A phase II multicenter clinical trial of systemic bexarotene in psoriasis

Smit, Jeroen M.; Franssen, M.E.J.; Jong, E.M.G.J. de; Lambert, Julien; Roseeuw, Diane; Weert, J. De; Yocum, Richard C.; Stevens, Victor J.; Kerkhof, P.C.M. van de

doi:10.1016/j.jaad.2002.08.001

Cited by 34 publications

(22 citation statements)

References 14 publications

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“…1 Bexarotene is currently being evaluated for the treatment of other cancers 1 and psoriasis. 2 Thus, bexarotene is both an element of the current antitumoral therapeutic arsenal and a molecule with emerging and promising effects in various pathologies.…”

mentioning

confidence: 99%

The RXR Agonist Bexarotene Improves Cholesterol Homeostasis and Inhibits Atherosclerosis Progression in a Mouse Model of Mixed Dyslipidemia

Lalloyer

Fiévet

Lestavel

et al. 2006

ATVB

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Objective-The activity of the antitumoral agent bexarotene (Targretin, Bexarotene) depends on its binding to the nuclear retinoid-X receptor (RXR) and subsequent transcriptional regulation of target genes. Through RXR activation, bexarotene may modulate numerous metabolic pathways involved in atherosclerosis. Here, we investigated the effect of bexarotene on atherosclerosis progression in a dyslipidemic murine model, the human apolipoprotein E2 knockin mouse, that develops essentially macrophage-laden lesions. Methods and Results-Atherosclerotic lesions together with different metabolic pathways involved in atherosclerosis were investigated in mice treated or not with bexarotene. Bexarotene protects from atherosclerosis development in mice, at least in part by improving the circulating cholesterol distribution profile likely via a marked decrease of dietary cholesterol absorption caused by modulation of intestinal expression of genes recently identified as major players in this process, Niemann-Pick-C1-Like1 (NPC1L1) and CD13. This atheroprotection appears despite a strong hypertriglyceridemia. Moreover, bexarotene treatment only modestly modulates inflammatory gene expression in the vascular wall, but markedly enhanced the capacity of macrophages to efflux cellular lipids. Conclusion-These data provide evidence of a favorable pharmacological effect of bexarotene on atherosclerosis despite the induction of hypertriglyceridemia, likely via a beneficial action on intestinal absorption and macrophage efflux. exarotene [Targretin,6,7,5,5,8, ethenyl] benzoic acid] is an antitumoral agent used as chemotherapy in the treatment of cutaneous T-cell lymphoma. 1 Bexarotene is currently being evaluated for the treatment of other cancers 1 and psoriasis. 2 Thus, bexarotene is both an element of the current antitumoral therapeutic arsenal and a molecule with emerging and promising effects in various pathologies.Atherosclerosis is a complex inflammatory pathology of the vascular wall, precipitated by systemic factors, such as qualitative or quantitative abnormalities of circulating lipids and lipoproteins. Blood lipid concentrations reflect an equilibrium between absorption of dietary lipids in the small intestine, production after endogenous synthesis in the liver, and removal by different peripheral tissues and the liver. In pathological conditions, circulating atherogenic lipoproteins can be taken up by macrophages in the vascular wall, thus initiating an inflammatory process leading to a progressive evolution of atherosclerosis. Through the action of locally produced cytokines and other inflammatory proteins leading to cell migration and proliferation, the vascular wall is continuously remodeled. Atherosclerosis progressively evolves from the simple fatty streak to advanced atherosclerotic plaques, which may ultimately lead to plaque rupture and thrombus formation.The pharmacological responses to bexarotene originate from the transcriptional control of gene programs via activation of a member of the nuclear receptor superf...

