Tretinoin

Last updated

Tretinoin
Tretinoin structure.svg
Clinical data
Pronunciation See pronunciation note
Trade names Retin-a, Avita, Renova, others
Other namesATRA
AHFS/Drugs.com Monograph
Topical Monograph
MedlinePlus a608032
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-life 0.5–2 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 InfoCard 100.005.573 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C20H28O2
Molar mass 300.442 g·mol−1
3D model (JSmol)
Melting point 180 °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+ Yes check.svgY
  • Key:SHGAZHPCJJPHSC-YCNIQYBTSA-N Yes check.svgY
   (verify)

Tretinoin, also known as all-trans retinoic acid (ATRA), is a medication used for the treatment of acne and acute promyelocytic leukemia. [8] [9] [10] For acne, it is applied to the skin as a cream, gel or ointment. [10] For acute promyelocytic leukemia, it is effective only when the RARA-PML fusion mutation is present [11] and is taken by mouth for up to three months. [8] Topical tretinoin is also the most extensively investigated retinoid therapy for photoaging. [12]

Contents

Common side effects when used as a cream are limited to the skin and include skin redness, peeling, and sun sensitivity. [10] 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. [8] Other severe side effects include high white blood cell counts and blood clots. [8] Use during pregnancy is contraindicated due to the risk of birth defects. [8] [1] It is in the retinoid family of medications. [9]

Tretinoin was patented in 1957, and approved for medical use in 1962. [13] It is on the World Health Organization's List of Essential Medicines. [14] Tretinoin is available as a generic medication. [15] In 2021, it was the 206th most commonly prescribed medication in the United States, with more than 2 million prescriptions. [16] [17]

Medical uses

Skin use

Acne

Tretinoin is most commonly used to treat acne, [6] both inflammatory and noninflammatory. Multiple studies support the efficacy of topical retinoids in the treatment of acne vulgaris. [18] [19] It is sometimes used in conjunction with other topical acne medications to enhance their penetration. [20] In addition to treating active acne, retinoids accelerate the resolution of acne-induced postinflammatory hyperpigmentation. [21] 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. [22]

Photoaging

Photoaging is premature skin aging resulting from prolonged and repeated exposure to solar radiation. Features of photoaging include fine and coarse wrinkles, change 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. [23] 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 a duration of 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. [24]

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. [5] [25] [26]

Tretinoin is not effective for the treatment of non-APL forms of Acute Myeloid Leukemia [27] or other forms of leukemia. Preclinical studies and clinical data analysis suggests that retinoic acid promotes the growth of T cell acute lymphoblastic leukemia. [28]

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. [6] 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 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 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. [29]

Acute Promyelocytic Leukemia

The oral form of the drug has boxed warnings concerning the risks of retinoic acid syndrome and leukocytosis. [5] Other significant side effects include a risk of thrombosis, benign intracranial hypertension in children, high lipids (hypercholesterolemia and/or hypertriglyceridemia), and liver damage. [5]

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%). [5]

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%. [5] Around 23% of people taking the drug have reported earache or a feeling of fullness in their ears. [5] 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%. [5]

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. [5]

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. [5]

In the urinary system, side effects include chronic kidney disease (11%) and several others at less than 10% frequency. [5]

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. [30] 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. [31]

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). [21] These events contribute to the normalization of follicular keratinization and decreased cohesiveness of keratinocytes, resulting in reduced follicular occlusion and microcomedone formation. [32] The retinoid-receptor complex competes for coactivator proteins of AP-1, a key transcription factor involved in inflammation. [21] Retinoids also down-regulate expression of toll-like receptor (TLR)-2, which has been implicated in the inflammatory response in acne. [33] Moreover, tretinoin and retinoids may enhance the penetration of other topical acne medications. [20]

The combination of the 10% benzoyl peroxide and light results in more than 50% degradation of tretinoin in about 2 hours and 95% in 24 hours. [34] This lack of stability in the presence of light and oxidizing agents has led to the development of novel formulations of the drug. When microencapsulated tretinoin is exposed to benzoyl peroxide and light only 1% degradation takes place in about 4 hours and only 13% after 24 hours. [35]

The biological mechanism behind triglyceride and cholesterol elevations remains under investigation.

Synthesis

Biosynthetic pathway of tretinon 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 [36] .

History

Tretinoin was co-developed for its use in acne by James Fulton and Albert Kligman when they were at University of Pennsylvania in the 1960s. [37] [38] Phase I trials, the first conducted on human subjects, were performed on inmates at Holmesburg Prison during a long-running regime of non-therapeutic and unethical testing on prison inmates at Holmesburg. [39] [40] The University of Pennsylvania held the patent for Retin-A, which it licensed to pharmaceutical companies. [38]

Treatment of acute promyelocytic leukemia was first introduced at Ruijin Hospital in Shanghai by Wang Zhenyi in a 1988 clinical trial. [41]

