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 co-administration with food can improve the bioavailability of oral retinoids. Objective: To evaluate the effect of food on the pharmacokinetics (PK) of a single oral dose of retinoic acid. Methods: This was a single-dose, open-label, randomized, crossover study that included 30 healthy men aged 18 to 44 years. Subjects received 40 mg of retinoic acid either on an empty stomach (Group A) or 5 minutes after a standard breakfast (Group B), with the dosing order randomized (A/B or B/A). The washout period between the two doses was 1 week. Plasma drug concentration versus time curves were plotted, and standard pharmacokinetic parameters [area under the plasma concentration-time curve (AUC), maximum plasma concentration (Cmax), time to peak concentration (tmax), and elimination half-life (t1/2)] were determined. Results: Compared with fasting, co-administration of retinoic acid with food significantly increased drug exposure, with significantly elevated mean Cmax (82.8 ng/mL vs. 25.4 ng/mL) and AUC (220.2 ng/mL/hr vs. 55.7 ng/mL/hr). Food had a weaker delay in tmax (median 3.0 h vs. 2.0 h). Compared with fasting, co-administration with food significantly reduced the variability of drug exposure (coefficients of variation for AUC were 40% and 74%, respectively; coefficients of variation for tmax were 49% and 85%, respectively). Overall, retinoic acid was well tolerated, with the main adverse reactions being typical of retinoids, including headache. Conclusion: Co-administration with food significantly improves the bioavailability of retinoic acid, but reduces the variability of exposure. Therefore, oral retinoic acid should be taken with food as directed in the manufacturer's product characteristics summary. Background: Like all retinoids, retinoic acid is teratogenic and therefore should only be used in women of reproductive age after pregnancy has been ruled out and strict contraception has been implemented. Objective: This study aimed to determine whether retinoic acid in the semen of men taking retinoic acid poses a teratogenic risk to their female partners. Methods: Twenty-four healthy men aged 18–45 years were enrolled and received either 20 mg (n = 12) or 40 mg (n = 12) of retinoic acid once daily for 14 days. Subjects in the 40 mg dose group provided semen samples at baseline, before and approximately 4 hours after administration on day 1 and day 2, and at follow-up on day 21 (± 2 days). Results: Retinoic acid and 4-oxoretinoic acid were detected in 11 of the 12 semen samples. The highest concentration of retinoic acid in semen was 7.92 ng/mL. Assuming an ejaculation volume of 10 mL per ejaculation, the amount of drug transferred into the semen would be approximately 80 ng, equivalent to 1/375,000 of a single 30 mg capsule. Assuming the volume of distribution is limited to 5 L of circulating blood in the partner, the 80 ng of retinoic acid completely absorbed from the semen would result in a 0.016 ng/mL increase in plasma retinoic acid concentration, which appears negligible. The increase in plasma levels of related retinoids is also minimal compared to the measured endogenous plasma levels. Conclusion: Men taking no more than 40 mg of retinoic acid daily are unlikely to have retinoic acid in their semen associated with teratogenic risks to their female partners. Therefore, men taking retinoic acid do not need to use barrier contraception.
/Breast Milk/ It is unclear whether retinoic acid or its metabolites are excreted into human breast milk.
Limited data suggest that retinoic acid is not extensively absorbed systemically after topical application.

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Metabolism/Metabolites
Although no 9-cis-retinoic acid metabolites were detected in plasma after topical application of Panadine gel, in vitro studies have shown that the drug is metabolized to 4-hydroxy-9-cis-retinoic acid and 4-oxo-9-cis-retinoic acid via CYP 2C9, 3A4, 1A1, and 1A2 enzymes. In vivo studies have shown that 4-oxo-9-cis-retinoic acid is the major circulating metabolite after oral administration of 9-cis-retinoic acid.
4-Hydroxy-9-cis-retinal is a known human metabolite of 9-cis-retinal.

