Systemic retinoid; psoriasis.

In mice used as models for Alzheimer's disease, citiretin (10 mg/kg; intraperitoneal; ip for 7 days) raises IL-6 in the central nervous system[3].

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In this experimental study the possible effects of the Acitretin on the spermatogenesis of the rats were investigated histopathologically. Thirty-nine male adult Wistar albino rats were divided into 3 groups as two experimental groups and one control group. The first group consisting 14 rats were applied orally standard dose (0.75 mg/kg/day) acitretin and the second group consisting 16 rats were applied high dose (1.5 mg/kg/day) Acitretin. Acitretin was given within dimetil sulphoxide (DMSO), which was diluted with saline solution as a ratio of 1/10, in order to increase its solubility. The control group consisting 9 rats were given only saline solution including DMSO for 8 weeks. After 8 weeks of the administration, half of the rats in the first and second groups and the entire control group were sacrificed under deep ether anaesthesia and bilateral orchiectomy was made. The remaining rats were compared with the control group using a similar method at the end of 8 weeks of wash-off period. The orchiectomy materials were histopathologically evaluated under the light microscope for spermatogenesis according to parameters including spermatogenetic activity, spermatogenetic organization, seminiferous tubular diameter, interstitial Leydig cells and fibroblasts. The groups, which were evaluated at the end of the 8(th) and 16(th) weeks, were compared with the control group regarding the mentioned parameters and no statistical significance was observed among the groups. In our study it was concluded that the standard and high doses of Acitretin do not have any effect on the spermatogenesis of the rats.[2]

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These days, the important role of retinoids in adult brain functionality and homeostasis is well accepted and has been proven by genomic as well as non-genomic mechanisms. In the healthy brain, numerous biological processes, e.g., cell proliferation, neurogenesis, dendritic spine formation as well as modulation of the immune system, have been attributed to retinoid signaling. This, together with the finding that retinoid metabolism is impaired in Alzheimer's disease (AD), led to preclinical and early clinical testing of natural and synthetic retinoids as innovative pharmaceuticals with multifactorial properties. Acitretin, an aromatic retinoid, was found to exert an anti-amyloidogenic effect in mouse models for AD as well as in human patients by stimulating the alpha-secretase ADAM10. The lipophilic drug was already demonstrated to easily pass the blood brain barrier after i.p. administration and evoked increased nest building capability in the 5xFAD mouse model. Additionally, we analyzed the immune-modulatory capacity of acitretin via a multiplex array in the 5xFAD mouse model and evaluated some of our findings in human CSF derived from a pilot study using acitretin. Although several serum analytes did not display changes, Interleukin-6 (IL-6) was found to be significantly increased in both-mouse and human neural material. This demonstrates that Acitretin exerts an immune stimulatory effect-besides the alpha-secretase induction-which could impact the alleviation of learning and memory disabilities observed in the mouse model [3].

ADAM10 Activity Assay [3]
A fluorescent enzyme assay was used according to the manufacturer’s recommendations. Brains were homogenized in ice-cold PBS supplemented with protease inhibitor cocktail (without EDTA). Homogenates were centrifuged at 3,000 g (3 min, 4°C); the resulting pellet was washed and resuspended with assay buffer. For each sample, a solvent control and a GM6001-treatment were measured at 480/520 (exc./em.) using the FluostarOmega (BMG; 1 measurement per minute). Usage of the metalloprotease inhibitor GM6001 ascertains control for unspecific signals obtained by the in vitro assay. Forty minutes from the linear range were used to calculate the fluorescence increase per minute. Specific RFU (relative fluorescence units) were calculated by subtracting the values from each GM6001-treatment sample from its corresponding solvent control.