Etymology

The origin of the name tretinoin is uncertain, [42] [43] although several sources agree (one with probability, [42] < one with asserted certainty [44] ) 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/ , [43] [44] [42] [45] it is natural that /ˌtrɛtɪˈnoʊɪn/ is a commonly heard pronunciation. Dictionary transcriptions also include /ˌtrɪˈtɪnoʊɪn/ (tri-TIN-oh-in) [43] [42] and /ˈtrɛtɪnɔɪn/ . [44] [45]

Hair loss

Tretinoin has been explored as a treatment for hair loss, 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. [46] [47]

Related Research Articles

<span class="mw-page-title-main">Vitamin A</span> Essential nutrient

Vitamin A is a fat-soluble vitamin that is an essential nutrient. The term "vitamin A" encompasses a group of chemically related organic compounds that includes retinol, retinyl esters, and several provitamin (precursor) carotenoids, most notably beta-carotene. Vitamin A has multiple functions: essential in embryo development for growth, maintaining the immune system, and healthy vision, where it combines with the protein opsin to form rhodopsin – the light-absorbing molecule necessary for both low-light and color vision.

<span class="mw-page-title-main">Acne</span> Skin condition characterized by pimples

Acne, also known as acne vulgaris, is a long-term skin condition that occurs when dead skin cells and oil from the skin clog hair follicles. Typical features of the condition include blackheads or whiteheads, pimples, oily skin, and possible scarring. It primarily affects skin with a relatively high number of oil glands, including the face, upper part of the chest, and back. The resulting appearance can lead to lack of confidence, anxiety, reduced self-esteem, and, in extreme cases, depression or thoughts of suicide.

<span class="mw-page-title-main">Isotretinoin</span> Medication primarily used to treat severe acne

Isotretinoin, also known as 13-cis-retinoic acid and sold under the brand name Accutane among others, is a medication used to treat skin diseases like harlequin-type ichthyosis, and lamellar ichthyosis, and severe cystic acne or moderate acne that is unresponsive to antibiotics. Isotretinoin is used off-label to treat basal cell carcinoma and squamous cell carcinoma, although clinical evidence suggests it is not effective in this setting. It is a retinoid, meaning it is related to vitamin A, and is found in small quantities naturally in the body. Its isomer, tretinoin, is also an acne drug.

<span class="mw-page-title-main">Adapalene</span> Third-generation topical retinoid

Adapalene is a third-generation topical retinoid primarily used in the treatment of mild-moderate acne, and is also used off-label to treat keratosis pilaris as well as other skin conditions. Studies have found adapalene is as effective as other retinoids, while causing less irritation. It also has several advantages over other retinoids. The adapalene molecule is more stable compared to tretinoin and tazarotene, which leads to less concern for photodegradation. It is also chemically more stable compared to the other two retinoids, allowing it to be used in combination with benzoyl peroxide. Due to its effects on keratinocyte proliferation and differentiation, adapalene is superior to tretinoin for the treatment of comedonal acne and is often used as a first-line agent. The Swiss company Galderma sells adapalene under the brand name Differin.

<span class="mw-page-title-main">Retinoid</span> Group of tetraterpenes

The retinoids are a class of chemical compounds that are natural derivatives of vitamin A or are chemically related to it. Synthetic retinoids are used in medicine where they regulate skin health, immunity and bone disorders.

<span class="mw-page-title-main">Hyperpigmentation</span> Darkening of an area of skin or nails due to increased melanin

Hyperpigmentation is the darkening of an area of skin or nails caused by increased melanin.

<span class="mw-page-title-main">Acute promyelocytic leukemia</span> Subtype of acute myeloid leukaemia characterised by accumulation of promyelocytes

Acute promyelocytic leukemia is a subtype of acute myeloid leukemia (AML), a cancer of the white blood cells. In APL, there is an abnormal accumulation of immature granulocytes called promyelocytes. The disease is characterized by a chromosomal translocation involving the retinoic acid receptor alpha (RARA) gene and is distinguished from other forms of AML by its responsiveness to all-trans retinoic acid therapy. Acute promyelocytic leukemia was first characterized in 1957 by French and Norwegian physicians as a hyperacute fatal illness, with a median survival time of less than a week. Today, prognoses have drastically improved; 10-year survival rates are estimated to be approximately 80-90% according to one study.

<span class="mw-page-title-main">Arsenic trioxide</span> Chemical compound (industrial chemical and medication)

Arsenic trioxide is an inorganic compound with the formula As
2O
3. As an industrial chemical, its major uses include the manufacture of wood preservatives, pesticides, and glass. It is sold under the brand name Trisenox among others when used as a medication to treat a type of cancer known as acute promyelocytic leukemia. For this use it is given by injection into a vein.

<span class="mw-page-title-main">Tazarotene</span> Topical retinoid medication

Tazarotene, sold under the brand name Tazorac, among others, is a third-generation prescription topical retinoid. It is primarily used for the treatment of plaque psoriasis and acne. Tazarotene is also used as a therapeutic for photoaged and photodamaged skin. It is a member of the acetylenic class of retinoids.