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mentioning

confidence: 99%

The RXR Agonist Bexarotene Improves Cholesterol Homeostasis and Inhibits Atherosclerosis Progression in a Mouse Model of Mixed Dyslipidemia

Lalloyer

Fiévet

Lestavel

et al. 2006

ATVB

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Section: Discussionmentioning

confidence: 99%

“…There are three subtypes in each subfamily, specifically RARa, RARb, RARg, and RXRa, RXRb, and RXRg [8]. Each retinoid shows specific affinity and activation for the retinoid receptor subtypes, representing receptor-ligand specificity [8]. These receptors homodimerize and bind DNA to affect the function of genes downstream of retinoid acid response elements (RAREs) [7].…”

Section: Discussionmentioning

confidence: 99%

“…These receptors homodimerize and bind DNA to affect the function of genes downstream of retinoid acid response elements (RAREs) [7]. Additionally, RXRs have the unique capacity to heterodimerize with other classes of nuclear receptors, including RARs, vitamin D receptor (VDR), thyroid receptor (TR), and peroxisome proliferation activating receptors (PPARs) [8,9]. Therefore, retinoids that bind RXRs, also known as "rexinoids," can affect a variety of cellular pathways.…”

Section: Discussionmentioning

confidence: 99%

“…In the skin, there are five times as many RXRs as there are RARs [8]. Here, RXRa is the predominant subtype, with RARg also highly expressed [8].…”

Section: Discussionmentioning

confidence: 99%

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A Novel Case of Recalcitrant Juvenile Pityriasis Rubra Pilaris with Response to Bexarotene

Word¹,

Patel²,

M³

2011

J Clin Exp Dermatol

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Pityriasis rubra pilaris (PRP) is generally treated with single or combination regimens of topical agents, systemic retinoids, methotrexate, biologics, various other immunosuppressant agents, and light therapy; however, cases of PRP that are not amenable to these therapies can be challenging to control. We present the case of a male with biopsy-proven juvenile PRP followed for ten years, with failure to respond to all traditional treatment regimens. Significant improvement in the patient's cutaneous and rheumatological symptoms occurred when the patient was treated with bexarotene (Targretin ® ). To our knowledge, this represents the first reported successful treatment of PRP with bexarotene. Thus, treatment with bexarotene may represent a beneficial option for cases of PRP recalcitrant to traditional treatment modalities.

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Retinoids

Dawson¹

2010

Burger's Medicinal Chemistry and Drug Discovery

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Retinoid drugs find major applications in the topical treatment of cutaneous proliferative disorders such as acne, psoriasis, and photoaging and cutaneous cancers such as cutaneous T‐cell lymphoma (CTCL) and Kaposi's sarcoma. Oral retinoids are successfully used to treat nodular/cystic acne, systemic CTCL, and acute promyelocytic leukemia. This overview of available retinoid drugs and those in the preclinical or clinical pipeline covers their development, indications, clinical trial results, adverse effects, and pharmacology/metabolism. Retinoids have been described historically and functionally in the context of interaction with their nuclear receptors—retinoic acid receptors (RARs) and retinoid X receptors (RXRs)—in inducing gene transcription. RAR‐selective retinoids or their prodrugs include first‐generation all‐ trans ‐retinoic acid (tretinoin) and its 13‐ cis isomer (isotretinoin), and second‐generation acitretin and its ethyl ester (etretinate), both having an aromatic 2,3,6‐trimethyl‐4‐methoxyphenyl terminus. Third‐generation more aromatic analogs include ethyl ester tazarotene (Tazorac®) and adapalene (Differin®), both selective for RAR subtypes β and γ, and RARα‐selective pipeline candidates Am80 and NRX 195183, which are in clinical trials. RAR and RXR transcriptional panagonist 9‐ cis ‐retinoic acid is next and is followed by RXR‐selective bexarotene (Targretin™) and two RXR‐selective clinical trial candidates, 9cUAB and NRX 194204. The fourth generation includes three compounds that may have applications in the treatment or prevention of cancer. While originally considered as retinoids, such as N ‐(4‐hydroxyphenyl) retinamide, or as retinoid‐related or derived, such as ST1926 (AHPC) and SHetA2, they subsequently were found to function independently of the RARs and RXRs in inhibiting cancer cell proliferation and inducing apoptosis.

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A phase II multicenter clinical trial of systemic bexarotene in psoriasis

Cited by 34 publications

References 14 publications

The RXR Agonist Bexarotene Improves Cholesterol Homeostasis and Inhibits Atherosclerosis Progression in a Mouse Model of Mixed Dyslipidemia

The RXR Agonist Bexarotene Improves Cholesterol Homeostasis and Inhibits Atherosclerosis Progression in a Mouse Model of Mixed Dyslipidemia

A Novel Case of Recalcitrant Juvenile Pityriasis Rubra Pilaris with Response to Bexarotene

Retinoids

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