0.75, 1.5 mg/kg/day; Acitretin was given within dimetil sulphoxide (DMSO), which was diluted with saline solution as a ratio of 1/10, in order to increase its solubility. Thirty-nine male adult Wistar albino rats were divided into 3 groups as two experimental groups and one control group. The first group consisting 14 rats were applied orally standard dose (0.75 mg/kg/day) acitretin and the second group consisting 16 rats were applied high dose (1.5 mg/kg/day) acitretin. Acitretin was given within dimetil sulphoxide (DMSO), which was diluted with saline solution as a ratio of 1/10, in order to increase its solubility. The control group consisting 9 rats were given only saline solution including DMSO for 8 weeks. After 8 weeks of the administration, half of the rats in the first and second groups and the entire control group were sacrificed under deep ether anaesthesia and bilateral orchiectomy was made. The remainingrats were compared with the control group using a similar method at the end of 8 weeks of wash-off period. The orchiectomy materials were histopathologically evaluated under the light microscope for spermatogenesis according to parameters including spermatogenetic activity, spermatogenetic organization, seminiferous tubular diameter, interstitial Leydig cells and fibroblasts. In our study it was concluded that the standard and high doses of Acitretin do not have any effect on the spermatogenesis of threats. Clinical indications: Psoriasis FDA Approved Date: Toxicity: nausea; headache; itching; red or flaky skin; dry or red eyes; dry mouth; depression; 0cystitis acne or hair loss. \n\n

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\nIn this study, 39 adult male Wistar albino rats weighing 250–300 g were used. The rats were kept in standard conditions (stainless-steel cages, 18–21 °C, 55–60% relative humidity, 12 h light and 12 h dark cycle). The standard chow in tablet form, as well as water, was available. The animals were divided into three groups as group I (n= 14), group II (n= 16) and control (n= 9). Acitretin 0.75 mg/kg/day, 1.5 mg/kg/day and physiological saline were administered to group I, group II and control, respectively, through gastric gavage daily for 5 days for the first 8 weeks. To increase the solubility of acitretin in physiological saline, dimethyl sulfoxid (Sigma, Milan, Italy) was diluted with physiological saline at a ratio of 1 : 10.\n\nHalf of the animals from group I (n= 7) and group II (n= 8), and all of the control group (n= 9) were sacrificed using ether anaesthesia at the end of the 8th week. Bilateral orchiectomy materials were obtained from all of these animals. The remaining animals in group I (n= 7) and group II (n= 8) were sacrificed after an additional Acitretin-free interval of 8 weeks, and bilateral orchiectomy was also performed. Synthetic retinoids have been shown to be effective in many dermatosis at a dosage of 0.5–1 mg/kg daily, therefore we used 0.75 mg/kg acitretin daily in group I. In group II, we chose 1.5 mg/kg daily doses of Acitretin since synthetic retinoids can be used in suppression of carcinogenesis in a variety of tissue types at higher doses.[2]

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\nTreatment of Mice [3]
\nMice were injected intraperitonally [daily dosage: 10 mg Acitretin in corn oil (Sigma Aldrich)/kg] for 7 days including a 2-day break (see treatment schedule, Figure 1A).\n

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\nClinical Study [3]
\nThe Acitretin-treatment study has been described in detail in Endres et al. (2014). In brief, men as well as women aged over 50 years with mild to moderate dementia and a diagnosis of probable AD were randomized to either placebo or acitretin group. Thirty milligrams of Acitretin were taken daily. CSF was collected at two time points: before start of treatment (“baseline”) and after 30 days (“treatment”). IL-4 and -6 in CSF were analyzed by ELISA following the manufacturer’s instructions. The study is registered with ClinicalTrials.gov (NCT01078168). Patients provided written informed consent before enrolment.

