Tretinoin

Structural formula
General
Non-proprietary name	Tretinoin
other names	all - trans -3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexenyl) nona-2,4,6,8-tetraenoic acid
Molecular formula	C 20 H 28 O 2
External identifiers / databases
EC number	206-129-0
ECHA InfoCard	100.005.573
PubChem	444795
ChemSpider	392618
DrugBank	DB00755
Wikidata	Q29417
Drug information
ATC code	D10 AD01 ; L01 XX14 ;
Drug class	non-aromatic retinoid
properties
Molar mass	300.435 g mol −1
Physical state	firmly
Melting point	182 ° C
safety instructions
	Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
H and P phrases	H: 302-411
	P: 273
Toxicological data	2000 mg kg −1 ( LD 50 , rat , oral )
	As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Tretinoin , also vitamin A acid (abbreviated VAS ) or all- trans -retinoic acid ( English : all- trans -retinoic acid, in short: ATRA) is a substance whose chemical structure from vitamin A ₁ ( retinol ) is derived . It is one of the first generation of non-aromatic retinoids .

presentation

Tretinoin is produced by oxidation of all- trans - retinal , which can be obtained from all- trans - retinol by oxidation :

application areas

Tretinoin is used as a medicinal substance : it is used systemically in the treatment of acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia (AML). Topically it is used as an effective component of cream and gel preparations or alcoholic solutions in the therapy of acne and other hyperkeratotic skin diseases as well as in cosmetics . Tretinoin is approved in Europe and North America, and the corresponding drugs usually require a prescription.

It is now also being evaluated whether tretinoin (ATRA) can also be used in addition to chemotherapy in patients with acute myeloid leukemia. The evidence is very uncertain about the effect of ATRA in addition to chemotherapy on degree third / fourth diarrhea, degree third / fourth nausea / vomiting, and degree third / fourth cardiac toxicity. ATRA added to chemotherapy is likely to result in little or no change in mortality within 24 months, mortality during the study, and grade 3/4 infections. In addition, ATRA, in addition to chemotherapy, is likely to cause very little or no reduction in mortality, relapses, and disease progression.

Mechanisms of Action

A translocation on the genetic level creates a hybrid receptor for retinoic acid in the promyelocytes . Cell division is activated and leukemic cells expand. Systemically used tretinoin intervenes in this process by leading to differentiation (maturation) of the leukemia cells. Mature granulocytes develop with a loss of mitotic activity. Tretinoin is used in combination with chemotherapy and thus provides healing rates of up to 80 percent.

Tretinoin stimulates mitotic activity on keratinizing epithelia and at the same time inhibits keratin production. This leads to parakeratosis and thinning of the stratum corneum . For acne therapy, this means that the pathologically altered cell differentiation of the keratinocytes in the follicle infundibulum is favorably influenced, the coherence of the horny lamellae is loosened and the keratin plug is lifted out of the follicle infundibulum. In addition to real comedolysis, there is also prophylaxis against new comedones .

Tretinoin offers a broad immunomodulatory spectrum: depending on the condition of the treated skin, it can have an immunosuppressive, immunostimulatory, pro-inflammatory or anti-inflammatory effect.

Side effects

In the treatment of promyelocytic leukemia, the binding of the now mature leukemia cells to the pulmonary vessels can lead to an acute respiratory distress syndrome . This can result in fluid retention (pleural or pericardial effusion or pulmonary edema ) or infiltrate formation in the lungs with fever. To treat respiratory distress syndrome, the systemic supply of tretinoin is interrupted. The mortality of the syndrome is around 10%. In addition, headache, pseudotumor cerebri and undesirable effects on the skin and gastrointestinal tract can occur with systemic use .

Combinations with other active ingredients

Tretinoin is combined with other active ingredients to improve the therapeutic effect and reduce undesirable effects when applied topically . The combination with the antibiotic erythromycin for acne therapy and the combination with urea (urea) for the treatment of severe cornification disorders such as ichthyosis are offered as finished preparations .

In 2013, a prospective comparative study with 60 participants found that the combination of tretinoin with a certain aloe vera gel after eight weeks of treatment achieved better results for mild to moderate acne than the retinoid alone.

pregnancy and breast feeding period

In women of childbearing potential, tretinoin must not be used systemically or only after pregnancy has been ruled out due to its general teratogenic effect . (Certain types of ear malformations, for example, are typical of vitamin A derivatives). The Pharmacovigilance Risk Assessment Committee (PRAC) estimates that after topical retinoid application, systemic exposure is likely to be negligible and adverse effects to the fetus are unlikely. However, excessive use and a damaged skin barrier could lead to increased systemic exposure, so that the teratogenic risk cannot be completely ruled out even after only topical application. As a precaution, and in light of the fact that topical application does not affect life-threatening diseases, the PRAC recommended that the use of topical retinoids, including tretinoin, should be contraindicated during pregnancy and in women planning pregnancy.

Trade names

Monopreparations

Airol (D, CH), Cordes VAS (D), Eudyna (A), Retin-A (A, CH), Vesanoid (D, A, CH)

Combination preparations

Aknemycin plus (D), Balisa VAS (D), Carbamid + VAS Creme Widmer (D, CH), Keratosis Creme forte (A), Pigmanorm (D, CH), Sebo-psor (CH), Ureotop + VAS Creme (D ), Verra-med (CH)

Vesanoid is taken as a capsule while the other preparations are used externally as a solution, cream or ointment.

