9-cis-Retinoic Acid (1-10 μM; 0-5 days; CA 9-22 and NA cells) the swelling of CA 9-22 and NA cells can be considerably decreased by quantitative irrigation [1]. Treatment of CA 9-22 and NA respiratory digestion cells with 1 μM retinoic acid for 24 hours dramatically enhanced PPARγ functional activity to >200% [1]. In CA 9-22 cells, 9-cis-retinoic acid treatment led to nuclear PPARγ-RXRα heterodimer complexes being supershifted [1]. Time-dependent and time-regulated induction of apoptosis is induced by 9-cis-retinoic acid, which also decreases the potential of cutaneous T-cell clearance (CTCL). Cyclin D1 is the mechanism by which 9-cis-retinoic acid also stimulates G0/G1 cyclins. The phosphorylation of JAK1, STAT3, and STAT5 is greatly decreased by 9-cis-retinoic acid, which also causes Bcl-xL and cyclin D1 to be increased[2]. Expansion test [1]

9-cis-Retinoic Acid (1 mg/kg; i.v.; daily; for 10 days; safe in C57BL/6J mice) therapy significantly lowered serum ALT and AST levels and increased bile duct ligation (BDL) in the liver and kidneys of mice [3

Proliferation assay[1]
Cell Types: CA 9-22 and NA Cell
Tested Concentrations: 1 μM, 10 μM
Incubation Duration: 0 day, 1 day, 3 day, 5 day
Experimental Results: Proliferation was Dramatically diminished.

Animal/Disease Models: Male C57BL/6J mice (6-8 weeks; 19-22 g) bile duct ligation treatment [3]
Doses: 1 mg/kg
Route of Administration: intravenous (iv) (iv)injection; ]. Daily; results for 10 days: serum ALT and AST levels dropped Dramatically, and liver necrosis was alleviated.

Absorption, Distribution and Excretion
BACKGROUND: Previous studies have shown that concomitant administration of food may enhance the bioavailability of oral retinoids. AIM: To assess the influence of food on the pharmacokinetics (PK) of alitretinoin after a single oral dose. METHODS: This was a single-dose, open-label, randomized, crossover study, which enrolled 30 healthy men, aged 18-44 years. Subjects received sequential doses of alitretinoin 40 mg either after fasting (treatment A) or 5 min after completion of a standard breakfast (treatment B), with the dosing sequence randomized (A/B or B/A). The washout period between the two doses was 1 week. Plasma concentrations over time were plotted and standard PK variables [area under the curve (AUC) of plasma concentration vs. time, maximum plasma concentration (C(max)), time to maximum plasma concentration (t(max)) and elimination half-life (t(1/2)] were determined. RESULTS: Drug exposure was markedly increased when alitretinoin was taken with food compared with fasting, and there were significant increases in mean C(max) (82.8 vs.25.4 ng/mL, respectively) and AUC (220.2 vs. 55.7 ng/mL/hr). The delaying effect of food on t(max) was less marked (median of 3.0 vs. 2.0 h). Administration with food also increased exposure to drug metabolites. Variability in exposure was markedly reduced if alitretinoin was taken with vs. without food (percentage coefficient of variation 40% vs. 74% for AUC; 49% vs. 85% for C(max)). Alitretinoin was generally well tolerated, with typical retinoid adverse reactions, mostly comprising headache. CONCLUSIONS: Intake of alitretinoin with food substantially increased the bioavailability of alitretinoin, but variability in exposure was reduced. Consequently, oral alitretinoin should be taken with food as outlined in the manufacturer's summary of product characteristics.
BACKGROUND: Alitretinoin, like all retinoids, is teratogenic, and can only be given to women of childbearing potential if pregnancy is excluded and a strict contraceptive programme is followed. AIM: This study was designed to determine whether alitretinoin in the semen of men treated with alitretinoin poses a teratogenic risk to their female partners. METHODS: In total, 24 healthy men aged 18-45 years received alitretinoin 20 mg (n = 12) or 40 mg (n = 12), once daily for 14 days. Subjects in the 40 mg dose group provided ejaculate at baseline, on day 1, before and approximately 4 hr after dosing on day 2, and at follow-up on study day 21 (+/- 2). RESULTS: Alitretinoin and 4-oxo-alitretinoin were detected in 11 of the 12 semen samples. The highest level of alitretinoin in semen was 7.92 ng/mL. Assuming an ejaculate volume of 10 mL, the amount of drug transferred in semen would be about 80 ng, 1/375,000 of a single 30 mg capsule. Complete absorption of 80 ng of alitretinoin from semen, presuming a volume of distribution confined to 5 L of circulating blood in the partner, would lead to an increase in plasma alitretinoin concentration of 0.016 ng/mL, which appears to be negligible compared with measured endogenous plasma levels. Increases in plasma levels of related retinoids are also negligible. CONCLUSIONS: Alitretinoin in the semen of men receiving up to 40 mg of oral alitretinoin per day is unlikely to be associated with teratogenic risk in their female partners. Barrier contraception is therefore not required for men taking alitretinoin.
/MILK/ It is not known whether alitretinoin or its metabolites are excreted in human milk.
Limited data indicate that alitretinoin is not substantially absorbed systemically following topical application of the drug.

