Zileuton for Pruritus in Sjögren-Larsson Syndrome: A Randomized Double-blind Placebo-controlled Crossover Trial

Fuijkschot, Joris; Seyger, M.M.B.; Bastiaans, Diane E. T.; Wevers, Ron A.; Roeleveld, Nel; Willemsen, M.A.A.P.

doi:10.2340/00015555-2195

Cited by 13 publications

(14 citation statements)

References 12 publications

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“…However, in a subsequent randomized double-blind placebo-controlled crossover study of 10 patients, only one patient showed a favorable response to zileuton. [121] This drug also did not affect the ichthyosis or neurologic symptoms. An alternate approach to pharmacologically block LTB4 receptors with small bioactive molecules may be more fruitful.…”

Section: Prospective Therapeutic Targets and Interventionsmentioning

confidence: 96%

Genetics and prospective therapeutic targets for Sjögren-Larsson Syndrome

Rizzo

2016

Expert Opinion on Orphan Drugs

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Introduction Sjögren-Larsson syndrome (SLS) is a rare neurocutaneous disease characterized by ichthyosis, spasticity, intellectual disability and a distinctive retinopathy. It is caused by inactivating mutations in ALDH3A2, which codes for fatty aldehyde dehydrogenase (FALDH) and results in abnormal metabolism of long-chain aliphatic aldehydes and alcohols. The potential disease mechanisms leading to symptoms include 1) accumulation of toxic fatty aldehydes that form covalent adducts with lipids and membrane proteins; 2) physical disruption of multi-lamellar membranes in skin and brain; 3) abnormal activation of the JNK cell signaling pathway; and 4) defective farnesol metabolism resulting in abnormal PPAR-α dependent gene expression. Currently, no effective pathogenesis-based therapy is available. Areas Covered The clinical, pathologic and genetic features of SLS are summarized. The biochemical abnormalities caused by deficient activity of FALDH are reviewed in the context of proposed pathogenic mechanisms and potential therapeutic interventions. Expert Opinion The most promising pharmacologic approach to SLS involves blocking the formation of potentially harmful fatty aldehyde adducts using aldehyde scavenging drugs, currently in phase 2 clinical trials. Other approaches needing further investigation include: 1) ALDH-specific activator drugs and PPAR-α agonists to increase mutant FALDH activity; 2) inhibitors of the JNK phosphorylation cascade; 3) antioxidants to decrease aldehyde load; 4) dietary lipid modification; and 5) gene therapy.

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Section: Prospective Therapeutic Targets and Interventionsmentioning

confidence: 96%

Genetics and prospective therapeutic targets for Sjögren-Larsson Syndrome

Rizzo

2016

Expert Opinion on Orphan Drugs

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“…1 More than 15 years ago, a therapeutic approach using zileuton, a 5-lipoxygenase inhibitor that blocks the synthesis of LTB 4 , was reported as helpful on pruritus and behavior in three of five patients with SLS in an open-label trial according to two papers from Willemsen et al 2,3 More recently, a double-blind placebo-controlled crossover study in 10 patients over a 16-week period showed improvement of pruritus in only one patient without efficacy on ichthyosis or neurologic symptoms. 4 Willemsen et al also reported that zileuton decreased LTB 4 levels in urine at 5 weeks of treatment in one child 2 and at 3 months of treatment in five adults and adolescents. 3 Three patients had a decreasing lipid peak at 1.3 ppm on 1 H-MRS. 2,3 No long-term follow-up of patients with SLS treated by zileuton has been published to date, and the effects of zileuton in children younger than 5 years remain unknown.…”

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confidence: 91%

“…LTB 4 and ω-hydroxy-LTB 4 levels were reported as decreased with a daily dose of 40 mg/kg of zileuton 1,2 in the initial studies but could not be technically assessed in the more recent study. 4 The dose used here was identical or even lower.…”

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confidence: 99%

Lack of Long-Term Neurologic Efficacy of Zileuton in Sjögren–Larsson's Syndrome

et al. 2017

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“…However, no convincing evidence has been found that Zileuton improves pruritus. 5 A subset of patients have a mild phenotype. 1 Whether dietary habits or other genetic factors that modulate endogenous lipogenesis govern the clinical severity remains to be established.…”

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confidence: 99%

“…However, Zileuton, a leukotriene antagonist, does not consistently improve pruritus, and the actual cause of pruritus is unknown. 5 Normal lipid metabolism is essential for normal structure and function of the stratum corneum. In SLS, skin becomes ichthyotic in an attempt to restore normal barrier function.…”

mentioning

confidence: 99%