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Archana J* and Vijaya Bhargavi Ch. R.B.V.R.R. College of Pharmacy,Barkatpura, Hyderabad- 5000027, A.P, INDIA. Abstract: comprise a family of polyisoprenoid lipids that include and its various natural and synthetic analogues. Although retinoids are having diversified clinical uses, they are important in dermatology as their main effect is on growth and normal differentiation of epithelial cells. Each has its own profile of pharmacological properties that determines its usefulness in clinical dermatology. Due to the existence of different types of retinoid receptors, response elements and cofactors, retinoid physiology is mediated by multiple discrete pathways and is highly complex. As a result, receptor selective retinoids are being developed which have more focused and targeted action and are likely to have a better therapeutic index. Oral retinoids such as and etretinate have promising results in the treatment of severe skin diseases like chronic acne, Darier’s disease, rosacea and lupus erythematosus. Topical retinoids like , and are useful in number of skin diseases such as , cutaneous lichen planus, melasma and many more. The development of receptor specific retinoids for topical treatment of psoriasis and/or acne may lead to interesting new compounds based on our current concepts of retinoid function. The major adverse effect of retinoids is teratogenicity; all other adverse effects are dose-dependent and controllable. Keywords: receptor (RAR), (RXR), Hyperkeratinization, pleiotropic effects, teratogenicity Introduction: Retinoids include both naturally occurring CH3 CH3 CH3 O molecules and synthetic compounds that 3CH have specific biologic activities that OCH3 resemble to those of vitamin A. Vitamin A O CH3 or is a fat soluble vitamin. Its CH esterified form, vitamin A palmitate, is 3 supplied in the diet by animal sources such Etretinate as fish oil, eggs, butter, fortified magarine CH CH CH O and animal liver. Vitamin A is also derived 3 3 3 3CH from pigments, particularly β- OH , which is found in many green and yellow vegetables.2 O CH3 Vitamin A and its metabolites, and CH retinoic acid are effective in various diseases 3 but associated with severe toxic effects. A search for less toxic substitutes for vitamin Etretinate and its free acid metabolite, A led to the development of the safer acitretin, showed a therapeutic index ten analogues. times more favourable than that of all- Second Generation: These are mono- trans- RA. Etretinate and acitretin became a aromatic retinoids which include etretinate standard treatment for psoriasis. Acitretin activates all three RAR subtypes but binds and acitretin. Through replacement of the β- 10 ionone ring in all- trans- retinoic acid with poorly to them and has a great an aromatic structure, newer retinoids with pharmacokinetic advantage because it is better therapeutic margins were synthesized eliminated more rapidly than etretinate. The in the 1970s. major metabolite of acitretin is 13-cis- isomer which is inactive.

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Third Generation: These are poly-aromatic retinoids called as arotinoids which include 3CH CH3 adapalene, , tazarotene, temarotene, mofarotene.

O CH CH 3 3 3CH OH Temarotene

The discovery of retinoic acid receptors in 1980s allowed research directed towards 3CH O receptor specific, third generation retinoids with a safer therapeutic index and a more selective action. In 1990s, researchers began devising molecules that would have greater conformational rigidity. As a result adapalene, a derivative of naphthoic acid having comedolytic, antiproliferative and Adapalene anti-inflammatory properties11 was found. It has similar efficacy to tretinoin but unlike tretinoin, stable in sunlight and tends to be N O less irritating. Bexarotene belongs to a S subclass of arotinoids called rexinoids, O because they bind to the retinoid X receptors which are responsible for controlling cell CH3 CH3 devision. It is the drug of choice in CTCL CH3 (cutaneous T-cell lymphoma). Tazarotene is a novel, acetylenic retinoid, Tazarotene and is the first topical retinoid developed for the treatment of psoriasis. It targets keratinocyte and modulates the major causes of psoriasis. It is rapidly metabolized to an 3CH CH3 active free acid form tazarotenic acid, which

CH3 is rapidly eliminated in animal species. Tazarotene selectively transactivates RAR β

CH2 and RAR γ subtypes which are predominant receptors in epidermis and is inactive at 3CH CH3 retinoid X receptors (RXRs). It has low systemic absorption after topical administration. Topical doses are neither teratogenic nor carcinogenic and are not sensitizing or photosensitizing. The RAR OOH nuclear receptor is the predominant receptor in the epidermis for which tazarotenic acid Bexarotene has high affinity. Temarotene and mofarotene are newer arotinoids awaiting