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Metabolism / Metabolites
Although there are no detectable plasma concentrations of 9-cis-retinoic acid metabolites after topical application of Panretin gel, in vitro studies indicate that the drug is metabolized to 4-hydroxy-9-cis-retinoic acid and 4-oxo-9-cis-retinoic acid by CYP 2C9, 3A4, 1A1, and 1A2 enzymes. In vivo, 4-oxo-9-cis-retinoic acid is the major circulating metabolite following oral administration of 9-cis-retinoic acid.
4-hydroxy-9-cis-retinals is a known human metabolite of 9-cis-retinal.

Toxicity Summary
IDENTIFICATION AND USE: Alitretinoin is an antineoplastic agent, used for topical treatment of cutaneous lesions in patients with AIDS-related Kaposi's sarcoma. HUMAN STUDIES: The most common adverse events were typical class effects of oral retinoids including headache, flushing, and skin disorders. There was a case of sensitization to alitretinoin reported in the literature. It was not found to be clastogenic in vitro in chromosome aberration test in human lymphocytes. ANIMAL STUDIES: Administration of alitretinoin to pregnant mice at 3 mg/kg on day 7.5 induced a 12% resorption rate and 0% exencephaly in 58 implants. In the 51 live fetuses that were given alitretinoin, there were 9 cases of microphthalmia and 6 cases of anophthalmia. Both the resorption and exencephaly rates indicate that alitretinoin is less potent than trans retinoic acid for these endpoints. An increased incidence of fused sternebrae and limb and craniofacial defects occurred in rabbits given oral doses of 0.5 mg/kg/day during the period of organogenesis. Limb and craniofacial defects also occurred in mice given a single oral dose of 50 mg/kg on day 11 of gestation. Oral alitretinoin was embryocidal, as indicated by early resorptions and post-implantation loss when it was given during the period of organogenesis to rabbits at doses of 1.5 mg/kg/day and to rats at doses of 5 mg/kg/day. Alitretinoin was not found to be mutagenic in in vitro tests including the Chinese hamster ovary cell HGPRT mutation assay. It was not found to be clastogenic in vivo (mouse micronucleus test). ECOTOXICITY STUDIES: In the Japanese flounder Paralichthys olivaceus, at 6-9 days post-hatching, all retinoic acid isomers (including alitretinoin) exerted toxic effects on the skeletal systems, mainly through the RAR pathway.

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Tretinoin has not been studied during breastfeeding. Breastfeeding should be avoided during oral use and for 1 week after the last dose. Because it is poorly absorbed after topical application, it is considered a low risk to the nursing infant. Do not apply tretinoin directly to the nipple and areola and ensure that the infant's skin does not come into direct contact with the areas of skin that have been treated.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
A review of adverse reaction reports on retinoids causing a breast reaction submitted to a French pharmacovigilance center found 1 case of gynecomastia was associated with topical tretinoin use.

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Interactions
BACKGROUND: Based on in vitro data with isolated cytochrome P450 (CYP) isoenzymes, alitretinoin interacts only with CYP3A4, and the potential for drug-drug interactions is considered negligible. AIM: To confirm in humans the lack of potential interactions between CYP3A4 and alitretinoin in vivo. METHODS: This was a multiple-dose, open-label, parallel-group, single-centre study, which enrolled 54 healthy male volunteers aged 18-45 years. Subjects were divided into three groups, with 18 in each group: group 1 received either alitretinoin 30 mg and ketoconazole 200 mg, group 2 alitretinoin 30 mg and simvastatin 40 mg, and group 3 alitretinoin 30 mg and cyclosporin A 300-mg. RESULTS: At the highest therapeutic dose of 30 mg, alitretinoin had no significant effect on the pharmacokinetics (PK) of ketoconazole and cyclosporin A. There was a significant but not clinically relevant effect of simvastatin on the area under the curve (AUC) of plasma concentration vs. time and on maximum plasma concentration (C(max)) after repeated administration of alitretinoin. Exposure to simvastatin concomitantly with alitretinoin was decreased by 16% for AUC and 23% for C(max). The CYP3A4 +/- PgP substrates of simvastatin and cyclosporin A did not affect the single or repeated dose PK of alitretinoin. The strong CYP3A4/PgP inhibitor ketoconazole led to significant increases in both AUC and C(max) values for alitretinoin. CONCLUSIONS: Single and repeated doses of alitretinoin do not alter the PK of cyclosporin A and ketoconazole. Simvastatin levels were slightly but significantly reduced by co-administration of alitretinoin. Substrates of CYP3A4 did not affect the PK of alitretinoin. However, ketoconazole significantly increased the plasma levels of alitretinoin, therefore, co-administration with CYP3A4 inhibitors such as ketoconazole may require a dose reduction of alitretinoin.
Patients who are applying Panretin gel should not concurrently use products that contain DEET (N,N-diethyl-m-toluamide), a common component of insect repellent products. Animal toxicology studies showed increased DEET toxicity when DEET was included as part of the formulation.

