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Keywords:

  • retinoids;
  • RAMBA;
  • psoriasis;
  • ichthyosis;
  • acne;
  • liarozole;
  • talarozole

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Retinoids: mechanism of action and metabolism
  5. Mechanism of Action
  6. The role of CRABP I and II
  7. Tissue uptake
  8. All-trans-RA catabolism
  9. Retinoic acid metabolism blocking agents
  10. Clinical use of RAMBAs
  11. Oral talarozole, a promising treatment for psoriasis and acne?
  12. Conclusions
  13. Conflict of interest
  14. References

Synthetic vitamin A derivatives, retinoids,have long been the mainstay of treatment for several disorders of keratinization, notably the ichthyoses and severe acne. Some forms of psoriasis also respond well. Their considerable power comes at a price.They have dose-limiting side effects and can be highly teratogenic, limiting their use in women of childbearing age.Thus, retinoids are used less often than their potential would warrant. However, the recent development of compounds that block the catabolism of endogenous vitamin A, called Retinioic Acid Metabolism Blocking Agents or RAMBAs, offers new possibilities. With these drugs, retinoid effects with less side effects and a reduction of the post-treatment teratogenicity period due to their favourable pharmacokinetic profile might be expected. In this review, we discuss how retinoids work, how they are metabolized and how RAMBAs influence this process.We also review the presently available data from clinical trials with RAMBAs.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Retinoids: mechanism of action and metabolism
  5. Mechanism of Action
  6. The role of CRABP I and II
  7. Tissue uptake
  8. All-trans-RA catabolism
  9. Retinoic acid metabolism blocking agents
  10. Clinical use of RAMBAs
  11. Oral talarozole, a promising treatment for psoriasis and acne?
  12. Conclusions
  13. Conflict of interest
  14. References

Disorders of keratinization such as the ichthyoses and some forms psoriasis can be treated systemically with derivatives of vitamin A, retinoids [1–3]. Despite almost a century of development, no retinoids have yet been developed that do away with the important side effects that limit their use, such as teratogenicity, hypertriglyceridaemia, and retinoid dermatitis [4, 5]. Because of the evident effectiveness of these compounds, alternatives are needed that provide a least a similar efficacy but an improved safety profile.

Retinoids are metabolized through an intricate series of enzymatic modifications. The relatively recent and serendipitous discovery of compounds that inhibit the catabolism of retinoids has now led to the development of specific retinoic acid metabolism blocking agents, or RAMBAs. RAMBAs temporarily raise the endogenous levels of all-trans-retinoic acid (all-trans-RA) in specific target tissues. In doing so, they induce a local retinoid effect and avoid excessive systemic retinoid exposure.

In addition, there are indications that RAMBAs may have retinoid-independent effects on gene expression and lipid metabolism that contribute to their clinical effect. Recent trials that we conducted show that second- and third-generation RAMBAs are indeed effective in ichthyosis, acne and psoriasis. Thus, these compounds should be further developed to provide patients with an alternative to retinoic acid derivatives. Here, we review the state of the art and outline future developments.

In order to understand how RAMBAs work, it is necessary to introduce the retinoids and their mechanism of action first.

Retinoids: mechanism of action and metabolism

  1. Top of page
  2. Summary
  3. Introduction
  4. Retinoids: mechanism of action and metabolism
  5. Mechanism of Action
  6. The role of CRABP I and II
  7. Tissue uptake
  8. All-trans-RA catabolism
  9. Retinoic acid metabolism blocking agents
  10. Clinical use of RAMBAs
  11. Oral talarozole, a promising treatment for psoriasis and acne?
  12. Conclusions
  13. Conflict of interest
  14. References

Retinoids are a group of natural and synthetic compounds that share structural and/or functional similarity with vitamin A (retinol, ROL). Wolbach and Howe showed in 1925 that vitamin A (retinol)-deficiency, or the absence of compounds with vitamin A activity, leads to keratinizing metaplasia and hyperkeratosis [6]. Based on these observations, vitamin A was investigated in psoriasis and acne. However, megadoses only resulted in slight improvement in psoriasis but led to hypervitaminosis A with unacceptable side effects such as intracranial hypertension, dryness of mucosae and skin peeling [7]. Thus, a great many analogues were subsequently synthesized and out of thousands, three generations are now established for the treatment of hyperkeratotic skin disorders.

First generation

Those retinoids are the non-aromatic ones: retinol, all-trans-retinoic acid (tretinoin) and 13-cis-retinoic acid (isotretinoin). The latter two turned out to be clinically useful and were developed further.