Absorption, Distribution and Excretion
Acitretin is best absorbed orally when taken with food, and the absorption rate increases linearly with the dose from 25 mg to 100 mg. In 12 healthy subjects, approximately 72% (range 47% to 109%) of the administered dose of 50 mg acitretin was absorbed. Both the parent compound and its isomers are further metabolized into chain-shortened metabolites and conjugates, which are ultimately excreted. Chain-shortened metabolites and conjugates of acitretin and its cis derivatives are ultimately excreted in feces (34% to 54%) and urine (16% to 53%). /Breast Milk/ Acitretin is distributed into breast milk… /Breast Milk/ A study investigated the transfer of retinoids into breast milk after a psoriasis patient took 40 mg of acitretin orally daily. During the first nine days of treatment, the concentrations of the parent compound and its major metabolite, 13-cis-acetate, in serum and mature breast milk were determined using reversed-phase high-performance liquid chromatography (RP-HPLC). After reaching steady state, trace amounts of the drug and metabolites (30–40 ng/mL) were present in breast milk, with a milk/serum concentration ratio of approximately 0.18. Acetate was almost entirely distributed in the fat layer of breast milk. Although the amount ingested by the lactating infant is estimated to be only 1.5% of the mother's dose, the potential toxicity of acetate is sufficient to justify its avoidance in breastfeeding women. Acetate is best absorbed when taken with food. Therefore, in all the following trials, acetate was taken with food. Following a single oral dose of 50 mg acetate in 18 healthy subjects, peak plasma concentrations ranged from 196 to 728 ng/mL (mean: 416 ng/mL), with a time to peak concentration ranging from 2 to 5 hours (mean: 2.7 hours). Oral absorption of tretinoin follows a linear relationship with doses from 25 to 100 mg. In 12 healthy subjects, approximately 72% (range: 47% to 109%) of a single 50 mg dose of tretinoin was absorbed. Tretinoin binds to plasma proteins at a rate exceeding 99.9%, primarily albumin. For more complete data on absorption, distribution, and excretion of tretinoin (7 items), please visit the HSDB record page. Metabolism/Metabolites Following oral absorption, tretinoin undergoes extensive metabolism and isomerizes to its 13-cis form (cis-tretinoin) via a simple isomerization. Both the parent compound and its isomers are further metabolized into chain-shortened breakdown products and conjugates, ultimately being excreted. Following oral absorption, tretinoin undergoes extensive metabolism and isomerizes to its 13-cis form (cis-tretinoin) via a simple isomerization. The dosage of oral tretinoin, whether taken on an empty stomach or after eating, does not affect the formation of c-tretinoin relative to the parent compound. The parent compound and its isomers are further metabolized into chain-shortened breakdown products and conjugates, ultimately excreted from the body. Steady-state plasma concentrations of tretinoin and c-tretinoin are reached approximately within 3 weeks after multiple doses of tretinoin. ...In the presence of ethanol, tretinoin is esterified to etretinate via the formation of tretinoin-CoA. Biological half-life: 49 hours (range 33 to 96 hours) ...Ten patients with severe psoriasis were treated with 30 mg of tretinoin daily for 3 months. After discontinuation of the drug, the elimination rates of tretinoin (half-life range 1.0 to 25.4 days) and 13-cis-tretinoin (half-life range 1.5 to 25.7 days) correlated with the observed mean steady-state levels of etratiate, with longer terminal half-lives observed in patients with higher plasma etratiate levels. …After multiple dosings, the terminal elimination half-life of tretinoin was 49 hours (range: 33 to 96 hours), while the terminal elimination half-life of cis-tretinoin under the same conditions was 63 hours (range: 28 to 157 hours).

