ADAPALEN, ETANERCEPT &TRIPTANADAPALEN, ETANERCEPT &TRIPTANMirfaidah N

ADAPALENE

• Vitamin A and its derivatives (retinoids) exert awide range of effects on embryonic development,cell growth, differentiation, and apoptosis.

• Vitamin A cannot be synthesized by any animalspecies and is only obtained through diet in theform of retinol, retinyl ester, or β-carotene

• Ingested vitamin A is stored as retinyl esters inhepatic stellate cells.

• Vitamin A and its derivatives (retinoids) exert awide range of effects on embryonic development,cell growth, differentiation, and apoptosis.

• Vitamin A cannot be synthesized by any animalspecies and is only obtained through diet in theform of retinol, retinyl ester, or β-carotene

• Ingested vitamin A is stored as retinyl esters inhepatic stellate cells.

Synopsis of factors involved in the pathogenesis of acne

Synopsis of the FGFR2b (Fibroblast growth factor) signaling pathway orchestrating all major downstream cascadesinvolved in the pathogenesis of acne. The three major downstream FGFR2b-signaling cascades: the MAPK (Mitogen-activated protein kinase) pathway-inducing cell proliferation and MMP/Matrix metalloproteinase expression, thePI3K/Akt- (Phospatidylinositol 3-kinase) and Shh/MC5R (Melanocortin-5 receptor) pathway-inducing lipogenesis andterminal sebocyte differentiation, and the phospholipase Cg/protein kinace C pathway-inducing IL-1a, andinflammatory reactions.

Hypothetical synopsis of anti-acne agents targeting the FGFR2 pathway. (1) Anti-androgens compete with an androgenreceptor and reduce FGF- ligand expression, (2) benzoyl peroxide induces lysosomal FGFR2 degradation byROS(Reactif oxygen spesies) formation, (3) azelaic acid depletes cellular ATP levels for phosphorylation events, (4)atRA induces expression of Sprouty thereby inhibiting the MAPK cascade and induces MKP3 (MAP Kinasephosphatase) for de-activation of ERK, 13cRA downregulates 5a-reductase 1 expression, and (5) tetracyclines inhibit theexpression and activity of MMPs.

• Retinol is reversibly oxidized by retinoldehydrogenases to yield retinal. Subsequently,retinal may be irreversibly oxidized to all-transretinoic acid (all-trans RA) by retinaldehydrogenases and further oxidized by cytochromeP450 enzymes (mainly CYP26) in hepatic tissue.

• All-trans RA isomerizes under experimental andphysiological conditions. Different isomers activatedifferent receptors and thus lead to differentbiological effects. RAs designed to be receptorspecific can improve efficacy and avoid unwantedside effects.

• Retinoids that specifically bind to RXR are calledrexinoids and have been effective in cancertreatment.

• Retinol is reversibly oxidized by retinoldehydrogenases to yield retinal. Subsequently,retinal may be irreversibly oxidized to all-transretinoic acid (all-trans RA) by retinaldehydrogenases and further oxidized by cytochromeP450 enzymes (mainly CYP26) in hepatic tissue.

• All-trans RA isomerizes under experimental andphysiological conditions. Different isomers activatedifferent receptors and thus lead to differentbiological effects. RAs designed to be receptorspecific can improve efficacy and avoid unwantedside effects.

• Retinoids that specifically bind to RXR are calledrexinoids and have been effective in cancertreatment.

Retinol

At-retinaldehyde

At-retinoic acid (RA)

Degradation

At-RA for T cells

Vitamin A (retinyl ester)in food

Vitamin A (retinyl ester)in food

REH: retinyl ester hydrolase ADH: alcoholdehydrogenase AKR: aldo-keto reductaseRALDH: aldehyde dehydrogenaseCYP26: cytochrome P450SDR: short-chain dehydrogenase/reductase

REH

AKR, SDR ADH1 & 4, SDR

RALDH1 & 2

CYP 26

Synthesis of retinoic acid in the dendritic cells of the in- testine. Vitamin A is consumed asretinyl ester and hydrolyzed by retinyl ester hydrolase (REH). Retinol, entered into cells, isoxi- dized to retinaldehyde by alcohol dehydrogenase (ADH) or short- chaindehydrogenase/reductase (SDR). The reverse reaction is me- diated by aldo-keto reductase(AKR) or SDR. Retinaldehyde can be converted to retinoic acid (all-trans retinoic acid orAt-RA) by retinaldehyde dehydrogenase (RALDH). Retinoic acid is degraded in cells bycytochrome P450 (CYP26). It is known that dendritic cells in the gut-associated lymphoidtissues (GALT) such as Peyer’s patches and MLN express high levels of ADH1, ADH4,RALDH1, and/or RALDH2. The retinoic acid produced by dendritic cells can be exportedfor other cells such as T cells during the cognate inter- action between dendritic cells and Tcells.