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for FDA approval. Temarotene shows no 26-28 Tazarotene is available as topical sign of hypervitaminosis A and is not formulation and can be used for mild to teratogeneic presumably due to lack of a moderate psoriasis. Severe cases need oral polar group. This can be used clinically in retinoid therapy. the treatment of proliferative dermatological Darier’s disease: diseases. Mofarotene can be used as It is an autosomal dominant condition antineoplastic agent in lymphomas and characterized by a defect in tonofilament- breast cancer. desmosome complex that connects epithelial Therapeutic Effects: cells in the epidermis. It is associated with Acne vulgaris: dark crusty patches on the skin, sometimes Acne vulgaris is a common skin condition containing pus in seborrhoic areas. These caused by changes in pilosebaceous units, can become generalized and complicated by skin structures consisting of a hair follicle a foul odour from secondary infection and and its associated sebaceous gland via etretinate is effective. Acitretin is more androgen stimulation. It is characterized by effective for hyperkeratotic lesion. non-inflammatory follicular papules, Adapalene or tazarotene are acceptable pustules and nodules in its more severe alternative topical retinoids29, 30 used in form. Severe acne is inflammatory, but acne Darier’s disease. can also manifest in non-inflammatory Cutaneous T-cell lymphomas (CTCL): forms.20 These are heterogenous group of Topical retinoids such as adapalene and lymphoproliferative disorders characterized tazarotene can normalize the follicle cell life by localization of malignant T-lymphocytes cycle. Tazarotene showed greater efficacy to the skin at presentation. Retinoic acid, and comparable tolerability and was cost selective retinoids (All- trans-RA, 13-cis- effective alternative to tretinoin.24 Although RA, isotretinoin, etretinate and acitretin) are tretinoin and adapalene have similar efficacy used for the treatment of CTCL. Orally in the resolution of acne, tretinoin result in a administered bexarotene, the first synthetic faster action in reducing comedones whereas highly selective X receptor retinoid to be adapalene is more chemically stable less approved by the FDA for CTCL and is photoliable, more lipophilic and also having active against the early cutaneous greatest tolerability.25 manifestations of CTCL. Bexarotene Psoriasis: treatment induces apoptosis of CTCL cells Psoriasis vulgaris is characterized by with down regulation of its receptor. erythmatous plaque with a severely scale. In Synergistic effects in the treatment of CTCL severe cases the erythmatous eruption have been reported33 by using the covers almost the entire body. In addition combination of acitretin or isotretinoin with there are various pustular forms of psoriasis oral vit D3 (). which may either localized or acute and Premalignant and malignant skin lesions: generalized with high fever or systemic Etretinate and acitretin are effective in toxic effects. All forms of psoriasis respond treatment of premalignant skin lesions, well to either etretinate or acitretin. Acitretin including human papillomavirus induced is the retinoid of choice and is effective in tumours and acitinic keratoses. In basal cell severe psoriasis particularly pustular and nevus syndrome and in xeroderma erythrodermic types. Other forms require pigmentosum, these drugs reduce combination therapy with PUVA ( dramatically the incidence of malignant + UVA) phototherapy degeneration of skin lesions. Acitretin also

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prevents the development of premalignant topically applied compounds. Paronychia and malignant skin lesions in renal (changes in hair texture and increased skin transplant recipients.34 fragility) can also occur with retinoid Lupus erythematosus: therapy. A more troublesome but uncommon Lupus erythematosus is a chronic side effect is dose dependent, reversible autoimmune inflammatory disease that diffuse thinning of the hair that first appears prevents a striking diversity of clinical 3-8 weeks43 after the start of therapy patterns with variable evolution and especially with etretinate. is the prognosis. Skin involvement occurs in 70- earliest and the more frequent sign followed 85% of all patients with lupus by blepharoconjunctivitis, dry eyes, dry nose erythmatosus.36 Interactions between and dry mouth. Photosensitivity is observed genetic, infective and hormonal factors especially with isotretinoin and probably trigger alterations of immunoregulation that reflects the reduction of thickness of stratum mediate the pathogenesis of this disease.37 corneum. Bexarotene appears to induce Retinoids are considered second line fewer mucocutaneous and ocular side effects systemic drugs in treatment of DLE ( than other classes of retinoids. Localized or Discoid lupus erythmatosus). Etretinate and extensive exfoliative dermatitis is the most isotretinoin are especially useful in common side effect with bexarotene. hypertrophic lupus erythmatosus. Hyperlipidemia: Side Effects: Depending on the type and dosage of The side effects of systemic retinoids retinoids, triglyceride levels are elevated in qualitatively resemble hypervitaminosis A 50-80% and cholesterol levels in 30-50% of syndrome. The most prominent features of treated patients. Disturbance of blood lipid chronic hypervitaminosis A are dry scaling levels is generally higher with isotretinoin skin, cheilitis and loss of hair followed by and bexarotene than with acitretin. In cases bone pain, anorexia, headache, deplopia due of severe retinoid induced to increased intracranial pressure. hypertriglyceridemia, eruptive xanthomas Hepatosplenomegaly often occurs with and acute pancreatitis may occur. perisinusoidal deposition of lipids and Discontinuation of therapy is required if fibrosis seen in biopsy specimens. In triglyceride concentration reaches contrast to vitamin A the relatively non- 800mg/dL.41 Retinoids probably cause toxic retinoids have few serious systemic hyperlipidemia by increasing the expression side effects. of apolipoprotein C3 which prevents uptake Teratogenic effects: of lipids from very low density lipoproteins Teratogenicity is the major adverse effect into the cells. caused by almost all systemic retinoids. Hepatotoxicity: Retinoids are not mutagenic but they cause Transitory abnormal elevations in serum serious fetal malformations, including major transaminase levels have been reported in abnormalities of CNS, cardiac and ear approximately 20% of patients treated with defects.42 etretinate or acitretin and occur much less Mucocutaneous effects: frequently with isotretinoin and bexarotene. These are dose related, tolerable and Transaminase elevations more than three reversible. Retinoids impair barrier function times the upper normal range should lead to and enhance evaporation and causes dryness discontinuation of retinoid therapy. of skin and mucous membranes, thirst and increased percutaneous absorption of other