Toxicity Summary
Identification and Uses: Acitretin is a keratolytic agent indicated for the treatment of severe psoriasis in adults. Acitretin has also been used to treat a small number of patients with discoid lupus erythematosus. Human Studies: Overdose symptoms are similar to those of acute vitamin A poisoning, including headache and dizziness. Elevated blood lipids are reported in 25-50% of acitretin patients. Elevated triglyceride levels to levels that can lead to fatal fulminant pancreatitis are rare; however, there have been reports of acitretin-related cases. Rare cases of pancreatitis without hypertriglyceridemia have also been reported. Angioedema (without urticaria) has been reported in a female psoriasis patient after oral administration of acitretin. Acitretin should be considered a possible cause of thrombotic stroke. In one reported overdose case, a 32-year-old man with Daryl's disease took a single dose of 525 mg. He vomited several hours later, but no other adverse reactions occurred. In 31 men (17 with psoriasis, 8 with keratosis disorders, and 6 healthy volunteers), no decrease in sperm count or concentration, nor any change in sperm motility or morphology was observed after daily administration of 30 to 50 mg of tretinoin for at least 12 weeks. No adverse effects on testosterone, luteinizing hormone (LH), or follicle-stimulating hormone (FSH) levels were observed in any of the 31 men in these trials. No adverse effects on the hypothalamic-pituitary axis were also observed in 18 men who underwent hypothalamic-pituitary axis function testing. Tretinoin is a known human teratogen, and serious birth defects are highly likely to occur if a patient becomes pregnant during or after taking tretinoin (birth defects have been reported two years or more after the last use of tretinoin). Teratogenicity typically manifests as malformations of craniofacial, cardiovascular, skeletal, and central nervous system structures. The mutagenicity of tretinoin was assessed in an unplanned DNA synthesis assay in human fibroblasts. No mutagenicity of tretinoin was observed in this assay. Animal studies: An 80-week carcinogenicity study in mice using etretinate, an ethyl ester of retinoic acid, has been completed. Blood concentration data obtained during the study showed that etretinate is metabolized to retinoic acid, and that retinoic acid blood concentrations were higher than etretinate at all study time points. In the etretinate study, an increased incidence of vascular tumors (hemangiomas and angiosarcomas occurring in multiple different sites) was observed in male mice (but not female mice). A carcinogenicity study of retinoic acid in rats has been completed at doses up to 2 mg/kg/day, administered 7 days a week for 104 weeks. No neoplastic lesions associated with retinoic acid treatment were observed. Chronic toxicity studies in dogs showed testicular changes (reversible mild to moderate spermatogenesis arrest and the appearance of multinucleated giant cells) in the highest dose group (50 mg/kg/day, followed by 30 mg/kg/day). In a rat fertility study, fertility was not impaired in the test animals treated with the highest tested dose (3 mg/kg/day) of tretinoin. The mutagenicity of tretinoin was assessed in the Ames test, the Chinese hamster (V79/HGPRT) test, the rat hepatocyte unprogrammed DNA synthesis assay, and the in vivo mouse micronucleus assay. No evidence of mutagenicity of tretinoin was found in any of the tests. Hepatotoxicity
Up to one-third of patients taking tretinoin experience abnormal liver function, but only 1% to 5% experience significantly elevated liver function indicators exceeding three times the upper limit of normal. These abnormalities are usually transient, asymptomatic, and resolve spontaneously with continued use of tretinoin; however, up to 4% of patients may experience mild symptoms requiring discontinuation of the drug. Tretinoin can also cause clinically significant liver injury, accompanied by symptoms and jaundice. Although uncommon, acute liver injury caused by tretinoin has been described in detail, with an estimated incidence between 0.1% and 0.5%. Injury can occur within 1 week to 9 months after the start of treatment. Elevated liver enzymes are usually hepatocellular (Case 1), but cholestatic hepatitis caused by acitretin has also been reported (Case 2). Most cases resolve rapidly upon discontinuation of acitretin. Rash, fever, eosinophilia, and other symptoms of hypersensitivity occur in many cases, but not in all; autoantibodies are rare. This injury is distinctly different from that caused by vitamin A and is not associated with fat deposition in stellate cells. Due to the potential hepatotoxicity of acitretin, routine monitoring of serum transaminase levels is recommended during acitretin treatment.
Probability score for acitretin: B (Possibly rare, but may cause clinically significant liver injury).
Similar acute liver injury has been reported with etretinate (a related retinoid used to treat psoriasis and acne, but withdrawn from the US market in 1998).
Probability score for etretinate: B (Very likely to cause clinically significant liver injury).