Degradation

Retinoid PathwayRetinoid Pathway

Retinoids absorbed from food are converted to retinol and bound to CRBP in the intestine. Then, retinol is converted to retinyl esters and enters intoblood circulation. The liver up takes retinyl esters, which are converted to retinol-RBP complex in the hepatocyte. In the serum, the retinol-RBPcomplex is bound to transthyretin (TTR) in a 1:1 ratio to prevent elimination by the kidney and to ensure retinol is delivered to the target cell. Theuptake of retinol by the target cell is mediated by a trans-membrane protein named “stimulated by retinoic acid 6” (STRA6), which is a RBP receptor.In the target cell, retinol either binds to CRBP or is oxidized to retinaldehyde by retinol dehydrogenase (RDH) in a reversible reaction. Then,retinaldehyde can be oxidized by retinaldehyde dehydrogenase (RALDH) to RA. In the target cell, RA either binds to CRABP or enters the nucleus andbinds to nuclear receptors to regulate gene transcription. Alternatively, RA can mediate via nongenomic mechanism and regulate cellular function.Hepatocytes not only process retinoids, but also are the target cells. In addition, hepatocytes located next to the storage site (stellate cell). Thus,retinoid-mediated signaling must have a profound effect in regulating hepatocyte function and phenotype

Non-genomic Actions• Retinoids also exert their effects via transcription

independent pathway, which can occur in thepresence or absence of nuclear receptor. Retinoidsmediated via RARs inhibit AP-1-regulated cellproliferation

• RA also inhibits NFκB activity in mice• Mediated through RARβ, RA changes the

intracellular Ca++ level and thus controls PI3Kactivation in neural cell

• RARα can interact with mRNA in cytoplasm andcontrol translation

• Via nuclear receptor independent pathway, RArapidly activates cAMP response element (CREB)binding protein in human bronchial epithelial cells

• Retinoids also exert their effects via transcriptionindependent pathway, which can occur in thepresence or absence of nuclear receptor. Retinoidsmediated via RARs inhibit AP-1-regulated cellproliferation

• RA also inhibits NFκB activity in mice• Mediated through RARβ, RA changes the

intracellular Ca++ level and thus controls PI3Kactivation in neural cell

• RARα can interact with mRNA in cytoplasm andcontrol translation

• Via nuclear receptor independent pathway, RArapidly activates cAMP response element (CREB)binding protein in human bronchial epithelial cells

The nongenomic RXRα actions. The cytoplasmic tRXRα through its interaction with p85αsubunit of PI3K or undefined factors associated with TNF-R1 regulates cell survival,inflammation, and apoptosis. In addition, RXRα can target mitochondria throughheterodimerization with Nur77 to modulate mitochondria-dependent apoptosis.

ETANERCEPT

• RA is diagnosed through its distinc- tive effectson the joints and in skin, and the diagnosis isreinforced by the presence in serum of therheumatoid factor (RF), although its presence isnot mandatory for diagnosis of RA.

• RA is diagnosed through its distinc- tive effectson the joints and in skin, and the diagnosis isreinforced by the presence in serum of therheumatoid factor (RF), although its presence isnot mandatory for diagnosis of RA.

Important environmental and biological factors associatedwith or possibly contributory to the pathogenesis of RA

• Cigarette smoking.• Tumour necrosis factor (TNF)-a activity.• Abnormal and inappropriate B-lymphocyte activity, i.e. abnormal

antibody production.• Detection of circulating autoantibodies against Ig Fc; these

autoantibodies have been termed ‘rheumatoid factor’, and they maybe involved in the inappropriate presentation of antigens to T cellsby B cells.

• Abnormal activity of certain signalling pathways in synovial tissue,e.g. the Wnt signalling pathway, which is involved in embryonicdevelopment and cell renewal. In patients with RA, it has beenreported that the synovial cells have abnormally high activity of theWnt gene, as well as a number of other genes for several of thecytokines, cell adhesion molecules and chemokines. At present, itis not known whether these abnormalities are causative or a resultof the more fundamental abnormalities.