Second generation

The mono-aromatic retinoids etretinate and its active metabolite acitretin are effective systemic treatments for psoriasis and several disorders of keratinisation with a comparable side effect profile. However, today, acitretin is preferred because of its better pharmacokinetic profile [8].

Third generation

The search for retinoids with more favourable safety profiles has now resulted in the development of polyaromatic retinoids, or arotenoids. Examples are tazarotenic acid, adapalene and RXR-ligands such as bexarotene. Adapalene and tazarotene are now in widespread use for the topical treatment of acne and the latter one also for psoriasis. [9,10] Oral bexarotene has a specific niche in oncology, and is currently in clinical development for psoriasis [11,12].

The search for retinoids with fewer side effects continues, but we expect it to be in vain because, for retinoids, the desired effects are caused by the same molecular mechanisms as the side effects and the two thus cannot be dissociated.

Mechanism of Action

  1. Top of page
  2. Summary
  3. Introduction
  4. Retinoids: mechanism of action and metabolism
  5. Mechanism of Action
  6. The role of CRABP I and II
  7. Tissue uptake
  8. All-trans-RA catabolism
  9. Retinoic acid metabolism blocking agents
  10. Clinical use of RAMBAs
  11. Oral talarozole, a promising treatment for psoriasis and acne?
  12. Conclusions
  13. Conflict of interest
  14. References

Retinoids exert most of their biological activities through binding to specific nuclear receptors that belong to a large family that includes the steroid, vitamin D (VDR), thyroid (TR) and peroxisome proliferator-activated (PPAR) receptors. Nuclear receptors regulate transcription of genes by acting as ligand-inducible transcription factors.

There are two classes of retinoid receptors: RAR and RXR, each containing three subtypes: α, β and γ. Each subtype is encoded by a different gene and has been reviewed in Chambon et al. [13].

There are multiple isoforms of these subtypes that are generated by alternative splicing and by differential use of promotors. All-trans-RA is a potent activator and high affinity ligand for the RARs, whilst its 9-cis isomer, 9-cis-RA, appears to be the natural ligand for RXRs, at least in vitro [14–16]. 9-cis-RA not only binds and activates all 3 RXR subtypes at physiological concentrations (Kd ∼ 15 nM) but also the 3 RAR subtypes at lower Kd values (0.2–0.7 M) [17, 18]. However, tissue concentrations of 9-cis-RA appear to be in the low nanomolar range i.e. 3–5 fold lower than all-trans-RA. Thus, it is still unclear whether binding of 9-cis-RA to RXRs has physiological relevance [14].

RARs form obligate heterodimers with RXRs, whereas the RXRs may act either as homodimers or as a heterodimer complex with a variety of other nuclear receptors that play an important role in cell function and physiology. Therefore specific RXR ligands may have broader biological activities than RAR ligands. The expression pattern of the retinoid receptors is cell and tissue specific, depending upon factors such as state of differentiation, inflammation and diseases [19]. The various RAR and RXR isoforms are widely expressed, indicating that most, if not all, tissues are potential targets of retinoid action, although different RXR homodimer and RAR-RXR heterodimer complexes will transduce the retinoid signal in different tissue [20].

In adult human skin, the predominant RAR protein expressed is RAR-γ whilst only minimal levels are found for RAR-γ; RAR-β is undetectable [21]. The concentration of RXRs is five times as high as the total concentration of RARs, with RXR-α being the most abundantly expressed; RXR-β is minimally detectable and RXR-γ undetectable [21]. The mRNA levels of the receptors are compatible with the protein levels. The predominant receptor complexes in the human skin are RARγ-RXRα and the RXR-VDR, the latter being of major importance in RXR-signaling [22].

Retinoid receptors consist of 6 functional domains, of which the 2 most important are the ligand binding domain (where the ligand binds to the receptor) and the DNA binding domain (where the receptor binds to the DNA of the target genes) [23]. Retinoid receptor dimers are localized in the nucleus of the cell where they bind, even in their unliganded state, to specific DNA regulatory sequences termed retinoid response elements (RARE or RXRE) in the promotor regions of retinoid-responsive genes. Heterodimers bind more efficiently and more selectively to RAREs than homodimers. Therefore, RAR-RXR heterodimers are suggested to be the functional units in vivo that transduce the retinoid signal [13].

Retinoid response elements are usually located within the 5′-regulatory region of retinoid regulated genes, sometimes they are found within introns. RAREs consist of a direct repeat (DR) of a core hexameric sequence, 5′-AGTTCA- (n)1/2/5-AGTTCA-3′. The repeats are separated by 1, 2 or 5 base-pairs (DR1, DR2 and DR5), depending on the genes [13]. A large number of genes contain 1 or more RARE and therefore are potentially responsive to RA. More than 500 genes with diverse functions are known to be regulated by retinoic acid, and RAREs have been localized in many of them [24]. Because the RXR functions as a partner for several nuclear receptors other than RAR, the RXR and the ligands that bind to them have the potential to influence an even wider variety of genes than are regulated by RARs [25].