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Effects during pregnancy and lactation
◉ Overview of medication use during lactation
After a woman took 0.65 mg/kg of tretinoin daily, the drug concentration in her breast milk was low. Since there is currently no published experience regarding the use of tretinoin during lactation, opinions differ on whether it is appropriate to breastfeed during tretinoin treatment. During lactation, especially with newborns or premature infants, topical medications that are not easily absorbed by the mother should be preferred. Only water-soluble creams or gels should be applied to the breasts, as ointments may expose the infant to high concentrations of mineral oil through licking.
◉ Effects on breastfed infants
As of the revision date, no relevant published information was found.
◉ Effects on lactation and breast milk
After reviewing submitted adverse reaction reports of breast reactions caused by retinoids, the French National Center for Drug Surveillance found 8 cases of gynecomastia associated with tretinoin use. Protein Binding: Over 99.9% binds to plasma proteins, primarily albumin. Interactions: Long-term immunosuppression in organ transplant recipients (OTRs) increases the risk of developing skin malignancies. Oral retinoids have become an effective tool for pharmacological prophylaxis in the OTR population. Immunosuppressants that inhibit mTOR, such as sirolimus, can be used in combination with systemic retinoids for chemoprevention of skin malignancies. We report a case of a male patient who, after a second kidney transplant, began prophylactic treatment with acitretin for numerous squamous cell carcinomas (SCC), resulting in a sudden and unexpected increase in sirolimus levels to above therapeutic levels. Sirolimus levels returned to baseline after discontinuation of acitretin. Systemic drug interactions are an important phenomenon, especially in solid organ transplant recipients. We hypothesize that this interaction is mediated by acitretin's inhibition of CYP3A4 (the main enzyme responsible for sirolimus metabolism). The Drug Interaction Probability Scale (DIPS) indicates this is a "possible" drug interaction. No such interaction has been reported in the literature to date. This case underscores the importance of close monitoring for adverse drug interactions when taking multiple medications with an oral solid anticoagulant (OTR).
Concomitant use of alcohol with tretinoin can lead to the formation of etratilate, a known human teratogen with a longer elimination half-life than tretinoin; this interaction may prolong the duration of teratogenic effects of tretinoin. Concomitant use may also lead to hepatotoxicity. Women of childbearing age should avoid alcohol from any source during tretinoin treatment and for 2 months after discontinuation.
Concomitant use of tretinoin with vitamin A may result in additive adverse reactions (e.g., hypervitaminosis A). Concomitant use is contraindicated.
Concomitant use of tretinoin with methotrexate increases the risk of hepatitis. Concomitant use is contraindicated.
For more complete data on interactions of tretinoin (15 in total), please visit the HSDB record page.

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Non-human toxicity values
Mouse intraperitoneal LD50 >4000 mg/kg (1 day)
Mouse intraperitoneal LD50 700 mg/kg (10 days)
Mouse intraperitoneal LD50 700 mg/kg (20 days)

[1]. A review of acitretin, a systemic retinoid for the treatment of psoriasis. Expert Opin Pharmacother. 2005 Aug;6(10):1725-34.

[2]. Effects of acitretin on spermatogenesis of rats. J Eur Acad Dermatol Venereol. 2006 Jul;20(6):689-92.

[3]. The Synthetic Retinoid Acitretin Increases IL-6 in the Central Nervous System of Alzheimer Disease Model Mice and Human Patients. Front Aging Neurosci. 2019 Jul 23;11:182.

All-trans acitretin acid is an retinoic acid, belonging to the retinoid class of drugs, and is also an α,β-unsaturated monocarboxylic acid. It is a keratolytic agent. It is an oral retinoid drug effectively used to treat psoriasis. It is the major metabolite of etretinate, and has a shorter half-life compared to etretinate. Acitretin is a retinoid drug. Acitretin is a retinoid and vitamin A derivative currently used to treat psoriasis. Like many retinoids, retinoic acid can cause elevated serum transaminase levels and has been shown to be associated with acute liver injury, which can be severe and even fatal. Acitretin is the orally active metabolite of the synthetic aromatic retinoid drug etretinate and has potential antitumor, chemopreventive, anti-psoriatic, and embryotoxic effects. Acitretin activates nuclear retinoic acid receptors (RARs), thereby inducing cell differentiation, inhibiting cell proliferation, and suppressing inflammatory cell infiltration into tissues. The drug may also inhibit tumor angiogenesis. (NCI04)
An oral retinoid medication for the effective treatment of psoriasis. It is the major metabolite of etretinate and has a shorter half-life compared to etretinate.

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Indications
For the treatment of severe psoriasis in adults.
FDA Label

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Mechanism of Action
The mechanism of action of acitretin is not fully understood, but it is believed to work by targeting specific receptors in the skin, such as retinoid receptors RXR and RAR, to help normalize the growth cycle of skin cells.

