dexamethasone to reduce inflammation and prevent progression to . Metabolic disturbances are common, including affecting up to 60% of patients and hypercholesterolemia in a similar proportion, often requiring weekly lipid monitoring during induction to detect levels exceeding 800 mg/dL that may necessitate intervention such as fibrates. These changes are attributed to tretinoin's influence on and typically resolve post-treatment. Hematologic effects include , which can exacerbate differentiation syndrome, and an increased risk of due to hypercoagulability in APL compounded by tretinoin. Neurological symptoms such as occur frequently, while pseudotumor cerebri (benign intracranial hypertension) affects 3-10% of patients, presenting with and visual disturbances that usually resolve upon drug discontinuation and supportive care. Other systemic effects encompass from rapid cellular turnover, , and severe teratogenicity, with oral tretinoin classified as FDA X due to its high risk of causing congenital malformations including craniofacial, cardiac, and defects if exposure occurs during . Long-term use in APL survivors is associated with a potential increased risk of secondary malignancies, though studies indicate this elevation may not be statistically significant compared to the general population. To mitigate these risks, patients on tretinoin for APL require close monitoring, including weekly complete blood counts (CBC) to track and , for , and lipid profiles during the induction phase.

Safety and interactions

Contraindications and precautions

Tretinoin is contraindicated in patients with known to tretinoin, any component of the formulation, or other retinoids, as this may manifest as , pruritus, facial , or dyspnea. For systemic (oral) formulations used in , tretinoin is absolutely contraindicated during due to its potent teratogenic effects, including severe central nervous system abnormalities, craniofacial dysmorphia, and cardiovascular defects observed in studies and human case reports. There are no adequate and well-controlled studies in pregnant women using topical tretinoin, but reproduction studies have shown adverse effects on the , including malformations at doses 5-19 times the maximum recommended human dose (based on ); it should be used during only if the potential benefit justifies the potential risk to the . Women of childbearing potential should discontinue systemic tretinoin at least one month prior to attempting conception, and both oral and topical forms require effective contraception during treatment and for one month afterward for oral use. For oral tretinoin, pregnancy testing is mandatory before initiation, with two forms of contraception required for females and effective contraception for males during therapy and for one week post-treatment. Topical application should be limited to the smallest effective area and duration in individuals. In special populations, systemic tretinoin should be avoided during , as it is excreted in human milk and may pose risks to the ; breastfeeding should be discontinued during treatment and for at least one week after the last dose. Topical tretinoin has minimal systemic absorption, and while data are limited, it is generally considered low risk if not applied to area, though caution is advised. Hepatic impairment warrants caution with oral tretinoin due to reduced and potential for , with frequent monitoring of recommended; dose reduction or withholding may be necessary if transaminases exceed five times the upper limit of normal. Topical use involves negligible hepatic impact. For pediatric patients, topical tretinoin is not recommended for children under 12 years due to lack of established and , while oral tretinoin is approved for those aged one year and older but requires close monitoring for pseudotumor cerebri. Key precautions include heightened photosensitivity with topical tretinoin, necessitating daily use of broad-spectrum with SPF 30 or higher, protective clothing, and avoidance of excessive sun exposure, sunlamps, or tanning beds to prevent sunburn or . Concurrent use of keratolytic agents or cleansers should be minimized with topical formulations to reduce risk. In patients with , oral tretinoin requires monitoring of profiles, as it can elevate triglycerides and in up to 60% of cases, potentially exacerbating diabetic . Overdose risks are primarily associated with oral ingestion, where acute toxicity is rare but may include symptoms of such as , , , flushing, , and ; these are generally reversible with supportive care, and no specific exists. Topical overdose typically causes localized excessive but no systemic effects due to low absorption.

