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 Alitretinoin

Alitretinoin is an orally- and topically-active naturally-occurring retinoic acid with antineoplastic, chemopreventive, teratogenic, and embryotoxic activities. Alitretinoin binds to and activates nuclear retinoic acid receptors (RAR) and retinoid X receptors (RXR); these activated receptors act as transcription factors, regulating gene expression that results in the inhibition of cell proliferation, induction of cell differentiation, and apoptosis of both normal cells and tumor cells. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus)

Panretin® gel 0.1% contains alitretinoin and is intended for topical application only.  Chemically, alitretinoin is related to vitamin A. It is a yellow powder with a molecular weight of 300.44 and a molecular formula of C20H28O2. It is slightly soluble in ethanol (7.01 mg/g at 25oC) and insoluble in water. Panretin® gel is a clear, yellow gel containing 0.1% (w/w) alitretinoin in a base of dehydrated alcohol USP, polyethylene glycol 400 NF, hydroxypropyl cellulose NF, and butylated hydroxytoluene NF.

According to http://en.wikipedia.org/wiki/Alitretinoin, Alitretinoin, or 9-cis-retinoic aicd, is an antineoplastic agent developed by Ligand Pharmaceuticals. It is a first generation retinoid. Ligand gained Food and Drug Administration (FDA) approval for alitretinoin in February 1999.

In the United States, topical alitretinoin (trade name Panretin) is indicated for the treatment of skin lesions in AIDS-related Kaposi's sarcoma. Alitretinoin is not indicated when systemic therapy against Kaposi's sarcoma is required.

Under the trade name Toctino (marketed by Basilea, Switzerland) it has been granted prescription rights in the UK (08/09/2008) for oral use in chronic hand eczema.  In May 2009 the National Institute for Health and Clinical Excellence (NICE) issued preliminary guidance[4] on the use of Alitretinoin for the treatment of severe chronic hand eczema in adults. The recommendation stated that only patients with severe chronic hand eczema who are unresponsive to potent topical corticosteroids, oral immunosuppressants or phototherapy should receive the drug. Final NICE guidance is expected in August 2009.

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10: Baumann L, Vujevich J, Halem M, Martin LK, Kerdel F, Lazarus M, Pacheco H, Black L, Bryde J. Open-label pilot study of alitretinoin gel 0.1% in the treatment of photoaging. Cutis. 2005 Jul;76(1):69-73. PubMed PMID: 16144296.

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12: Dedicoat M, Vaithilingum M, Newton R. Treatment of Kaposi's sarcoma in HIV-1 infected individuals with emphasis on resource poor settings. Cochrane Database Syst Rev. 2003;(3):CD003256. Review. PubMed PMID: 12917957.

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19: Nowfar S, Teplitzky SR, Melancon K, Kiefer TL, Cheng Q, Dwived PD, Bischoff ED, Moro K, Anderson MB, Dai J, Lai L, Yuan L, Hill SM. Tumor prevention by 9-cis-retinoic acid in the N-nitroso-N-methylurea model of mammary carcinogenesis is potentiated by the pineal hormone melatonin. Breast Cancer Res Treat. 2002 Mar;72(1):33-43. PubMed PMID: 12004806.

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21: Bodsworth NJ, Bloch M, Bower M, Donnell D, Yocum R; International Panretin Gel KS Study Group. Phase III vehicle-controlled, multi-centered study of topical alitretinoin gel 0.1% in cutaneous AIDS-related Kaposi's sarcoma. Am J Clin Dermatol. 2001;2(2):77-87. PubMed PMID: 11705307.

22: Cheer SM, Foster RH. Alitretinoin. Am J Clin Dermatol. 2000 Sep-Oct;1(5):307-14; discussion 315-6. Review. PubMed PMID: 11702321.

23: Hess KR, Wong ET, Jaeckle KA, Kyritsis AP, Levin VA, Prados MD, Yung WK. Response and progression in recurrent malignant glioma. Neuro Oncol. 1999 Oct;1(4):282-8. PubMed PMID: 11550320; PubMed Central PMCID: PMC1920759.