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Therapeutic Use
Keratoplast
/Clinical Trials/ ClinicalTrials.gov is a registry and results database that includes human clinical studies funded by public and private institutions worldwide. This website is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each record on ClinicalTrials.gov provides a summary of the study protocol, including the following: disease or condition; intervention (e.g., the medical product, behavior, or procedure being studied); study title, description, and design; participation requirements (eligibility criteria); study location; contact information for the study location; and links to other relevant health websites, such as MedlinePlus (providing patient health information) and PubMed (providing citations and abstracts of academic articles in the medical field) of the National Library of Medicine (NLM). Acitretin is included in the database. Acitretin capsules (USP) are indicated for the treatment of severe psoriasis in adults. Due to the potential for significant adverse reactions, only physicians familiar with systemic retinoid use should prescribe acitretin capsules (USP). For women of childbearing age, acitretin capsules (USP) should only be used in non-pregnant patients who have not responded to other therapies or whose clinical condition precludes the use of other therapies. /Included on US Product Label/
Acitretin has been used in a small number of patients to treat discoid lupus erythematosus; its efficacy is similar to hydroxychloroquine, but acitretin's adverse reactions are more severe and more frequent. Further research is needed to determine the role of acitretin in the treatment of this disease. /Not Included on US Product Label/
For more complete data on the therapeutic uses of acitretin (out of 9), please visit the HSDB record page.

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Drug Warnings
/Black Box Warning/Contraindications and Warnings: Pregnancy. Acitretin is contraindicated in women who are pregnant or who plan to become pregnant during treatment or for at least 3 years after discontinuation of treatment. Additionally, acitretin is contraindicated in women who may be unable to use reliable contraception during treatment and for at least 3 years after discontinuation of treatment. Acitretin is a metabolite of etretinate (TEGISON), and there have been reports of serious human fetal malformations resulting from concomitant use of acitretin and etretinate. Any fetus exposed to acitretin may be affected. Clinical evidence suggests that concomitant administration of tretinoin and ethanol leads to the formation of etratiate, with etratiate having a significantly longer elimination half-life than tretinoin. Due to the longer elimination half-life of etratiate, the risk of teratogenicity in female patients is prolonged; therefore, women of childbearing age should avoid ethanol intake during tretinoin treatment or for two months after discontinuation. This allows tretinoin to be eliminated, thus removing the substrate for the transesterification reaction to etratiate. The metabolic mechanism of tretinoin to etratiate is not fully understood. It is currently unclear whether other substances besides ethanol are involved in the transesterification reaction. Studies have shown that tretinoin has embryotoxic and/or teratogenic effects in rabbits, mice, and rats at oral doses of 0.6, 3, and 15 mg/kg, respectively. Based on mg/m² comparisons, these doses are approximately 0.2, 0.3, and 3 times the maximum recommended therapeutic dose, respectively. It has been reported that taking tretinoin and/or etratic acid can cause serious fetal malformations in humans, including myelomeningocele, meningocele, multiple suture closure, facial deformities, syndactyly, loss of distal phalanges, hip, ankle, and forearm deformities, low-set ears, and high palate. Other possible causes include reduced skull volume, cardiovascular malformations, and skull and cervical spine changes. Tretinoin should only be prescribed by physicians with specialized expertise in the diagnosis and treatment of severe psoriasis, experience using systemic retinoids, and awareness of its teratogenic risks. Due to the teratogenicity of tretinoin, a program called "Prevention of Pregnancy During Treatment is Crucial" (PPET) was developed to educate women of childbearing age and their healthcare providers about the serious risks associated with tretinoin and to help prevent pregnancy during use of the drug and within three years after discontinuation. /Warning: Hepatotoxicity: In a US clinical trial of 525 participants, two developed clinical jaundice with elevated serum bilirubin and transaminases, considered associated with tretinoin treatment. These participants' liver function returned to normal after discontinuation of tretinoin. In a European clinical trial of 1289 participants, two developed biopsy-confirmed toxic hepatitis. A second biopsy of one participant showed nodule formation, suggesting cirrhosis. In a Canadian clinical trial involving 63 participants, one participant experienced a three-fold increase in transaminase levels. This participant's liver biopsy revealed mild lobular dysplasia, multifocal hepatocyte loss, and a mild portal triad, consistent with the pathology of acute reversible liver injury. This participant's transaminase levels returned to normal two months after discontinuation of tretinoin. An open-label trial involving 128 participants prospectively assessed the potential for tretinoin-induced hepatotoxicity using liver biopsy. Eighty-seven participants provided liver biopsy samples before and after treatment. Comparison of liver biopsy results before and after treatment showed no change in liver biopsy results in 49 participants (58%), improvement in 21 participants (25%), and deterioration in 14 participants (17%). The liver biopsy grade changed from grade 0 (no pathological changes) to grade I (normal fatty infiltration; nuclear atypia and portal vein inflammation; both mild) in 6 participants; from grade I to grade II (fatty infiltration, nuclear atypia, portal vein inflammation, and focal necrosis; all moderate to severe) in 7 participants; and from grade II to grade IIIb (fibrosis, moderate to severe) in 1 participant. No correlation was found between abnormal liver function test results and changes in liver biopsy results, nor with cumulative dose. Approximately one-third of participants receiving acitretin treatment experienced elevated AST (SGOT), ALT (SGPT), GGT (GGTP), or LDH levels. In clinical trials conducted in the United States, 20 out of 525 participants (3.8%) discontinued treatment due to abnormal liver function test results. If hepatotoxicity is suspected during acitretin treatment, the drug should be discontinued immediately and the cause investigated. In a clinical trial of etradicide (acitretin's active metabolite) conducted in the United States, 10 out of 652 participants developed clinical or histological hepatitis, considered possibly or very likely related to etradicide treatment. Hepatitis-related deaths have been reported globally; some of these patients had received etradicide treatment for less than one month before developing liver symptoms or signs. Acitretin is a known teratogen in humans, and the risk of serious birth defects is extremely high if a patient becomes pregnant while taking or after discontinuing acitretin (birth defects have been reported even 2 years or more after the last dose of acitretin). Teratogenicity typically manifests as malformations of the craniofacial, cardiovascular, skeletal, and central nervous system structures. Acitretin is contraindicated during pregnancy. Women should not use this drug during treatment with acitretin or for at least 3 years after discontinuation, or if reliable contraception may be unavailable during treatment or for at least 3 years after discontinuation. If pregnancy occurs during treatment or for at least 3 years after discontinuation, the clinician and patient should discuss the potential effects of the drug on pregnancy. Acitretin is excreted into breast milk; women taking this drug should not breastfeed. For more complete (20) drug warnings for acitretin, please visit the HSDB record page.