Drug interactions

Tretinoin, particularly in its oral formulation used for (APL), undergoes hepatic primarily via enzymes, including , CYP2C8, and CYP2E1. Inhibitors of , such as , can significantly elevate tretinoin plasma levels; for instance, co-administration with administered one hour prior increases the mean area under the curve (AUC) by approximately 72% (from 218 ± 224 ng·h/mL to 375 ± 285 ng·h/mL). Conversely, inducers like rifampin may accelerate tretinoin's , thereby reducing its plasma concentrations and potentially decreasing therapeutic efficacy. Tretinoin also exhibits autoinduction of its own , leading to a decline in plasma levels to about one-third of initial values after one week of . For oral tretinoin, absorption is enhanced when taken with , particularly high-fat meals, as is typical for retinoids as a class, though specific data for tretinoin are limited. In contrast, topical formulations of tretinoin have no major reported interactions with food or systemic absorption-altering substances. Pharmacodynamic interactions are prominent with photosensitizing agents, especially for topical tretinoin used in dermatological applications. Concomitant use with drugs such as tetracyclines, fluoroquinolones, thiazides, phenothiazines, or sulfonamides can exacerbate tretinoin's photosensitizing effects, increasing the risk of severe sunburn or ; patients are advised to minimize sun exposure, use broad-spectrum sunscreens (SPF 15 or higher), and wear protective clothing. Concurrent administration of supplements with tretinoin, whether oral or topical, poses a of additive toxicity leading to , manifesting as symptoms like dry skin, , or ; supplementation should be limited to the recommended dietary allowance (RDA) or avoided entirely to prevent exacerbation. In the context of APL treatment with oral tretinoin, agents such as , , or can increase the of fatal thrombotic complications due to synergistic effects on ; rare cases of have been reported, and such combinations should be used with extreme caution or avoided.

History

Discovery and synthesis

Tretinoin, chemically known as all-trans-retinoic acid, was first synthesized in 1946 by J. F. Arens and D. A. van Dorp at the laboratories in the . Their pioneering work established as a biologically active derivative of , demonstrating its ability to support growth in vitamin A-deficient rats while lacking activity in visual processes. The synthesis began with β-ionone, a key precursor derived from natural sources, and utilized a Reformatsky reaction with to form a β-ketoester intermediate, followed by chain extension and adjustments to yield the polyene carboxylic acid structure. As a natural of (), tretinoin occurs endogenously in animal tissues, where it is produced via sequential oxidation by alcohol and . Early biochemical studies in the mid-1950s confirmed its presence in tissues such as liver and intestinal mucosa, highlighting its role in local signaling, though isolation in pure form was challenging due to low concentrations. Due to these low yields, industrial production relies on synthetic methods rather than extraction from animal sources or precursors like β-carotene. Hoffmann-La Roche advanced the synthesis in the 1950s, patenting an optimized route in 1957 that improved efficiency for large-scale production. This process starts from β-ionone and proceeds through a intermediate, incorporating the to assemble the conjugated polyene chain from phosphonium ylides and aldehydes, followed by selective oxidation of the terminal alcohol to the using reagents like or . Synthetic routes were further refined in the , with detailed chemical characterization of the all-trans isomer completed around 1960 and the first commercial synthetic sample achieved in 1962, enabling broader research and application.

Regulatory milestones

Tretinoin received its initial U.S. (FDA) approval in 1971 for topical use in the treatment of acne vulgaris, marketed as Retin-A by Ortho Pharmaceutical Corporation. This approval marked the first therapeutic application of tretinoin as a topical , establishing its role in dermatological care. In 1995, the FDA approved oral tretinoin, under the brand name Vesanoid, for the induction of remission in patients with (APL), expanding its indications to . The European Medicines Agency (EMA) approved oral tretinoin for the treatment of APL in 1995, facilitating its availability across for this hematological condition. Tretinoin was included on the World Health Organization's (WHO) Model List of in 2009, specifically under cytotoxic agents for APL, underscoring its global importance in essential healthcare. The 1995 FDA approval for oral tretinoin includes pediatric patients aged 1 year and older with APL, broadening access for younger populations. During the 1980s, the (AAD) began endorsing topical tretinoin for in managing through clinical guidelines and publications, based on studies demonstrating its efficacy in reducing fine wrinkles and improving texture. In recent years, the FDA has approved additional generic versions of topical tretinoin formulations; for instance, in July 2025, Encube Ethicals received approval for tretinoin cream USP 0.025%, and in August 2025, Alembic Pharmaceuticals gained approval for the same strength, enhancing market competition and accessibility. The original patent for Retin-A expired in the 1990s, leading to widespread generic availability that now dominates the market for topical tretinoin. In 2023, tretinoin ranked as the 197th most commonly prescribed medication in the United States, with over 2 million prescriptions dispensed, reflecting its enduring clinical utility primarily for acne and skin aging.