<span class="mw-page-title-main">Azelaic acid</span> Organic chemical compound

Azelaic acid (AzA) is an organic compound with the formula HOOC(CH2)7COOH. This saturated dicarboxylic acid exists as a white powder. It is found in wheat, rye, and barley. It is a precursor to diverse industrial products including polymers and plasticizers, as well as being a component of a number of hair and skin conditioners. AzA inhibits tyrosinase.

Retinoic acid syndrome (RAS) is a potentially life-threatening complication observed in people with acute promyelocytic leukemia (APML) and first thought to be specifically associated with all-trans retinoic acid (ATRA) treatment. Subsequently, so-called RAS was recognized in APML patients who had been treated with another highly efficacious drug, arsenic trioxide, and yet did not appear in patients treated with tretinoin for other disorders. These facts and others support the notion that RAS depends on the presence of the malignant promyelocytes. This has led to the growing deprecation of the term 'retinoic acid syndrome' and to an increasing use of the term differentiation syndrome to signify this APML treatment complication.

The retinoic acid receptor (RAR) is a type of nuclear receptor which can also act as a ligand-activated transcription factor that is activated by both all-trans retinoic acid and 9-cis retinoic acid, retinoid active derivatives of Vitamin A. They are typically found within the nucleus. There are three retinoic acid receptors (RAR), RAR-alpha, RAR-beta, and RAR-gamma, encoded by the RARA, RARB, RARG genes, respectively. Within each RAR subtype there are various isoforms differing in their N-terminal region A. Multiple splice variants have been identified in human RARs: four for RARA, five for RARB, and two for RARG. As with other type II nuclear receptors, RAR heterodimerizes with RXR and in the absence of ligand, the RAR/RXR dimer binds to hormone response elements known as retinoic acid response elements (RAREs) complexed with corepressor protein. Binding of agonist ligands to RAR results in dissociation of corepressor and recruitment of coactivator protein that, in turn, promotes transcription of the downstream target gene into mRNA and eventually protein. In addition, the expression of RAR genes is under epigenetic regulation by promoter methylation. Both the length and magnitude of the retinoid response is dependent of the degradation of RARs and RXRs through the ubiquitin-proteasome. This degradation can lead to elongation of the DNA transcription through disruption of the initiation complex or to end the response to facilitate further transcriptional programs. RAR receptors are also known to exhibit many retinoid-independent effects as they bind to and regulate other nuclear receptor pathways, such as the estrogen receptor.

<span class="mw-page-title-main">Alitretinoin</span> Chemical compound

Alitretinoin, or 9-cis-retinoic acid, is a form of vitamin A. It is also used in medicine as an antineoplastic (anti-cancer) agent developed by Ligand Pharmaceuticals. It is a first generation retinoid. Ligand gained Food and Drug Administration (FDA) approval for alitretinoin in February 1999.

<span class="mw-page-title-main">Promyelocyte</span> Granulocyte precursor cell

A promyelocyte is a granulocyte precursor, developing from the myeloblast and developing into the myelocyte. Promyelocytes measure 12–20 microns in diameter. The nucleus of a promyelocyte is approximately the same size as a myeloblast but their cytoplasm is much more abundant. They also have less prominent nucleoli than myeloblasts and their chromatin is more coarse and clumped. The cytoplasm is basophilic and contains primary red/purple granules.

<span class="mw-page-title-main">Retinoic acid receptor alpha</span> Protein found in humans

Retinoic acid receptor alpha (RAR-α), also known as NR1B1, is a nuclear receptor that in humans is encoded by the RARA gene.

<span class="mw-page-title-main">Photoaging</span> Ultraviolet light-induced biological development over time

Photoaging or photoageing is a term used for the characteristic changes to skin induced by chronic UVA and UVB exposure. Tretinoin is the best studied retinoid in the treatment of photoaging.

Infantile acne is a form of acne that begins in very young children. Typical symptoms include inflammatory and noninflammatory lesions, papules and pustules most commonly present on the face. No cause of infantile acne has been established but it may be caused by increased sebaceous gland secretions due to elevated androgens, genetics and the fetal adrenal gland causing increased sebum production. Infantile acne can resolve by itself by age 1 or 2. However, treatment options include topical benzyl peroxide, topical retinoids and topical antibiotics in most cases.

<span class="mw-page-title-main">Anne Dejean-Assémat</span> French biologist (born 1957)

Anne Dejean-Assémat is a French molecular biologist working on the mechanisms leading to the development of human cancers. Professor at the Pasteur Institute and Research Director at Inserm, she heads the laboratory of Nuclear Organization and Oncogenesis at the Pasteur Institute.

Hugues de Thé, is a French doctor and researcher. He is currently a hospital doctor and professor at the Collège de France, holder of the chair of cellular and molecular oncology (2014), member of the French Academy of sciences since 2011. His work, at the interface between biology and medicine, has radically transformed the management of a rare form of leukaemia, which has become the paradigm for targeted cancer treatments.

The RARA gene, also known as NR1B1, is a protein coding gene located on chromosome 17 that provides the instructions required to make transcription factor Retinoic Acid Receptor Alpha.

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