Toxicity Summary
Identification and Uses: Alivitaic acid is an antitumor drug used topically to treat skin lesions in patients with HIV-associated Kaposi's sarcoma. Human Studies: The most common adverse reactions are typical of oral retinoids, including headache, flushing, and skin lesions. One case of alivitaic acid sensitization has been reported in the literature. In vitro human lymphocyte chromosome aberration assays did not reveal any chromosome breakage-inducing effect. Animal Studies: In pregnant mice, administration of 3 mg/kg alivitaic acid on day 7.5 of gestation resulted in 12% embryo resorption and 0% anencephaly after implantation of 58 embryos. Among 51 surviving fetuses treated with alivitaic acid, 9 had microphthalmia and 6 had anencephaly. Embryo resorption and ectropion rates indicate that alivitaic acid is less potent than trans-retinoic acid for these endpoints. During organogenesis, rabbits administered alivitaic acid orally at a dose of 0.5 mg/kg/day had an increased incidence of sternal fusion, limb and craniofacial defects. On day 11 of gestation, mice given a single oral dose of 50 mg/kg of retinoic acid also developed limb and craniofacial defects. During organogenesis, early embryonic resorption and post-implantation embryonic loss were observed in rabbits given 1.5 mg/kg/day and rats given 5 mg/kg/day of retinoic acid, indicating embryolet lethality of retinoic acid. In vitro assays (including the HGPRT mutation assay in Chinese hamster ovary cells) did not reveal mutagenicity of retinoic acid. In vivo assays (mouse micronucleus assay) also did not reveal chromosome breakage. Ecotoxicity studies: In Japanese flounder (Paralichthys olivaceus), 6–9 days after hatching, all retinoic acid isomers (including retinoic acid) exhibited toxic effects on the skeletal system, primarily through the RAR pathway.

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Effects during pregnancy and lactation
◉ Overview of use during lactation
The use of retinoic acid during lactation has not been studied. Breastfeeding should be avoided during oral retinoic acid administration and for one week after the last dose. Due to poor absorption of topical application, the risk to breastfeeding infants is low. Do not apply retinoic acid directly to the nipple and areola, and ensure that the infant's skin does not come into direct contact with the applied retinoic acid.
◉ 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 Vigilance found one case of gynecomastia associated with topical retinoic acid.

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Interactions
Background: Based on in vitro isolated cytochrome P450 (CYP) isoenzyme data, avitamin A acid interacts only with CYP3A4, and the possibility of drug interactions is considered negligible. Objective: To confirm the absence of a potential interaction between CYP3A4 and azithromycin in humans. Methods: This was a multi-dose, open-label, parallel-group, single-center study that enrolled 54 healthy male volunteers aged 18 to 45 years. Subjects were randomly assigned to three groups of 18 each: Group 1 received azithromycin 30 mg and ketoconazole 200 mg; Group 2 received azithromycin 30 mg and simvastatin 40 mg; and Group 3 received azithromycin 30 mg and cyclosporine A 300 mg. Results: At the highest therapeutic dose of 30 mg, azithromycin had no significant effect on the pharmacokinetics (PK) of ketoconazole and cyclosporine A. Simvastatin significantly affected the area under the plasma drug concentration-time curve (AUC) and maximum plasma concentration (Cmax) after repeated administration of azithromycin, but this effect was not clinically significant. When simvastatin was co-administered with azithromycin, the AUC and Cmax decreased by 16% and 23%, respectively. Simvastatin and cyclosporine A's CYP3A4+/- PgP substrates do not affect the pharmacokinetics of iliretinoin with single or repeated dosing. The potent CYP3A4/PgP inhibitor ketoconazole significantly increased the AUC and Cmax values of iliretinoin. Conclusion: Single and repeated dosings of iliretinoin do not alter the pharmacokinetics of cyclosporine A and ketoconazole. Co-administration of iliretinoin may slightly but significantly decrease the plasma concentration of simvastatin. CYP3A4 substrates do not affect the pharmacokinetics of iliretinoin. However, ketoconazole significantly increases the plasma concentration of iliretinoin; therefore, when co-administered with CYP3A4 inhibitors such as ketoconazole, a dose reduction of iliretinoin may be necessary. Patients using Panretin gel should not concurrently use products containing DEET (N,N-diethyl-m-toluamide), a common ingredient in mosquito repellent products. Animal toxicology studies have shown that the toxicity of DEET increases when the formulation contains DEET.