24: Ponthan F, Borgström P, Hassan M, Wassberg E, Redfern CP, Kogner P. The vitamin A analogues: 13-cis retinoic acid, 9-cis retinoic acid, and Ro 13-6307 inhibit neuroblastoma tumour growth in vivo. Med Pediatr Oncol. 2001 Jan;36(1):127-31. PubMed PMID: 11464864.

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26: James JS. Kaposi's sarcoma: new topical treatment approved. AIDS Treat News. 1999 Feb 19;(No 313):1. PubMed PMID: 11366235.

27: Miller WH Jr, Reyno LM, Loewen GR, Huan S, Winquist E, Moore M, Cato A 3rd, Jaunakais D, Truglia JA, Matthews S, Dancey J, Eisenhauer E. A phase I-II study of 9-cis retinoic acid and interferon-alpha2b in patients with advanced renal-cell carcinoma: an NCIC Clinical Trials Group study. Ann Oncol. 2000 Nov;11(11):1387-9. PubMed PMID: 11142476.

28: Duvic M, Friedman-Kien AE, Looney DJ, Miles SA, Myskowski PL, Scadden DT, Von Roenn J, Galpin JE, Groopman J, Loewen G, Stevens V, Truglia JA, Yocum RC. Topical treatment of cutaneous lesions of acquired immunodeficiency syndrome-related Kaposi sarcoma using alitretinoin gel: results of phase 1 and 2 trials. Arch Dermatol. 2000 Dec;136(12):1461-9. PubMed PMID: 11115156.

29: Wu K, Kim HT, Rodriquez JL, Munoz-Medellin D, Mohsin SK, Hilsenbeck SG, Lamph WW, Gottardis MM, Shirley MA, Kuhn JG, Green JE, Brown PH. 9-cis-Retinoic acid suppresses mammary tumorigenesis in C3(1)-simian virus 40 T antigen-transgenic mice. Clin Cancer Res. 2000 Sep;6(9):3696-704. PubMed PMID: 10999763.

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34: Kurie JM, Hong WK. Retinoids as antitumor agents: a new age of biological therapy. Cancer J Sci Am. 1999 May-Jun;5(3):150-1. PubMed PMID: 10367170.

35: Gel approved for KS. AIDS Patient Care STDS. 1999 May;13(5):309. PubMed PMID: 10356816.

36: Laaksovirta S, Rajala P, Nurmi M, Tammela TL, Laato M. The cytostatic effect of 9-cis-retinoic acid, tretinoin, and isotretinoin on three different human bladder cancer cell lines in vitro. Urol Res. 1999;27(1):17-22. PubMed PMID: 10092149.

37: McCormick DL, Rao KV, Steele VE, Lubet RA, Kelloff GJ, Bosland MC. Chemoprevention of rat prostate carcinogenesis by 9-cis-retinoic acid. Cancer Res. 1999 Feb 1;59(3):521-4. PubMed PMID: 9973192.

38: Lovat PE, Irving H, Annicchiarico-Petruzzelli M, Bernassola F, Malcolm AJ, Pearson AD, Melino G, Redfern CP. Apoptosis of N-type neuroblastoma cells after differentiation with 9-cis-retinoic acid and subsequent washout. J Natl Cancer Inst. 1997 Mar 19;89(6):446-52. PubMed PMID: 9091647.

39: Giannini F, Maestro R, Vukosavljevic T, Pomponi F, Boiocchi M. All-trans, 13-cis and 9-cis retinoic acids induce a fully reversible growth inhibition in HNSCC cell lines: implications for in vivo retinoic acid use. Int J Cancer. 1997 Jan 17;70(2):194-200. PubMed PMID: 9009160.

40: Shalinsky DR, Bischoff ED, Gregory ML, Lamph WW, Heyman RA, Hayes JS, Thomazy V, Davies PJ. Enhanced antitumor efficacy of cisplatin in combination with ALRT1057 (9-cis retinoic acid) in human oral squamous carcinoma xenografts in nude mice. Clin Cancer Res. 1996 Mar;2(3):511-20. PubMed PMID: 9816198.

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42: Clinical development plan: 9-cis-retinoic acid. J Cell Biochem Suppl. 1996;26:158-67. PubMed PMID: 9154176.