According to a current model of transcriptional activation, the unliganded receptor dimers, when bound to DNA, recruit histone deacetylases that function as transcriptional co-repressors by inducing chromatin condensation and subsequent gene silencing [26]. Ligand binding causes the receptors to undergo a conformational change, releasing co-repressors and recruiting histone acetylases that open up the chromatin and thus function as transcriptional co-activators [27]. Despite our quite extensive knowledge of the interaction between retinoids and their ligands, we have a very limited perception of their role in normal human physiology and development. Despite intensive research, it is not yet possible to provide a concise overview of retinoid physiology.

The role of CRABP I and II

  1. Top of page
  2. Summary
  3. Introduction
  4. Retinoids: mechanism of action and metabolism
  5. Mechanism of Action
  6. The role of CRABP I and II
  7. Tissue uptake
  8. All-trans-RA catabolism
  9. Retinoic acid metabolism blocking agents
  10. Clinical use of RAMBAs
  11. Oral talarozole, a promising treatment for psoriasis and acne?
  12. Conclusions
  13. Conflict of interest
  14. References

Intracellularly, all-trans-RA is bound to either CRABP I or CRABP II; CRABP I binds it with a higher affinity than does CRABP II [28]. Natural metabolites of all-trans-RA, including 4-hydroxy-RA, 4-oxo-RA, 18-hydroxy-RA and 3,4-didehydro-RA can also bind to CRABPs. Binding of 9-cis-RA to CRABPs occurs with a lower affinity than all-trans-RA and there is only little, if any, binding of 13-cis-RA or 9,13-dicis-RA [29, 30]. CRABP I is expressed almost ubiquitously whereas CRABP II has a much more restricted expression pattern. The skin and liver are among the tissues expressing CRABP II. Although both CRABP I and II are widely expressed in the embryo, they don't coexist in the same cells. Both CRABP isoforms are present in the cytosol and the nuclei of cells. In general, expression of CRABP II has been associated with cells that synthesize large amounts of all-trans-RA. Neither the exact functions nor the distinct roles of the 2 CRABP isoforms are completely understood at present [31].

CRABP I and CRABP II null mutant mice have no phenotype and so does the double knockout [32].

Tissue uptake

  1. Top of page
  2. Summary
  3. Introduction
  4. Retinoids: mechanism of action and metabolism
  5. Mechanism of Action
  6. The role of CRABP I and II
  7. Tissue uptake
  8. All-trans-RA catabolism
  9. Retinoic acid metabolism blocking agents
  10. Clinical use of RAMBAs
  11. Oral talarozole, a promising treatment for psoriasis and acne?
  12. Conclusions
  13. Conflict of interest
  14. References

Ultimately, all retinoids in the body are derived from the diet, where they are ingested either as retinyl esters (RE) derived from animal fat or as carotenoids (pro-vitamin β-carotene) derived from yellow and green vegetables [33, 34].

Ingested RE are converted to all-tran-sretinoic acid, or retinol (ROL) in the intestinal lumen, absorbed by enterocytes and then converted into retinal (RAL). β-carotene can enter the enterocytes directly and is also converted into RAL. RAL, in turn, binds to cellular retinol binding protein II (CRBP II) and is reduced to ROL by a microsomal retinal reductase [35]. The ROL-CRBP II complex serves as a substrate for a lecithin:retinol acyltransferase (LRAT) that re-esterifies ROL to RE which will be incorporated into chylomicrons (triacylglycerol- rich lipoproteins) during absorption of normal loads of vitamin A [36]. When large amounts of ROL are rapidly absorbed into enterocytes (due to a vitamin A rich meal or high pharmacological doses), free ROL accumulates in the cell membranes as CRBP II and LRAT become saturated, and the activity of another enzyme, the acyl-CoA:retinolacyltransferase (ARAT), increases. ROL is esterified by ARAT and temporarily stored in lipid droplets [37].