• Cigarette smoking.• Tumour necrosis factor (TNF)-a activity.• Abnormal and inappropriate B-lymphocyte activity, i.e. abnormal

antibody production.• Detection of circulating autoantibodies against Ig Fc; these

autoantibodies have been termed ‘rheumatoid factor’, and they maybe involved in the inappropriate presentation of antigens to T cellsby B cells.

• Abnormal activity of certain signalling pathways in synovial tissue,e.g. the Wnt signalling pathway, which is involved in embryonicdevelopment and cell renewal. In patients with RA, it has beenreported that the synovial cells have abnormally high activity of theWnt gene, as well as a number of other genes for several of thecytokines, cell adhesion molecules and chemokines. At present, itis not known whether these abnormalities are causative or a resultof the more fundamental abnormalities.

TNF-α is a pleiotropic pro-inflammatory cytokine with many actions that arecentral to the pathogenesis of rheumatoid arthritis . Along withinterleukin 1, another important pro-inflammatory cytokine, TNF-α hastherefore been a target for biological therapy in rheumatoid arthritis.

Mechanisms of TNF-α signaling in injured nerve. By occupying either of the two TNF-α receptors, the soluble TNF-αprotein can produce different effects ranging from apoptosis to up-regulation of itself, other proinflammatory cytokines,or anti-inflammatory cytokines. While the full details of these effects are not known, it is clear that stimulation of the p38mitogen-activated protein kinase (MAPK) pathway is a critical signaling mechanism. Activation of the JNK pathway canproduce radically different effects, depending in part on activity in the pathway. Studies with TNF-/- and TNFRI-/- andRII-/- mice are helpful in defining the inter-relationships of cytokines and their receptors.

Biology of TNF production, receptor interaction and signaling. Stimulation of a TNF-producing cell (top)results in cell surface expression of tmTNF trimers and enzymatic cleavage by TACE to release sTNF. BothtmTNF and sTNF can bind to cell surface TNFR1 or TNFR2 on a TNF-responsive cell (bottom), initiatingsignaling pathways that lead to apoptosis or NF-κB activation and inflammatory gene activation. Theinduction of apoptosis by sTNF via TNFR1 involves internalization of the ligand–receptor complex andassociation of death domains (DD) in the cytoplasmic tail of TNFR1 with adapter proteins and is normallyblocked by FADD-like IL-1β–converting enzyme (FLICE). Reverse signaling can be initiated by TNFR2 orTNF antagonist binding to cell surface tmTNF, resulting in cytokine suppression or apoptosis. Soluble TNFreceptors (sTNFR1 and sTNFR2) can be released from a TNF-responsive cell following enzymatic cleavage

In the pathophysiology of RA, Crohn's disease and psoriasis, TNF is produced at high concentrations by a variety of cell types,presumably induced by endogenous or microbial stimuli. A cascade and network of cellular responses mediated by TNF that arecommon to these 3 diseases are shown in the enclosed area in the center of the diagram. Mechanisms and cellular features restrictedto a particular disease are shown outside of the enclosed area.

Four categories of putative mechanisms of action of TNF antagonists are illustrated. The large panel illustrates the primary mechanisms ofaction, resulting from direct blocking of TNFR-mediated biologic activities. In these instances, the TNF antagonists bind to the cognateligands (sTNF or tmTNF for all 5 TNF antagonists and additionally LTα3 and LTα2β1 for etanercept), thereby blocking their capacities tobind TNFR1 or TNFR2. The right panel illustrates several mechanisms induced by the binding of TNF antagonists to tmTNF, which caninclude reverse signaling via tmTNF or cytotoxicity of the tmTNF-bearing cell by CDC or ADCC. The small panel on the lower left illustrates2 LTαβ-mediated mechanisms thought to be blocked by etanercept, the only TNF antagonist that binds LT family members. The lowercenter panel shows pharmacokinetic-related mechanisms that involve TNF antagonist binding to FcRn or forming complexes with sTNF orantidrug (TNF antagonist) antibodies.Denotes a TNF antagonist (infliximab, etanercept, adalimumab, certolizumab, golimumab). Denote TNFR1 and TNFR2. ETN =etanercept.

• The pharmacological class of TNF alphainhibitors includes etanercept (Enbrel)infliximab (Remicade) and adalimumab(HUMIRA)

• etanercept molecule consists of 2 extracellulardomains of human soluble TNF receptor p75that binds to TNF and a Fc fragment of humanIgG that serves as a stabilizer.