[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
Anti-tumor drugs / Clinical trials / ClinicalTrials.gov is a registry and results database that lists human clinical studies funded by public and private institutions worldwide. The website is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each record on ClinicalTrials.gov includes summary information about the study protocol, including: the disease or condition; the intervention (e.g., the medical product, behavior, or procedure being studied); the title, description, and design of the study; participation requirements (eligibility criteria); the location of the study; contact information for the study location; and links to relevant information from other health websites, such as the NLM's MedlinePlus (which provides patient health information) and PubMed (which provides citations and abstracts of academic articles in the medical field). Alivitaic acid is listed in the database.
Panruitin gel is indicated for the topical treatment of skin lesions in patients with HIV-associated Kaposi's sarcoma. When systemic anti-Kaposi's sarcoma therapy is required (e.g., more than 10 new Kaposi's sarcoma lesions in the past month, symptomatic lymphedema, symptomatic pulmonary Kaposi's sarcoma, or symptomatic visceral involvement), the use of Panoretin gel is not recommended. There is currently no experience with the combined use of Panoretin gel and systemic anti-Kaposi's sarcoma therapy. /Listed under US Product Label/
/Treatment Trials/ Lichenoid amyloidosis (LA) is characterized by amyloid protein deposition and may respond to chronic scratching, which may be secondary to atopic dermatitis, stasis dermatitis, or interface dermatitis. Although various treatment strategies have been developed, including topical corticosteroids, oral antihistamines, cyclosporine, and retinoids, no effective treatment regimen for LA has yet been established. A 49-year-old woman with a 7-year history of irregular atopic dermatitis presented with localized brown papules on her left forearm and right elbow. These papules appeared 3 months prior to presentation and had progressively worsened despite treatment with cyclosporine, oral antihistamines, and topical corticosteroids for 5 months prior to consultation. Skin biopsy revealed amyloid deposition in the papillary dermis, and the patient was diagnosed with erythema localization (LA) associated with atopic dermatitis. After 6 months of daily oral administration of 30 mg retinoic acid, the thickness and color of the papules significantly improved without exacerbating the patient's atopic dermatitis. Histological evaluation showed clearance of the amyloid deposition and near-normal epidermal lesions. This article reports a case of erythema localization (LA) treated with retinoic acid and suggests that retinoic acid may be a potential treatment option for LA, particularly for patients with inflammatory skin diseases, including atopic dermatitis. For more complete data on the therapeutic uses of retinoic acid (13 items in total), please visit the HSDB record page.
Drug Warnings
Retinoic acid drugs are associated with photosensitivity. No photosensitivity has been reported with the use of Perretinoin gel in clinical studies. However, because in vitro data suggest that 9-cis-retinoic acid may have mild photosensitivity, patients are advised to minimize exposure of the treated area to sunlight and fluorescent light while using Perretinoin gel. It is currently unknown whether avitamin A acid or its metabolites are excreted into human breast milk. Since many drugs are excreted into breast milk, and adverse reactions may occur in breastfeeding infants using Perretinoin gel, mothers should discontinue breastfeeding before using this medication. There is currently insufficient information to assess the safety and efficacy of this drug in patients aged 65 years and older. The safety and efficacy of this drug in pediatric patients have not been established. For more complete data on drug warnings for avitamin A acid (9 of 9), please visit the HSDB record page.

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Pharmacodynamics
Avitamin A acid (9-cis-retinoic acid) is a naturally occurring endogenous retinoic acid indicated for the topical treatment of skin lesions in patients with HIV-associated Kaposi's sarcoma.
Alivitamin A acid can inhibit 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.)