[1]. Raul Rosas, et al. Retinoids Augment Thiazolidinedione PPARγ Activation in Oral Cancer Cells. Anticancer Res. 2020 Jun;40(6):3071-3080.
[2]. Hua Yang, et al. Effects of 9-cis-retinoic Acid on the Proliferation and Apoptosis of Cutaneous T-cell Lymphoma Cells. Anticancer Drugs. 2019 Jan;30(1):56-64.
[3]. Zhiqing Yuan, et al. 9-cis-retinoic Acid Elevates MRP3 Expression by Inhibiting Sumoylation of RXRα to Alleviate Cholestatic Liver Injury. Biochem Biophys Res Commun. 2018 Sep 3;503(1):188-194.
[4]. V M Manzano, et al. Human Renal Mesangial Cells Are a Target for the Anti-Inflammatory Action of 9-cis Retinoic Acid. Br J Pharmacol. 2000 Dec;131(8):1673-83.
[5]. Gro H Mathisen, et al. Delayed Translocation of NGFI-B/RXR in Glutamate Stimulated Neurons Allows Late Protection by 9-cis Retinoic Acid. Biochem Biophys Res Commun. 2011 Oct 14;414(1):90-5.

Therapeutic Uses
Antineoplastic Agents
/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Alitretinoin is included in the database.
Panretin gel is indicated for topical treatment of cutaneous lesions in patients with AIDS-related Kaposi's sarcoma. Panretin gel is not indicated when systemic anti-KS therapy is required (e.g., more than 10 new KS lesions in the prior month, symptomatic lymphedema, symptomatic pulmonary KS, or symptomatic visceral involvement). There is no experience to date using Panretin gel with systemic anti-KS treatment. /Included in US product labeling/
/EXPL THER/ Lichen amyloidosis (LA) is characterized by the deposition of amyloid that may respond to chronic scratching that may be secondary to atopic dermatitis, stasis dermatitis, or interface dermatitis. Despite the development of several therapeutic strategies, including topical steroids, oral antihistamines, cyclosporine, and retinoids, an effective treatment for LA has not been established. A 49-year-old woman who has been treated irregularly for atopic dermatitis for 7 years presented with localized brownish papules on the left forearm and right elbow. They developed 3 months prior and were becoming more prominent despite of treatment with cyclosporine, oral antihistamines, and topical steroids for 5 months prior to presentation. A skin biopsy revealed amyloid deposition in the dermal papillae and the patient was diagnosed with LA associated with atopic dermatitis. A 6-month course of daily oral alitretinoin 30 mg produced marked improvement in the thickness and color of the hyperkeratotic papules without aggravation of the patient's atopic dermatitis. Histologic evaluation showed clearance of amyloid deposition and almost normalization of the epidermal changes. Herein, we report a case of LA treated with alitretinoin and suggest that it could be a potential treatment option for LA, especially in patients with inflammatory skin diseases including atopic dermatitis.
For more Therapeutic Uses (Complete) data for Alitretinoin (13 total), please visit the HSDB record page.

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Drug Warnings
Retinoids as a class have been associated with photosensitivity. There were no reports of photosensitivity associated with the use of Panretin gel in the clinical studies. Nonetheless, because in vitro data indicate that 9-cis-retinoic acid may have a weak photosensitizing effect, patients should be advised to minimize exposure of treated areas to sunlight and sunlamps during the use of Panretin gel.
It is not known whether alitretinoin or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions from Panretin gel in nursing infants, mothers should discontinue nursing prior to using the drug.
Inadequate information is available to assess safety and efficacy in patients age 65 years or older.
Safety and effectiveness in pediatric patients have not been established.
For more Drug Warnings (Complete) data for Alitretinoin (9 total), please visit the HSDB record page.

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Pharmacodynamics
Alitretinoin (9-cis-retinoic acid) is a naturally-occurring endogenous retinoid indicated for topical treatment of cutaneous lesions in patients with AIDS-related Kaposi's sarcoma. Alitretinoin inhibits the growth of Kaposi's sarcoma (KS) cells in vitro.

C20H28O2

300.43512

300.208

5300-03-8

9-cis-Retinoic acid-d5

449171

Yellow fine needles from ethanol
Yellow powder

1.0±0.1 g/cm3

462.8±14.0 °C at 760 mmHg

189-191ºC

350.6±11.0 °C

0.0±2.5 mmHg at 25°C

1.556

6.83

1

2

5

22

567

0

C(O)(=O)/C=C(/C=C/C=C(\C=C\C1C(C)(C)CCCC=1C)/C)\C

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: (1). This product requires protection from light (avoid light exposure) during transportation and storage.  (2). Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture.

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

DMSO : ~25 mg/mL (~83.21 mM)

Solubility in Formulation 1: 2.5 mg/mL (8.32 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 25.0 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: 2.5 mg/mL (8.32 mM) 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; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 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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 (Please use freshly prepared in vivo formulations for optimal results.)