The chylomicrons containing the RE travel through the intestinal lymphatic system where they undergo lypolysis to give rise to chylomicron remnants, which are primarily cleared by the liver. Also, extrahepatic chylomicron uptake has been shown in bone marrow and spleen and to a lesser extent in testes, lung, kidney, fat and skeletal muscle [34, 38]. The remnants, with their load of RE, are endocytosed by hepatocytes via the apolipoprotein E receptor [39]. In hepatocytes, RE are hydrolyzed and free ROL is released into the blood together with retinol-binding protein (RBP) [40]. In the blood, 95 % of the ROL-RBP complex associates with transthyretin (TTR) which transports the complex to extrahepatic tissue. Excess ROL in the hepatocytes is transferred to the stellate cells in the liver, where it will form a complex with cellular binding protein 1 (CRBPI), which facilitates the esterification of ROL by LRAT to form RE for storage [41]. Thus, 50 to 80 % of the total body ROL is stored as RE in the stellate cells of the liver, from which it can be released to maintain constant ROL concentrations in the plasma. Extra-hepatic tissues also play a role in storage and mobilization of ROL and contribute to vitamin A homeostasis [41].

ROL is the most abundant retinoi ROL is the most abundant retinoid in blood. Under normal dietary conditions, the plasma ROL concentrations are relatively high (2 μmol/L), making ROL available throughout the body for potential conversion to all-trans-RA. RBP is the most important ROL carrier for delivery to other organs. Without RBP, normal vitamin A levels cannot be maintained.

Recently, STRA6, a multipass-transmembrane protein was identified as a cell surface receptor for RBP that mediates ROL cellular uptake from the ROLRBP complex [42]. Absence of this protein leads to severe birth defects consistent with vitamin A deficiency during embryonic development. Once inside the cell, ROL can associate with CRBPI and serve either as a substrate for esterification by LRAT or it can be converted to retinoic acid depending on the ratio free CRBPI / bound CRBPI [43]. It has been postulated that the quantity of free CRBPI present in the target cell also determines the amount of ROL that is taken up by the cell [44].

All-trans-RA catabolism

  1. Top of page
  2. Summary
  3. Introduction
  4. Retinoids: mechanism of action and metabolism
  5. Mechanism of Action
  6. The role of CRABP I and II
  7. Tissue uptake
  8. All-trans-RA catabolism
  9. Retinoic acid metabolism blocking agents
  10. Clinical use of RAMBAs
  11. Oral talarozole, a promising treatment for psoriasis and acne?
  12. Conclusions
  13. Conflict of interest
  14. References

Cytochrome P450-dependent hydroxylation All-trans-RA homeostasis is maintained by balancing its synthesis and degradation. RA catabolism governs tissue sensitivity to RA. All-trans-RA is catabolized by cytochrome P450-dependent enzymes (CYPs) to 4-OH-RA that further oxidizes to 4-oxo-RA and other polar metabolites, or to 18-OH-RA (Figure 1) [45, 46]. There is increasing evidence that ATRA can also be transformed into its isomers 9-cis-RA and 13-cis-RA, but these reactions are thermodynamically unfavourable. Several CYPs can catalyze the 4-hydroxylation of all-trans-RA but their specificity is generally low [47]. However, cytochrome P450RAI, known officially as CYP26A1, is highly specific towards all-trans-RA and is expressed in a number of adult tissues like liver, heart, hypophysis, adrenals, duodenum and colon [48]. Because CYP26A1 is induced by all-trans-RA, retinoid catabolism may include a positive feedback loop [49]. In the adult liver, the principal site of retinoid metabolism, CYP26A1 expression and all-trans-RA metabolism are not only acutely regulated by all-trans-RA administration, but also chronically depending upon the dietary intake of ROL [50].To date, four members of the CYP26 family have been characterized: CYP26A1, CYP26B1, CYP26C1 and CYP26D1. They have similar sequences but distinct catalytic activities and expression patterns. In the developing skin, CYP26B1 may play a role in hair follicle development because it is found in perifollicular dermis in mouse embryos [51–53]. Interestingly, the skin has its own preferred CYP isoforms. Isoenzymes of CYP families 1, 2, 3 and 4 are present in human epidermal foreskin keratinocytes and a constitutive expression of CYP26A1 has been found in vivo and in organotypic 3 D skin models. It is restricted to basal epidermal ker-atinocytes [54, 55]. A 4.5 fold increase in metabolism of all-trans-RA to 4-oxo-RA has been described in skin treated with all-trans-RA but the principal skin CYP enzyme has not yet been defined [56]. Smith et al. identified CYP2S1 in human skin and showed that it metabolizes all-trans-RA into 4-hydroxy and 5,6-detected as a metabolite [57, 58]. They also showed an induction of CYP2S1 expression by all-trans-RA, ultraviolet radiation, PUVA and coal tar. CYP2S1 is more strongly expressed in the skin than CYP26A1, which suggests a functional role of CYP2S1 in the cutaneous catabolism of all-trans-RA. The fact that no 4-oxo-RA was formed adds to the suggestion that another CYP may be responsible for the oxidization of 4-OH-RA in skin, which may be CYP26A1.

image

Figure 1. Retinoic acid metabolism. ATRA = all-trans-retinoic acid; RA = retinoic acid; CYP26 = cytochrome P450-dependent microsomal enzymes.

