Oral R115866 in the treatment of moderate to severe plaque‐type psoriasis

Verfaille, Christel J.; Thissen, Carleine A. C. B.; Bovenschen, H.J.; Mertens, Jorre S.; Steijlen, P.M.; Kerkhof, Peter C M van de

doi:10.1111/j.1468-3083.2007.02158.x

Cited by 33 publications

(27 citation statements)

References 25 publications

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“…Therapeutic targeting of local retinoid turnover to increase local retinoid levels is an alternative strategy (2), and inhibitors of cytochrome P450, family 26 (CYP26) enzymes have been used in clinical studies (16,17). However, knowledge about the metabolism of atRA and other RAR ligands in atherosclerosis has been lacking.…”

Section: Introductionmentioning

confidence: 99%

A CYP26B1 Polymorphism Enhances Retinoic Acid Catabolism and May Aggravate Atherosclerosis

Krivospitskaya

Elmabsout

Sundman

et al. 2012

Mol Med

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All-trans retinoic acid, controlled by cytochrome P450, family 26 (CYP26) enzymes, potentially has beneficial effects in atherosclerosis treatment. This study investigates CYP26 subfamily B, polypeptide 1 (CYP26B1) in atherosclerosis and the effects of a genetic polymorphism in CYP26B1 on retinoid catabolism. We found that CYP26B1 mRNA was induced by retinoic acid in human atherosclerotic arteries, and CYP26B1 and the macrophage marker CD68 were colocalized in human atherosclerotic lesions. In mice, Cyp26B1 mRNA was higher in atherosclerotic arteries than in normal arteries. Databases were queried for nonsynonymous CYP26B1 single nucleotide polymorphisms (SNPs) and rs2241057 selected for further studies. Constructs of the CYP26B1 variants were created and used for production of purified proteins and transfection of macrophagelike cells. The minor variant catabolized retinoic acid with significantly higher efficiency, indicating that rs2241057 is functional and suggesting reduced retinoid availability in tissues with the minor variant. rs2241057 was investigated in a Stockholm Coronary Atherosclerosis Risk Factor (SCARF) subgroup. The minor allele was associated with slightly larger lesions, as determined by angiography. In summary, this study identifies the first CYP26B1 polymorphism that alters CYP26B1 capacity to metabolize retinoic acid. CYP26B1 was expressed in macrophage-rich areas of human atherosclerotic lesions, induced by retinoic acid and increased in murine atherosclerosis. Taken together, the results indicate that CYP26B1 capacity is genetically regulated and suggest that local CYP26B1 activity may influence atherosclerosis.

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Section: Introductionmentioning

confidence: 99%

A CYP26B1 Polymorphism Enhances Retinoic Acid Catabolism and May Aggravate Atherosclerosis

Krivospitskaya

Elmabsout

Sundman

et al. 2012

Mol Med

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“…Nonetheless, our results provide a strong rationale for studying CYP26A1 inhibitors in appropriate patients. Liarozole and talarozole have been evaluated in clinical trials for diseases unrelated to FAP or colorectal cancer and are apparently well-tolerated (52,53). These or other agents that safely increase intestinal RA have the potential to reverse inflammation and reduce tumor burden as observed here in APC Min/+ mice.…”

Section: Discussionmentioning

confidence: 99%

Restoring Retinoic Acid Attenuates Intestinal Inflammation and Tumorigenesis in APCMin/+ Mice

Penny

Prestwood

Bhattacharya

et al. 2016

Cancer Immunology Research

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Chronic intestinal inflammation accompanies familial adenomatous polyposis (FAP) and is a major risk factor for colorectal cancer in patients with this disease, but the cause of such inflammation is unknown. Since retinoic acid (RA) plays a critical role in maintaining immune homeostasis in the intestine, we hypothesized that altered RA metabolism contributes to inflammation and tumorigenesis in FAP. To assess this hypothesis, we analyzed RA metabolism in the intestines of patients with FAP as well as APCMin/+ mice, a model that recapitulates FAP in most respects. We also investigated the impact of intestinal RA repletion and depletion on tumorigenesis and inflammation in APCMin/+ mice. Tumors from both FAP patients and APCMin/+ mice displayed striking alterations in RA metabolism that resulted in reduced intestinal RA. APCMin/+ mice placed on a vitamin A deficient diet exhibited further reductions in intestinal RA with concomitant increases in inflammation and tumor burden. Conversely, restoration of RA by pharmacological blockade of the RA-catabolizing enzyme CYP26A1 attenuated inflammation and diminished tumor burden. To investigate the effect of RA deficiency on the gut immune system, we studied lamina propria dendritic cells (LPDCs) since these cells play a central role in promoting tolerance. APCMin/+ LPDCs preferentially induced Th17 cells, but reverted to inducing Tregs following restoration of intestinal RA in vivo or direct treatment of LPDCs with RA in vitro. These findings demonstrate the importance of intestinal RA deficiency in tumorigenesis and suggest that pharmacological repletion of RA could reduce tumorigenesis in FAP patients.

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“…[67,68] Subsequently, talarozole has been used for psoriasis patients as this drug is a more selective inhibitor of the enzyme retinoic acid 4-hydroxylase, necessitating reduced dose and hence fewer side effects. Verfaille et al [69] treated 19 patients of psoriasis with 1 mg talarozole, resulting in significant reduction in PASI in 8 weeks. Talarozole is in the phase II clinical trial stage.…”

Section: Mycophenolate Mofetilmentioning

confidence: 98%

Psoriasis: What is new in nonbiologic systemic therapy in the era of biologics?

Kanwar¹,

Yadav²,

Dogra³

2010

Indian J Dermatol Venereol Leprol

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Psoriasis is a common debilitating disease significantly affecting the quality of life of the patients. Majority of the psoriasis patients have mild disease which can be managed by topical therapies. Around 30% of the psoriasis patients require systemic therapy during the course of their disease. There is a vast array of drugs for the treatment. Methotrexate, cyclosporine and retinoids are the most commonly used conventional systemic drugs. Newer studies provide insight into their more effective and safer use and as combination therapy with biologics. In recent times, many new drugs with novel mechanisms of action other than biologics have been tried in psoriasis. In this article, we have reviewed the current developments and new found role of the conventional drugs as well as the newer nonbiologic systemic drugs in the treatment of psoriasis.

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Oral R115866 in the treatment of moderate to severe plaque‐type psoriasis

Cited by 33 publications

References 25 publications

A CYP26B1 Polymorphism Enhances Retinoic Acid Catabolism and May Aggravate Atherosclerosis

A CYP26B1 Polymorphism Enhances Retinoic Acid Catabolism and May Aggravate Atherosclerosis

Restoring Retinoic Acid Attenuates Intestinal Inflammation and Tumorigenesis in APCMin/+ Mice

Psoriasis: What is new in nonbiologic systemic therapy in the era of biologics?

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