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Pharmacodynamics
Acitretin is a retinoid. Retinoids have a structure similar to vitamin A and are involved in the normal growth of skin cells. Acitretin works by inhibiting excessive cell proliferation and keratinization (the thickening of skin cells due to protein deposition), which are common in psoriasis. Therefore, it can reduce skin thickening, plaque formation, and scaling.

C21H26O3

326.43

326.188

C, 77.27; H, 8.03; O, 14.70

55079-83-9

Acitretin sodium;925701-88-8

5284513

Light yellow to yellow solid powder

1.1±0.1 g/cm3

521.3±38.0 °C at 760 mmHg

228-230ºC

180.3±20.3 °C

0.0±1.4 mmHg at 25°C

1.570

5.73

1

3

6

24

539

0

CC1=CC(=C(C(=C1/C=C/C(=C/C=C/C(=C/C(=O)O)/C)/C)C)C)OC

IHUNBGSDBOWDMA-AQFIFDHZSA-N

InChI=1S/C21H26O3/c1-14(8-7-9-15(2)12-21(22)23)10-11-19-16(3)13-20(24-6)18(5)17(19)4/h7-13H,1-6H3,(H,22,23)/b9-7+,11-10+,14-8+,15-12+

(2E,4E,6E,8E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethylnona-2,4,6,8-tetraenoic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: 2 mg/mL (6.13 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2 mg/mL (6.13 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2 mg/mL (6.13 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)