Oral liarozole in the treatment of patients with moderate/severe lamellar ichthyosis: results of a randomized, double‐blind, multinational, placebo‐controlled phase
            <scp>II</scp>
            /
            <scp>III</scp>
            trial

Vahlquist, Anders; Blockhuys, Stan; Steijlen, P.M.; Rossem, Koen van; Didona, Biagio; Blanco, Daisy M.; Traupe, Heiko

doi:10.1111/bjd.12626

Cited by 40 publications

(26 citation statements)

References 11 publications

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“…In a study on the efficacy of oral liarozole in lamellar ichthyosis, itch was measured as a secondary outcome variable. At baseline, pruritus scores were between 13.3 and 14.7 on a maximum scale of 36 . Treatment with oral liarozole failed to reduce pruritus scores.…”

Section: Discussionmentioning

confidence: 93%

Burden of itch in ichthyosis: a multicentre study in 94 patients

Palma

Mazereeuw‐Hautier

Giehl

et al. 2019

Acad Dermatol Venereol

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Background From clinical experience, we know that itch is a major concern for many ichthyosis patients. Nonetheless, no previous studies specifically addressed the issue of itch in ichthyosis. Objective The objective of this study was to specifically address the burden of itch and all its dimensions in ichthyosis patients. Methods Ninety‐four ichthyosis patients from four different centres were recruited to participate in this cross‐sectional, questionnaire‐based study. All participants completed the Leuven Itch Scale, a multidimensional self‐report instrument that quantifies the frequency, duration, severity, distress, consequences and surface area of itch. Results Participants included 18 keratinopathic types, 55 autosomal recessive congenital ichthyoses, 11 X‐linked recessive ichthyoses (XLRIs), 6 Netherton's ichthyoses, 1 Sjögren–Larsson type, 1 Iocrin ichthyosis and 2 unknown subtypes. Itch occurred in 93% of all patients. In patients with itch, 63% reported that it was often or always present, although most itch episodes were short in duration. Itch, in all its dimensions, was worst in patients with Netherton syndrome. Patients with XLRI had in general a lower itch profile. About half of all ichthyosis patients reported to experience flares during a change in weather, in a hot environment or in stressful situations, whereas a cold environment led to itch in only 26% of patients. The most significant consequences of itching were lesions from scratching, difficulties in falling asleep, bad mood and loss of concentration. Conclusions Itch is a major concern in patients with ichthyosis, with significant impact on daily life. Research on future treatments should therefore take itch into consideration and itch should be evaluated in clinical studies. Among the studied subgroups, Netherton patients experienced the most severe consequences.

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Section: Discussionmentioning

confidence: 93%

Burden of itch in ichthyosis: a multicentre study in 94 patients

Palma

Mazereeuw‐Hautier

Giehl

et al. 2019

Acad Dermatol Venereol

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“…However, oral acitretin and to a lesser extent isotretinoin remain the most popular drugs. Related drugs, such as alitretinoin [ 114 ] and retinoid acid metabolism-blocking agents (RAMBAs) [ 86 ], have been tested only on a limited scale. They are presently not generally approved therapies for ichthyosis and will therefore not be discussed further here.…”

Section: Treatment—what’s New?mentioning

confidence: 99%

Inherited Nonsyndromic Ichthyoses: An Update on Pathophysiology, Diagnosis and Treatment

2017

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Hereditary ichthyoses are due to mutations on one or both alleles of more than 30 different genes, mainly expressed in the upper epidermis. Syndromic as well as nonsyndromic forms of ichthyosis exist. Irrespective of etiology, virtually all types of ichthyosis exhibit a defective epidermal barrier that constitutes the driving force for hyperkeratosis, skin scaling, and inflammation. In nonsyndromic forms, these features are most evident in severe autosomal recessive congenital ichthyosis (ARCI) and epidermolytic ichthyosis, but to some extent also occur in the common type of non-congenital ichthyosis. A correct diagnosis of ichthyosis—essential not only for genetic counseling but also for adequate patient information about prognosis and therapeutic options—is becoming increasingly feasible thanks to recent progress in genetic knowledge and DNA sequencing methods. This paper reviews the most important aspects of nonsyndromic ichthyoses, focusing on new knowledge about the pathophysiology of the disorders, which will hopefully lead to novel ideas about therapy.

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“…However, imidazole and two other azole drugs were included to further explore the structure/function relationship between azoles and CYP3A enzymes. Liarozole is a retinoic acid metabolizing (CYP26) blocking agent used for a skin condition called lamellar ichthyosis (Lucker et al, 1997;Vahlquist et al, 2014). Letrozole is an aromatase (CYP19A1) inhibitor used in breast cancer treatment (Regan et al, 2011 (Yano et al, 2004) and flexible (Sevrioukova and Poulos, 2017) active site to accommodate diverse ligands, much less is known about these aspects of CYP3A7.…”

Section: Selection Of Azoles Evaluated With Cyp3a Enzymesmentioning

confidence: 99%

Comparison of Antifungal Azole Interactions with Adult Cytochrome P450 3A4 versus Neonatal Cytochrome P450 3A7

2018

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Adult drug metabolism is dominated by cytochrome P450 3A4 (CYP3A4), which is often inhibited by antifungal azole drugs, resulting in potential alterations in drug metabolism and adverse drug/drug interactions. In the fetal and neonatal stages of life, the 87%-identical cytochrome P450 3A7 (CYP3A7) is expressed but not CYP3A4. Azole antifungals developed for adults are also used in neonates assuming they interact similarly with both enzymes, but systematic information is lacking. Herein a method was developed for generating recombinant purified CYP3A7. Thirteen different azoles were then evaluated for binding and inhibition of purified human CYP3A4 vs. CYP3A7. All imidazole-containing azoles bound both enzymes via coordination to the heme iron and inhibited both with IC50 values ranging from 180 nM for clotrimazole to the millimolar range for imidazole itself. Across this wide range of potencies, CYP3A4 was consistently inhibited more strongly than CYP3A7, with clotrimazole being the least selective (1.5-fold) inhibitor and econazole the most selective (12-fold). Observations for 1,2,4-triazole-containing azoles were more varied. Most bound to CYP3A4 via coordination to the heme iron, but several also demonstrated evidence of a distinct binding mode at low concentrations.However, only posaconazole inhibited CYP3A4. Of the triazoles only posaconazole inhibited CYP3A7, again less potently than CYP3A4. Spectral evidence for binding was weak or nonexistent for all triazoles. Overall, while the details of binding interactions do vary, the same azole compounds inhibit both enzymes, albeit with weaker interactions with CYP3A7 compared to CYP3A4.

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Oral liarozole in the treatment of patients with moderate/severe lamellar ichthyosis: results of a randomized, double‐blind, multinational, placebo‐controlled phase II / III trial

Cited by 40 publications

References 11 publications

Burden of itch in ichthyosis: a multicentre study in 94 patients

Burden of itch in ichthyosis: a multicentre study in 94 patients

Inherited Nonsyndromic Ichthyoses: An Update on Pathophysiology, Diagnosis and Treatment

Comparison of Antifungal Azole Interactions with Adult Cytochrome P450 3A4 versus Neonatal Cytochrome P450 3A7

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