THERAPY 13

-Rodger Hall-

Topical retinoids such as tretinoin [all-trans retinoic add] are widdy used for treating severe acne. However, tretinoincauses skin irritation, and photosensitivity reactions may also occur. AdapaIene [Differin~;CIRD Galderma] isa new. retinoid-like compound that is being marketed in France for the treatment of acne. At DermatologyUpdate '95 [Montreal, Canada; October 1995]. Dr Braham Shroot from CIRD Galderma, Valbonne, France,summarised the discovery of adapalene, and presented the results of 2 trials comparing the novel retinoid withtretinoin.

Doalgn MulIk:entre, tandomIsed, 1nvestigator-ma$k8d, 'paIllIIeIgroup , E· x

Indlaltlon . Globallacial amellUigari& gia(fe 1-5 ~~,, ' ',," , t'i

TtefItment '.,.~gelO.l""Of tretinolngelO.025""":. } , " epplled eadl night lor 12 weeks \OJ

Total no. of patIMIs 26lI 323g

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~~: . '~ ~studyeniry. no~pteparaII~forT )i: "' 14 day&, no systen*:l anlll::8<:t8rIEl$ for 30 dily$ ,

;:>.,arF,no ayslemic~ for 6,month& 'y:GlobBJ flldBl acne gr8de.and litftammatory. :;.t, I'IClrH'lIamm8toly aoo totalleslon COWlls---'by 1tle~lor at baseline aoo~ 4 8 tIfld 12 after IJeaIment lnIllation

Unra..ning adapalene's mecIIanNnofactionin the epi<lenIm •••

According to Dr Shroot, the most recent ideasabout the action of retinoids in the epidermis rel ateto a mechanism by which gene transcription orrepression is controlled by retinoids binding to retinoicacid receptors (RARs) in ce ll nuclei. Retinoid-RARcomplexes form heterodimers with retinoid X receptors(RXRs), and the resulting RAR-RXR complexes bindto a specific sequence of nucleotides (a lso known asretinoic acid responsive elements or RAREs) located

; us

Reduced skin initatioo with adapaleneIn the European study, adapaIene showed significantly

lower mean scores , when compared wit h tre ti noin, foradverse events classed as retinoid-like ski n irritation,including:• burning after application (weeks 2- 12; p < 0.01)• persistent burning (week 8 ; p < 0.05)• pruritus after application (week 12; p < 0.05)• dryness and scaling (week s 8 and 12; p < 0.05) .

In the US study, retinoid-like skin irritation wa sge nerally mild fo r both treatments, but significan tlyfewer (p < 0.05) patients who received adapalene gelexperienced erythema, burning, or scaling and drynessthroughout the study.

non-inflammatory (p :::0 .02 ) and total (p :::0.0 1)lesion counts, compared wit h tretinoi n recipients.

When asked to comment on the different resultsobtained by the US and Eu ropean studies. Dr Shrootpointed out that. although both studies were carefullycontro lled . ac ne was a variable disease and there wa sa difference in the seasons during which the 2 studieswere running.

Adapalene is a naphthoic acid derivative witha methoxyphenyl adamantyl side chain {seefigure].

CH,O

Adapalane

Thpical adapalene and _oin rompared in acneDr Shroot reported the findings of 2 multicentre

studies that compared the efficacy and tolerability ofadapalene gel with tho se of tretinoin gel in individualswith acne vu lgaris [see table 1J.

In the European study. all measured parameters forboth adapalene and tretinoin decreased during the studyperiod. compared with baseline values. although therewere no significan t differences between the 2 treatmentgroup s. However. in the adapalene group. there wasa trend towards a greater reduction in the number ofinflammatory lesions and the total lesion count, whenevaluated at weeks 2 and 4 after treatment initiation .

TIle resu lts from theUS study were more encouraging:at week 12, adapalene-tceated patients showed a greatermean percentage reduction in inflammatory (p :::0.06).

Adapalene fonnulated asa gelDifferent formulations were studied to optimise dose .

efficacy and safety. Because of its phy sicochemicalproperties, adapalene was formu lated as a micro­suspension in a non-alcoholic. uon-comedogemc.fragrance-free vehicle. Studies fou nd that site deliveryof adapalene to pi losebaceous units in skin was enhancedby using panicles wit h a diam eter of 3- lOJ.I1ll.

Analysi s of cryosections. radioacti ve tracing andfluorescence studies in excised human skin have shownthat adapale ne ge l penetrates into the epidermi s anddermis (especially the pilosebaceous units). Adapaleneappears to penetrate the skin to a lesser extent thantre ti noin.

Adapalene displays activity in assays designed toestablish potency in modulating cell diffe rentiation orproliferation. These effects have also been demonstratedin vivo in a rhino mouse model of comedolysis .Adapa lene also shows potent activity in in vitro andin vivo models of inflammation. On the basis of thesefindings, and the good local to le rability of adapalene .the drug was selec ted for development as a treatmentfor acne.

14 THERAPY

near the promoter region in the target gene, Dr Shrootexplained. Subsequent interaction of specific portionsof the protein-DNA complex with gene tran scriptionmechanisms results in messenger RNA (mRNA)production. To date only acidic retinoids such astretinoin and adapalene are known to bind in this directmanner, Dr Shroot said.

• ••and the dennisIn the cells of the dermis, retinoid action may be

mediated by a different RAR subtype, which also formsdimers with RXR s and then binds to RAREs.

It is currently believed that the RAR mechanisminvolves endogenous 9-cis retinoic acid , a naturalligand for RXR. accordi ng to Dr Shroot. Affinity forRXR is not essential to produce retinoid action. Thu s.new retin cids such as adapaleoe should not interferewith the physiological role of endogenous retinoic acids.and the non-competitive nature of adapalene for thecellular retinoic acid-binding proteins (CRABP) I andII may repre sent an advantage. CRABPs are involvedin the metabolism and intracellular hand-ling of retinoids.

In addition, ligands bound to RAR s may bind tonuclear tran scription factors and con sequently preventtheir normal function. This protein-protein interactionaccounts for the so called 'transrepressor activity' ofadapalene.

'lB.ble2. ComparlsOJI of binding prortIes Iioradapalene and tretinoin

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Cellularretinoic NoadO-blrw:Ing proteIr1e, ',;;' ;'v

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NuclearrelinOld X , No-Anti-AP-1 Yes

Blndlng~ ...

Retinoids have different afIinitiesfor binding proteins

The full significance of these mechanistic con ­siderations is unlikely to be completely understooduntil the role of the retinoic acid binding proteins inthe pathogenesis of retinoid-responsive diseases ismore clearly defined, said Dr Shroot. What is clear isthat different retinoids have different affinities forbinding proteins; adapalene has a different bindingprofile to tretinoin [see table 2J. Thi s offers the hopethat specific retinoids can be developed for specificdiseases. -,-

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