Clinical data | |
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Pronunciation | See pronunciation note |
Trade names | Retin-a, Avita, Renova, others |
Other names | ATRA |
AHFS/Drugs.com | Monograph Topical Monograph |
MedlinePlus | a608032 |
License data | |
Pregnancy category | |
Routes of administration | Topical, by mouth |
ATC code | |
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Pharmacokinetic data | |
Protein binding | > 95% |
Elimination half-life | 0.5–2 hours |
Identifiers | |
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CAS Number | |
PubChem CID | |
IUPHAR/BPS | |
DrugBank | |
ChemSpider | |
UNII | |
KEGG | |
ChEBI | |
ChEMBL | |
CompTox Dashboard (EPA) | |
ECHA InfoCard | 100.005.573 |
Chemical and physical data | |
Formula | C20H28O2 |
Molar mass | 300.442 g·mol−1 |
3D model (JSmol) | |
Melting point | 180 °C (356 °F) |
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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 leukemia, it is taken by mouth for up to three months. [8] 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. [10] When used by mouth, side effects include 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. [12] It is on the World Health Organization's List of Essential Medicines. [13] Tretinoin is available as a generic medication. [14] In 2020, it was the 230th most commonly prescribed medication in the United States, with more than 2 million prescriptions. [15] [16]
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. [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 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. [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 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. [23]
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] [24] [25]
The evidence is very uncertain about the effect of tretinoin in addition to chemotherapy for patients with non-APL acute myeloid leukemia on diarrhoea, nausea/vomiting and heart-related toxicity grades III/IV. Furthermore, tretinoin in addition to chemotherapy probably results in little to no difference in the mortality, relapse, progress, mortality during the trial and infections grade III/IV. [26]
Topical tretinoin is only for use 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. [27]
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]
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. [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]
For its use in cancer, its mechanism of action is unknown, but on a cellular level, laboratory tests 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 and mature into neutrophils, allowing normal cells to repopulate the bone marrow. [5] A recent study showed that ATRA inhibits and degrades active PIN1. [28]
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. [29] 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. [30] Moreover, tretinoin and retinoids may enhance the penetration of other topical acne medications. [19]
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. [31] 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. [32]
Furthermore, studies have shown that tretinoin plays a regulatory role in the G1/S transition of neuroblastoma cells by influencing the activities of key kinases. Kinase-substrate enrichment analysis revealed increased CDK5 activity and reduced CDK2 activity during neuronal differentiation induced by tretinoin. [33] This alteration suggests that tretinoin influences multiple proteins involved in the G1/S transition, leading to the coordination of cell cycle arrest and inhibition of proliferation. By extending the duration of the G1 phase, tretinoin enables neuroblastoma cells to integrate environmental signals and respond to differentiation cues, promoting their differentiation and commitment to specialized cell fates instead of continued proliferation.
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. [34]
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. [35] [36] 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. [37] [38] The University of Pennsylvania held the patent for Retin-A, which it licensed to pharmaceutical companies. [36]
Treatment of acute promyelocytic leukemia was first introduced at Ruijin Hospital in Shanghai by Wang Zhenyi in a 1988 clinical trial. [39]
The origin of the name tretinoin is uncertain, [40] [41] although several sources agree (one with probability, [40] one with asserted certainty [42] ) 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/ , [41] [42] [43] [44] it is natural that /ˌtrɛtɪˈnoʊɪn/ is a commonly heard pronunciation. Dictionary transcriptions also include /ˌtrɪˈtɪnoʊɪn/ (tri-TIN-oh-in) [41] [43] and /ˈtrɛtɪnɔɪn/ . [42] [44]
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. [45] [46]
Vitamin A is a fat-soluble vitamin and an essential nutrient for animals. The term "vitamin A" encompasses a group of chemically related organic compounds that includes retinol, retinal, retinoic acid, and several provitamin (precursor) carotenoids, most notably beta-carotene. Vitamin A has multiple functions: it is essential for embryo development and growth, for maintenance of the immune system, and for vision, where it combines with the protein opsin to form rhodopsin – the light-absorbing molecule necessary for both low-light and color vision.
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.
Isotretinoin, also known as 13-cis-retinoic acid and sold under the brand name Accutane among others, is a medication primarily used to treat severe acne. It is also used to prevent certain skin cancers, and in the treatment of other cancers. It is used to treat harlequin-type ichthyosis, a usually lethal skin disease, and lamellar ichthyosis. 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.
Benzoyl peroxide is a chemical compound (specifically, an organic peroxide) with structural formula (C6H5−C(=O)O−)2, often abbreviated as (BzO)2. In terms of its structure, the molecule can be described as two benzoyl (C6H5−C(=O)−, Bz) groups connected by a peroxide (−O−O−). It is a white granular solid with a faint odour of benzaldehyde, poorly soluble in water but soluble in acetone, ethanol, and many other organic solvents. Benzoyl peroxide is an oxidizer, which is principally used as in the production of polymers.
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 product Differin.
The retinoids are a class of chemical compounds that are vitamers of vitamin A or are chemically related to it. Retinoids have found use in medicine where they regulate epithelial cell growth.
Hyperpigmentation is the darkening of an area of skin or nails caused by increased melanin.
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.
Melasma is a tan or dark skin discoloration. Melasma is thought to be caused by sun exposure, genetic predisposition, hormone changes, and skin irritation. Although it can affect anyone, it is particularly common in women, especially pregnant women and those who are taking oral or patch contraceptives or hormone replacement therapy medications.
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.
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.
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.
Retinoic acid receptor alpha (RAR-α), also known as NR1B1 is a nuclear receptor that in humans is encoded by the RARA gene.
Cytochrome P450 26A1 is a protein that in humans is encoded by the CYP26A1 gene.
Acne conglobata is a highly inflammatory disease presenting with comedones, nodules, abscesses, and draining sinus tracts.
Neonatal acne, also known as acne neonatorum, is an acneiform eruption that occurs in newborns or infants within the first 4-6 weeks of life, and presents with open and closed comedones on the cheeks, chin and forehead.
A pimple or zit is a kind of comedo that results from excess sebum and dead skin cells getting trapped in the pores of the skin. In its aggravated state, it may evolve into a pustule or papule. Pimples can be treated by acne medications, antibiotics, and anti-inflammatories prescribed by a physician, or various over the counter remedies purchased at a pharmacy.
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.