Research

Dermatological research

Recent dermatological research has continued to explore tretinoin's role in addressing , with a 2025 and of randomized controlled trials confirming that 0.05% topical tretinoin significantly improves fine and coarse wrinkles induced by photodamage compared to in trials with follow-ups of 16 weeks to 2 years. This study, involving 1,361 participants across 8 trials, highlighted tretinoin's efficacy in enhancing production and epidermal thickness, though mild irritation may persist in some users. Complementing this, a published in 2025 ranked tretinoin as effective for improving fine lines and overall photoaged skin texture, with favorable safety compared to alternatives like . In the realm of skin atrophy treatment, a 2025 self-controlled case study demonstrated that 0.05% topical tretinoin effectively reversed glucocorticoid-induced skin thinning in a patient with chronic topical corticosteroid use, showing marked improvements in skin elasticity, reduced bruising, and restored dermal thickness after 12 weeks of nightly application. The treatment promoted fibroblast activity and collagen remodeling without exacerbating atrophy, suggesting tretinoin's potential as an adjunct therapy for iatrogenic skin damage, though larger randomized trials are needed to confirm these findings. Ongoing clinical trials have investigated tretinoin combinations to mitigate common side effects like . For instance, formulations pairing tretinoin with have shown reduced , dryness, and burning sensations during the initial weeks of therapy, with one 2023 study reporting significant reductions in irritation symptoms when used adjunctively with 0.025% tretinoin. Similarly, combining tretinoin with niacinamide has demonstrated synergistic benefits, lowering inflammatory responses and enhancing tolerability in acne-prone skin. A 2025 prospective study is exploring topical oil blended with tretinoin for wrinkle reduction in postmenopausal women. Market trends reflect growing interest in tretinoin-based dermatological products, with the global tretinoin cream market projected to reach approximately $950 million by 2033, driven by rising demand for anti-aging formulations and via telemedicine. Innovations in digital integration, such as adherence-monitoring apps and smart dispensers, are emerging to support consistent use, with preliminary 2025 reports indicating up to 25% improvement in treatment compliance through reminders and progress tracking, though these tools remain under evaluation for tretinoin-specific efficacy. Recent dermatological consensus highlights that home-use beauty devices, such as LED masks and microcurrent tools, serve as auxiliary tools with milder and slower effects compared to tretinoin for managing acne and anti-aging. Dermatologists note that these devices cannot replace tretinoin's core efficacy, particularly for acne control and comprehensive anti-aging, with visible results often requiring 3-6 months or more and showing high individual variability. Despite these advances, limitations persist in certain applications. Evidence for tretinoin's efficacy in treating remains weak, with 2025 consensus guidelines noting only modest synergistic effects when combined with for androgenetic alopecia, but no standalone benefits or approvals for this indication. As of 2025, no new regulatory approvals have been granted for tretinoin in scar treatment, with emphasizing its for post-acne rather than atrophic or hypertrophic scars.

Emerging applications

Recent clinical investigations have expanded the potential role of tretinoin (all-trans retinoic acid, ATRA) beyond acute promyelocytic leukemia (APL) to other hematologic malignancies, including non-APL acute myeloid leukemia (AML). Basic research and early-phase trials demonstrate that ATRA can induce differentiation in non-APL AML cells, with combination regimens showing improved response rates in preclinical models. In solid tumors, exploratory studies are evaluating tretinoin in combination with immunotherapy agents, such as checkpoint inhibitors, for advanced melanoma and non-small cell lung cancer, where it may enhance antitumor immune responses by modulating retinoid X receptor (RXR) signaling. Additionally, 2024-2025 research has focused on overcoming retinoid resistance in APL through novel combinations, including arsenic trioxide, which has shown superior outcomes in high-risk cases compared to ATRA monotherapy. In , 2025 studies highlight tretinoin's role in promoting scarless and hair follicle neogenesis by modulating the Wnt/β-catenin pathway. Retinoids activate stem cells, supporting de novo follicle formation and dermal regeneration, as evidenced in multi-omic analyses of skin repair mechanisms. This pathway interaction reduces and enhances regeneration, offering potential for treating chronic wounds or fibrotic disorders. Novel formulations are addressing tretinoin's limitations in delivery and tolerability. A 2025 study introduced a scalable synthetic platform generating 23 new retinoids with optimized receptor selectivity and reduced toxicity, evaluated for enhanced therapeutic profiles in dermatologic and systemic applications. Exploratory formulations are under investigation for acute settings in hematologic crises, though oral routes remain standard. Emerging evidence suggests tretinoin may enhance efficacy in androgenetic alopecia by upregulating follicular sulfotransferase enzymes, though evidence for standalone benefits remains limited. In , fatty acid vesicle formulations of tretinoin exhibit antipsoriatic activity by improving skin permeability and reducing plaque severity in exploratory studies. For , short-contact tretinoin therapy stimulates formation, accelerating closure in full-thickness wounds, though results vary. Despite these advances, tretinoin's clinical expansion is constrained by toxicity, including , , and skin irritation, which limit dosing in non-APL settings. Ongoing Phase II trials, such as NCT06571721 evaluating tretinoin with almond oil for wrinkle reduction, underscore the need for therapies to mitigate adverse effects while enhancing .

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