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Glucuronidation: a second route of all-trans-RA metabolism

All-trans-RA has a short elimination half-life in vivo and in cultured cells (6–7 hours), except for B-lymphocytes [59, 60]. Glu-curonidation and enterohepatic circulation are also important metabolic routes of elimination/recirculation [61, 62]. This falls out of the scope of this review, it will not be further elaborated.

Retinoic acid metabolism blocking agents

  1. Top of page
  2. Summary
  3. Introduction
  4. Retinoids: mechanism of action and metabolism
  5. Mechanism of Action
  6. The role of CRABP I and II
  7. Tissue uptake
  8. All-trans-RA catabolism
  9. Retinoic acid metabolism blocking agents
  10. Clinical use of RAMBAs
  11. Oral talarozole, a promising treatment for psoriasis and acne?
  12. Conclusions
  13. Conflict of interest
  14. References

The main degradation pathway for all-trans-RA is its 4-hydroxylation to form 4-hydroxy-all-trans-RA, which is further oxidized to 4-keto-all-trans-RA and then transformed into more polar metabolites (Figure 1). This entire route involves mi-crosomal cytochrome P-450 (CYP) dependent enzymes [43, 63]. Retinoic acid metabolism blocking agents, or RAM-BAs block the CYP-dependent 4-hy-droxylation of all-trans-RA, which results in an increase of the intracellular all-trans-RA concentration [64–67]. The modulation of all-trans-RA concentration at the tissue level should limit systemic toxicity. The RAMBAs that we discuss are azoles, be it imidazoles or tri-azoles, see Figure 2. Other classes exist, such as disubstituted naphthalenes and benzoacetic acid derivatives, but those are presently not in clinical use and thus are outside the scope of this review [68]. The first azole with RAMBA properties was the antifungal ketoconazole. Besides its antifungal activity, ketoconazole was shown to inhibit, in an apparently competitive manner, the CYP mediated metabolism of all-trans-RA by hamster liver microsomes [64, 69]. The search for more selective CYP inhibitors of all-trans-RA metabolism led to the identification of liarozole. Liarozole is an imida-zole derivative that has no antifungal activity but shares with ketoconazole its inhibitory effects on epidermal all-trans-RA and on the CYP mediated 17-hy-droxylase-17,20-lyase in testes micro-somes. Administration of liarozole to rats enhances endogenous plasma concentrations of endogenous RA and reduces the elimination rate of intravenously injected RA from plasma [65, 66]. Liaro-zole also inhibits several other cy-tochrome P450-dependent steroid biosynthesis reactions – mainly the conversion of androgens to estrogens (aro-matase) and of 11-deoxycorticosterone to corticosterone (11-hydroxylase) [70, 71].

image

Figure 2. Chemical structures of ketoconazole, liarozole and talarozole.

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Developed in the 90's as a non-hormonal agent for the treatment of prostate and various other cancers, liarozole was considered to be of potential benefit in the treatment of skin disorders like psoriasis and ichthyosis, based on the fact that the reported adverse events in the cancer trials were mainly cutaneous reactions showing a striking similarity with vitamin A-related symptoms. Whereas the first RAMBAs, such as ketoconazole and liarozole, were non-selective CYP inhibitors, a thorough screening of hundreds of molecules against different CYP-isozymes yielded a very selective and highly active retinoic acid 4-hydrox-ylase inhibitor, talarozole (Rambazo-le™), formerly named R115866 [72, 73]. This is the first representative of the third RAMBA generation. Talarozole is a substituted benzyl-1, 2, 4,- triazole derivative which is a stable, enantiomeri-cally pure base. Talarozole inhibits all-trans RA catabolism in the nanomolar range (IC50=4 nM, human CYP26 transfected yeast microsomes) and is about three orders of magnitude more powerful than liarozole (IC50=3 μM).

At concentrations needed to inhibit all-trans-RA catabolism, talarozole displays only trivial inhibitory effects (IC50=1.2–2.6 μM) on the CYP-dependent biosynthesis of steroids (testosterone and oestradiol). Talarozole thus seems to be specific towards the skin isoforms of CYP26. It was found to have retinoid-mimetic biological activities in various retinoid sensitive animal models of kera-tinisation [72, 74]. In these studies, no major effects other than its primary pharmacodynamic effect were found.