• The pharmacological class of TNF alphainhibitors includes etanercept (Enbrel)infliximab (Remicade) and adalimumab(HUMIRA)

• etanercept molecule consists of 2 extracellulardomains of human soluble TNF receptor p75that binds to TNF and a Fc fragment of humanIgG that serves as a stabilizer.

• Etanercept is also a recombinant proteincomposed of an immunoglobulin backbone andtwo p75TNF-α soluble receptors. It is given as atwice-weekly subcutaneous injection.

• Etanercept is also a recombinant proteincomposed of an immunoglobulin backbone andtwo p75TNF-α soluble receptors. It is given as atwice-weekly subcutaneous injection.

Etanerceptin psioriasis

Dendritic cells,lymphocytes,macrophages,neutrophils,Chemokines for T, DCs,& polysIFN , TNF, IL-23 regulatedproducts

DC activation & DCApoptosis T activation

Blood vessels

iNOSAdhesion proteins

? VEGF

EpidermisIL-19, 20

? Anti-apoptoticproteinsiNOSNF B activation

• TNF blockade ‘‘tunes’’ pro-inflammatory gene expression and reverses psoriatic phenotype. Etanerceptdifferentially affects immune cells, blood vessels, and the epidermis, resulting in decreased inflammation andepidermal normalization. Leukocyte infiltration is interrupted by a reduction in chemotactic cytokines regulatedby IFN-g, TNF-a, and IL-23. This effect may be enhanced by the prevention of cellular adhesion and migrationby reductions in iNOS, adhesion proteins, and possibly VEGF. These results, in conjunction with decreases incytokine production, iNOS, NF-kB expression, and possibly anti-apoptotic proteins, promote normalization of theepidermis. There is decreased activation of NF-kB in epidermal and dermal cells, which may result in theapoptosis of DCs and possibly other cell types. Decreased DC counts and activation result in decreased T-cellactivation. These effects may collectively interrupt the self-sustaining cycle of inflammation and account forplaque clearance.

Apoptosis T activationNF B activation

Inflammation Inflammation Normalization

TRIPTANE

Tryptophan TryptophanHydroxylase 5-Hydroxytrophan (5-HTP)

Amino AcidDecarboxylase5-Hydroxytryptamine (5-HT)

migraine is benign recurring headache and/orneurological dysfunction usually attended by pain-free interludes and often provoked by stereotypedstimuli.

They were influenced by (1) the association betweenmigraine relieving properties of ergotamine tartrateinfusion and arterial vasoconstriction and (2) thefinding that compression of the common carotidartery or superficial temporal artery reduces pain inmany migraine attacks.

migraine is benign recurring headache and/orneurological dysfunction usually attended by pain-free interludes and often provoked by stereotypedstimuli.

They were influenced by (1) the association betweenmigraine relieving properties of ergotamine tartrateinfusion and arterial vasoconstriction and (2) thefinding that compression of the common carotidartery or superficial temporal artery reduces pain inmany migraine attacks.

• The vasoconstrictive properties of triptans aremediated by an action on 5-HT1B in arterialsmooth muscle

• The triptans are also thought to inhibit theabnormal activation of peripheral nociceptors.In an experimental model of migraine, calledsterile neurogenic inflammation, an abnormalactivation of nociceptors in the dura matertriggers vascular changes, including plasmaprotein extravasation (PPE)

• The vasoconstrictive properties of triptans aremediated by an action on 5-HT1B in arterialsmooth muscle

• The triptans are also thought to inhibit theabnormal activation of peripheral nociceptors.In an experimental model of migraine, calledsterile neurogenic inflammation, an abnormalactivation of nociceptors in the dura matertriggers vascular changes, including plasmaprotein extravasation (PPE)

5HT Receptors

receptor 5HT1 5HT2 5HT3 5HT4 5ht5 5ht6 5HT7

subtype 5HT1A,5HT1B,5HT1D,5ht1E,5HT1F

5HT2A,5HT2B,5HT2C

5HT3A,5HT3B

5ht1A,5ht1B

5HT1A,5HT1B,5HT1D,5ht1E,5HT1F

5HT2A,5HT2B,5HT2C

majorsignalingpathway

cAMP↓

IP3 ionchannel

cAMP cAMP? cAMP cAMP

G-Protein coupled receptors

5HT1A receptor

5HT1A Partial Agonist mechanism

5HT1A Antagonist mechanism

5HT2 receptor mechanism

5HT2 Antagonist mechanisms

Receptor Overview

5HT2 subtypes

SEKIAN & TERIMAKASIH