Individual evidence

↑ ^a ^b ^c ^d data sheet Retinoic acid from Sigma-Aldrich , accessed on April 24, 2011 ( PDF ).
↑ Yasemin Küley-Bagheri, Karl-Anton Kreuzer, Ina Monsef, Michael Lübbert, Nicole Skoetz: Effects of all-trans retinoic acid (ATRA) in addition to chemotherapy for adults with acute myeloid leukaemia (AML) (non-acute promyelocytic leukaemia ( non-APL)) . In: Cochrane Database of Systematic Reviews . August 6, 2018, doi : 10.1002 / 14651858.CD011960.pub2 ( wiley.com [accessed July 16, 2020]).
↑ Fanta, Messeritsch-Fanta, Steyr: Acne 1999: do we still need a dermatologist? In: The dermatologist . 12/1999, pp. 900-911. doi : 10.1007 / s001050051009 .
↑ M. Wetzler, G. Marcucci, C. Bloomfield: Acute and Chronic Myeloid Leukemia. In: Dan L. Longo, Anthony S. Fauci et al. (Eds.): Harrison's Principles of Internal Medicine. 18th edition. Volume 1, p. 912.
↑ Edward A. Sausville, Dan L. Longo: Principles of Cancer treatment. In: Dan L. Longo, Anthony S. Fauci et al. (Eds.): Harrison's Principles of Internal Medicine. 18th edition. Volume 1, p. 705.
↑ Zohreh Hajheydari, Majid Saeedi, Katayoun Morteza-Semnani, Aida Soltani: Effect of Aloe vera topical gel combined with tretinoin in treatment of mild and moderate acne vulgaris: a randomized, double-blind, prospective trial. In: Journal of Dermatological Treatment . 2013, pp. 1–7, doi: 10.3109 / 09546634.2013.768328 , PMID 23336746 .
↑ Ch. R .: ear malformation due to tretinoin. In: Journal of General Practice. Volume 68, No. 29, October 1992, p. 12.
↑ Appendix II to the Commission's implementing decision of June 21, 2018 regarding the authorizations for human medicinal products "Retinoids (acitretin, adapalen, alitretinoin, bexaroten, isotretinoin, tazaroten, tretinoin)" according to Article 31 of Directive 2001/83 / EC of the European Parliament and of the Council ( PDF ).
↑ ROTE LISTE 2017, Verlag Rote Liste Service GmbH, Frankfurt am Main, ISBN 978-3-946057-10-9 , p. 223.

[sigma-1] ta sheet Retinoic acid from Sigma-Aldrich , accessed on April 24, 2011 ( PDF ).

[2] Yasemin Küley-Bagheri, Karl-Anton Kreuzer, Ina Monsef, Michael Lübbert, Nicole Skoetz: Effects of all-trans retinoic acid (ATRA) in addition to chemotherapy for adults with acute myeloid leukaemia (AML) (non-acute promyelocytic leukaemia ( non-APL)) . In: Cochrane Database of Systematic Reviews . August 6, 2018, doi : 10.1002 / 14651858.CD011960.pub2 ( wiley.com [accessed July 16, 2020]).

[3] Fanta, Messeritsch-Fanta, Steyr: Acne 1999: do we still need a dermatologist? In: The dermatologist . 12/1999, pp. 900-911. doi : 10.1007 / s001050051009 .

[4] M. Wetzler, G. Marcucci, C. Bloomfield: Acute and Chronic Myeloid Leukemia. In: Dan L. Longo, Anthony S. Fauci et al. (Eds.): Harrison's Principles of Internal Medicine. 18th edition. Volume 1, p. 912.

[5] Edward A. Sausville, Dan L. Longo: Principles of Cancer treatment. In: Dan L. Longo, Anthony S. Fauci et al. (Eds.): Harrison's Principles of Internal Medicine. 18th edition. Volume 1, p. 705.

[DOI10.3109/09546634.2013.768328-6] Zohreh Hajheydari, Majid Saeedi, Katayoun Morteza-Semnani, Aida Soltani: Effect of Aloe vera topical gel combined with tretinoin in treatment of mild and moderate acne vulgaris: a randomized, double-blind, prospective trial. In: Journal of Dermatological Treatment . 2013, pp. 1–7, doi: 10.3109 / 09546634.2013.768328 , PMID 23336746 .

[7] Ch. R .: ear malformation due to tretinoin. In: Journal of General Practice. Volume 68, No. 29, October 1992, p. 12.

[8] Appendix II to the Commission's implementing decision of June 21, 2018 regarding the authorizations for human medicinal products "Retinoids (acitretin, adapalen, alitretinoin, bexaroten, isotretinoin, tazaroten, tretinoin)" according to Article 31 of Directive 2001/83 / EC of the European Parliament and of the Council ( PDF ).

[ROTE_LISTE-9] ROTE LISTE 2017, Verlag Rote Liste Service GmbH, Frankfurt am Main, ISBN 978-3-946057-10-9 , p. 223.