Unlike existing therapies where high amounts of synthetic or natural exogenous retinoids, are administered, a RAMBA modulates the body's own production of all-trans-RA to achieve the same therapeutic effects. Once treatment is stopped, the RAMBA is quickly eliminated, returning the metabolism of retinoic acid back to normal and declining the elevated all-trans-RA levels back to physiological levels within 24 hours [75]. It is interesting to note, that in many patients who participated in the talarozole trials, the plasma all-trans RA levels did not rise beyond physiological levels [76]. Findings for liarozole are essentially similar. The rapid clearance of the RAMBAs is important, because it decreases the potential for side effects in contrast to the available synthetic retinoids, which may stay in some organs for a long time, and which can cause retinoid related chronic toxicity and birth defects for months after discontinuation of therapy. The rapid clearance and limited impact on plasma all-trans-RA levels mean that RAMBAs might be given more readily to women and children than retinoids.

Clinical use of RAMBAs

  1. Top of page
  2. Summary
  3. Introduction
  4. Retinoids: mechanism of action and metabolism
  5. Mechanism of Action
  6. The role of CRABP I and II
  7. Tissue uptake
  8. All-trans-RA catabolism
  9. Retinoic acid metabolism blocking agents
  10. Clinical use of RAMBAs
  11. Oral talarozole, a promising treatment for psoriasis and acne?
  12. Conclusions
  13. Conflict of interest
  14. References

Several clinical trials have shown that RAMBAs, in particular liarozole and ta-larozole, are effective drugs with an acceptable safety profile for the treatment of ichthyosis, psoriasis and acne.

Liarozole in psoriasis and ichthyosis

A total of 6 clinical trials assessing the efficacy and safety of oral liarozole have so far been conducted in psoriasis [77–80]. All trials were double-blind, placebo-controlled, randomized, parallel group trials, except for one open pilot trial and one active-controlled trial with acitretin at daily doses of 25 mg. Liarozole was administered in daily doses ranging from 50 to 300 mg. A pooled analysis of the efficacy data of the 6 trials included in total 828 subjects of whom 501 had been randomized to liarozole treatment [81]. Both PASI score evaluations and global clinical evaluations showed that relative increases in response were largest when increasing the liarozole dose from 75 to 150 mg. Further dosage increases were of no use. All doses of liarozole were found to be well tolerated. Adverse events (e.g. skin disorders, pruritus, dry mouth) were more common in subjects receiving a liarozole dose > 150 mg daily. The incidence of those adverse events in the 150 mg liarozole group did not surpass that of the acitretin group. A liarozole dose of 150 mg was therefore found to be optimal for the treatment of psoriasis. Curiously, topical formulations were not effective in psoriasis.

Currently, liarozole is being developed for ichthyosis only. It was recently granted the orphan drug status for con-genital ichthyosis by the European Commission and the US Food and Drug Administration. Lucker et al. provided the first evidence in an open study that oral liarozole, 300 mg daily for 12 weeks, is an effective treatment for severe ichthyosis [82]. All patients showed marked improvement. The treatment was well tolerated. As expected, adverse events consisted mainly of mild mucocutaneous symptoms such as dry skin and cheilitis.

Based on the fact that the therapeutic dose with synthetic retinoids is similar for the various types of keratinisation disorders, including psoriasis and ichthyosis, the optimum liarozole dose for psoriasis, being 75 mg twice daily, was used in a double-blind comparative trial of liarozole versus acitretin (25 mg in the morning and 10 mg in the evening) in 32 patients with ichthyosis [83]. Clinical efficacy was comparable, while retinoid-related side effects tended to occur less frequently with liarozole. Interestingly, pre-treatment scaling was significantly worse in the liarozole group and improvement was more pronounced, as the result post-treatment was the same as that in the acitretin group [84].

To avoid side effects, a topical formulation was developed. A short-term study (10 weeks, n = 12) was conducted with a topical formulation (5 % cream) in patients with various types of ichthyosis (X-linked recessive and lamellar ichthyosis and bullous congenital ichthyosiform nance study (72 weeks, n = 8). After 6 weeks of double-blind treatment versus placebo, a significant unilateral improve ment was observed in favour of the liaro zole-treated side. The extent and severity of the lesions further improved during the 4 weeks open phase and 72 weeks maintenance phase. Of the 8 patients who completed the long-term study, responded favourably. Clinical side ef fects were only minimal. Topical liaro zole was well tolerated, even through the 72 weeks maintenance study.

Future perspectives with liarozole in ichthyosis

Dose-finding studies are required to optimize both the efficacy and safety of topical and oral liarozole treatment. Results from a large-scale multicentre phase II/III trial in lamellar ichthyosis evaluating 2 doses of oral liarozole (75 mg and 150 mg once daily) given during 12 weeks compared to placebo are expected shortly. The outcome of the study should clarify whether a once daily treatment regimen of liarozole also provides therapeutic activity while further improving the side effect profile of the drug.

Oral talarozole, a promising treatment for psoriasis and acne?

  1. Top of page
  2. Summary
  3. Introduction
  4. Retinoids: mechanism of action and metabolism
  5. Mechanism of Action
  6. The role of CRABP I and II
  7. Tissue uptake
  8. All-trans-RA catabolism
  9. Retinoic acid metabolism blocking agents
  10. Clinical use of RAMBAs
  11. Oral talarozole, a promising treatment for psoriasis and acne?
  12. Conclusions
  13. Conflict of interest
  14. References

Similar to all-trans-RA, both oral and topical talarozole exhibit modulating effects on epithelial growth and differentiation in various animal models of kera-tinisation which suggests a therapeutic potential in hyperkeratotic disorders like psoriasis. Compared to liarozole, talarozole is a more potent (IC50 in nM range) and selective retinoic acid 4-hydroxylase inhibitor, hence expected to be clinically effective at lower dosages, with consequently fewer side effects.

Oral talarozole in moderate to severe plaque type psoriasis

Oral talarozole, 1 mg daily, has been evaluated as a treatment for moderate to severe plaque type psoriasis. In an open-label study in 19 patients, conducted in the Netherlands, 26 % of the patients showed a 50 % reduction in PASI (PASI 50) after eight weeks [76]. We observed an interesting phenomenon – the psoriasis kept improving after discontinuation of the treatment, such that the PASI 50 was at 47 % after two weeks' follow-up (Figure 3). Presently, we have no explanation for this observation. A longer treatment period of up to 8 weeks, or higher dosages, may be needed to achieve optimal clinical efficacy. The most common adverse events with ta-larozole in this trial were pruritus, xero-sis, cheilitis and an increase in blood triglycerides. As psoriasis patients already tend to have higher triglycerides and cholesterol, this side effect may be unique to psoriasis [85–87].

image

Figure 3. Plaque-type psoriasis on elbow and leg of a patient (a, b) before treatment and (c, d) after treatment with 1 mg talarozole daily for 8 weeks.

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We did not observe hypertriglyceridemia in other talarozole trials at this moment. Kinetic data revealed no accumulation of talarozole throughout the study and a rapid clearance (within hours) from the body once treatment was stopped. At all time points, increases in plasma all-trans-RA levels remained within physiological limits Assessment of the dynamics of epidermal proliferation, keratinization, lesional T-cell subsets and cells expressing NK-receptors in only 6 patients revealed that clinical efficacy of talarozole is primarily the result of restoring (proliferation and) differentiation of epidermal ker-atinocytes [88]. Also, a tendency toward reduction of relevant T-cell subsets and cells expressing NK-receptors was shown, suggesting that talarozole might possess anti-inflammatory activities and supporting the concept that a longer treatment with talarozole will probably further improve clinical efficacy.

Future studies with talarozole in psoriasis

Our preliminary data suggest that talaro-zole has potential as a treatment for plaque-type psoriasis. Additional controlled and dose-finding studies will be required to confirm the efficacy and establish the optimum treatment dose and safety. The fact that some non-responders in our exploratory study had a very high body mass index (e.g. 49.4) could indicate that a ‘dose by weight’ (mg/kg) regimen might be necessary. The data also suggest that a longer treatment will probably improve clinical efficacy, so op-timisation of the treatment duration is definitely necessary. Future clinical studies should include a quality of life survey and close monitoring of triglycerides. The possible anti-inflammatory activity of talarozole needs further investigation as does its clinical efficacy in other types of psoriasis, psoriatic arthritis and pal-moplantar pustulosis. Dose-ranging studies are now being conducted in a multi-center trial with a treatment duration of 12 weeks.

Oral talarozole in facial acne vulgaris?

Next to its effect on epithelial growth and differentiation, oral talarozole also reduces the sebaceous gland size in hamsters. In addition, topical application of talarozole has revealed a reduction of utriculus size in rhino mouse back skin (predictive for acne) and a dose-dependent reduction of pro-inflammatory cytokines such as IL-1 α at the mRNA level in the skin of healthy volunteers, suggesting a possible anti-inflammatory activity [89]. Based on these properties, talarozole was hypothesized to be effective in skin disorders such as acne vulgaris where an aberrant keratinization is duction/excretion. In an open-label single-arm study, 17 patients with moderate to severe facial acne received 1 mg oral talarozole daily during 12 weeks, followed by a 4-week follow-up period [90]. Results were encouraging, with equally good effects on inflammatory and non-inflammatory lesions as shown in figure 4. At end of treatment a significant mean reduction in inflammatory lesion count of 77.4% (p less than 0.001), in non-inflammatory lesion count of 58.3 % (p less than 0.001), and in total lesion count of 76 % (p less than 0.001) was observed compared to baseline. Improvement was still pronounced 4 weeks after the last drug intake. Mild side effects, such as cheilitis and dry skin, were reported occasionally.

image

Figure 4. Healing of moderate and severe facial acne vulgaris (a) before treatment and (b) after treatment with 1 mg talarozole daily for 12 weeks.

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Future studies with talarozole in facial acne vulgaris

In order to further clarify the potential of oral talarozole in the treatment of moderate to severe facial acne vulgaris, larger clinical studies using a placebo-or active-controlled approach as well as dose-finding studies will be necessary.

As topical talarozole revealed a reduction of utriculus size in rhino mouse back skin (a commonly used model for certain aspects of acne) and also a dose-dependent reduction of pro-inflammatory cy-tokines in the skin of healthy volunteers, another option would be to investigate the potential of topical talarozole in the milder forms of facial acne vulgaris. If such studies would prove to be positive, one might consider employing oral ta-larozole as a short-term first line therapy for the moderate to severe forms of acne, followed by a maintenance treatment with topical talarozole.

Conclusions

  1. Top of page
  2. Summary
  3. Introduction
  4. Retinoids: mechanism of action and metabolism
  5. Mechanism of Action
  6. The role of CRABP I and II
  7. Tissue uptake
  8. All-trans-RA catabolism
  9. Retinoic acid metabolism blocking agents
  10. Clinical use of RAMBAs
  11. Oral talarozole, a promising treatment for psoriasis and acne?
  12. Conclusions
  13. Conflict of interest
  14. References

Retinoids are powerful drugs that have a definite place in dermatology. However, their mode of action implies that it will never be possible to dissociate their beneficial effects from the unwanted ones. Therefore, retinoid development has slowed down over the years and shows little signs of recovery, although the rexi-noids do show promise as anticancer drugs. While they have fewer cutaneous side effects, however, rexinoids do cause hypertriglyceridemia and can cause hypothyroidism. It would seem that, if we want to dissociate the desired retinoid effects from the unwanted ones, we need to explore alternative venues. As we have shown in this review, it seems that modulation of retinoic acid metabolism offers new possibilities.

Currently available data suggest that RAMBAs, compared to the oral retinoids available today, are at least equally effective treatments for hyperker-atotic disorders and display a trend towards a more favourable safety profile. However, larger and longer studies are needed to confirm these preliminary results. That said, we feel confident that for the ichthyoses, RAMBAs will soon supplant retinoids because of their more favorable pharmacokinetic profile. Retinoids have a remarkable range of activities and potential clinical uses. Other cutaneous disorders previously shown to be responsive to retinoids such as chronic (hyperkeratotic) hand eczema, photoag-ing, age-related hyperpigmentation and actinic keratosis, are likely to respond positively to RAMBAs, too. As more insight is gained into the mechanism of action of retinoids and their intracellular metabolism, more indications for RAM-BAs may surface. Several studies and research projects that evaluate the use of RAMBAs in a multitude of disorders are either ongoing or planned.

Conflict of interest

  1. Top of page
  2. Summary
  3. Introduction
  4. Retinoids: mechanism of action and metabolism
  5. Mechanism of Action
  6. The role of CRABP I and II
  7. Tissue uptake
  8. All-trans-RA catabolism
  9. Retinoic acid metabolism blocking agents
  10. Clinical use of RAMBAs
  11. Oral talarozole, a promising treatment for psoriasis and acne?
  12. Conclusions
  13. Conflict of interest
  14. References

Barrier Therapeutics is a biopharmaceu-tical company focusing on the development of drugs for dermatological disorders. Barrier Therapeutics owns the RAMBA discussed in the manuscript. The first author is an employee and the third a consultant for this company.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Retinoids: mechanism of action and metabolism
  5. Mechanism of Action
  6. The role of CRABP I and II
  7. Tissue uptake
  8. All-trans-RA catabolism
  9. Retinoic acid metabolism blocking agents
  10. Clinical use of RAMBAs
  11. Oral talarozole, a promising treatment for psoriasis and acne?
  12. Conclusions
  13. Conflict of interest
  14. References
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