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Musculoskeletal effects: Precautions to be taken while treatment Musculoskeletal side effects can be seen with retinoids: with high doses and after an extended period 1. Oral retinoids, being toxic , of continuous treatment. Arthralgias and should be used cautiously. Patients myalgias occur in upto 16% of patients should be made aware of the side effects receiving isotretinoin for acne.44 Muscle and the precautions to be taken before pain and cramps rarely occur in patients starting isotretinoin. taking etretinate or acitretin, however these 2. As the systemic retinoids can cause muscle effects are frequent with isotretinoin, deformities of the fetus, physician should particularly in individuals involved in confirm that their patients are not vigorous physical activity. Increased muscle pregnant before starting the . tone, axial muscle rigidity and myopathy The first dose of the medication may be were reported to be related to etretinate and started immediately after the menstrual acitretin therapy. A more serious side effect period. is the development of skeletal hyperostosis 3. Use double birth control measures before in which nerve tone form in areas of and during and for a full month after the ligamentous attachment. This occurs in retinoid therapy. longterm high dose treatment with 4. Retinoids increase blood lipid levels. isotretinoin. Hence intake of alcohol, oily, fried foods, CNS and other neurological effects: eggs and red meat should be reduced CNS side effects are rare. Although during the treatment period especially in individual signs of increased intracranial patients with high blood pressure and pressure such as headache nausea and diabetes. vomiting are observed occasionally, the 5. Other vitamin A containing vitamin complete syndrome with papilledema and supplements should not be taken while on impaired vision is exceptional. Concomitant retinoid therapy. use of isotretinoin along with tetracyclins 6. Start retinoid treatment with lowest produced an increase in intracranial strength. Later, a higher strength may be hypertension which is the major risk factor used when the skin becomes tolerant. for development of pseudotumour cerebri 7. Avoid excess sun exposure while on the (papilledema). Anecdotal reports suggest a retinoids, as these can sensitize the skin casual association between isotretinoin to sunlight. therapy and severe depression with suicide 8. Apply non-comedogenic moisturizer like attempts.45 Sebium cream if irritation occurs. Renal adverse effects: 9. Wait twenty minutes after washing the Renal toxicity has not been a characteristic face before applying the topical retinoid. consequence of retinoid administration. Conclusion: Isotretinoin has been administered safely to Vitamin A has long been known in patients with end stage kidney disease who dermatology to benefit disorders of were undergoing haemodialysis. However keratinization. The low therapeutic ratio and case reports describing reversible renal the resulting acute and chronic toxic effects function impairment during etretinate of vitamin A limited its clinical use. therapy advice monitoring of renal function, Although many retinoids are associated with particularly in patients with a history of hypervitaminosis A syndrome, newer renal disorders. retinoids with receptor specificity overcome many of these toxic effects. Retinoids with

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Table 1: Data on commercially available oral and topical Retinoids

Tretinoin Isotretinoin Etretinate Acitretin Tazarotene Adapalene Bexarotene

Chemical

Configuration

Ring structure Poly Poly Mono Poly Side chain β-ionone β -ionone β-ionone aromatic aromatic aromatic aromatic β-cis All-trans All-trans Not Not End group All-trans Not applicable Acid Acid Ethyl ester applicable applicable Molecular Acid Acid 300 300 354 Ester Ester weight 326 412 351 348 Therapeutic oral dose _ 0.5-2 0.5-1 0.3-0.75 _ _ 300 range (mg/kg/day)

Renova® Accutane® Soriatane® Retin A® Accure® Tegison® Tazorac® Differin® Targretin® Trade names Aceret® Isotrex®

0.01% gel Cream Capsules Gel 0.1% 0.1%, 0.05% 0.025%,0.05 5 mg, 10mg, Capsule Available Gel 0.1% %,0.1% 30 mg, and 10 mg Capsule Solution 0.1% Gel 0.1% dosage form cream 40 mg. Capsule 25mg Cream 0.1% and strength 20 mg Cream 0.1% Capsule 0.05% 0.05%gel 75 mg solution

greater specificity for target organs and exact molecular mechanism of retinoids in fewer systemic side effects are being dermatology is still under wraps. Research developed by.means of modification of basic should be done on establishment of exact structures. Current retinoid research targets mechanism of retinoids in dermatological the development of receptor-selective disorders so that to develop retinoids with retinoids for improving their therapeutic more specific action and with least side profile. Newer arotinoids like temarotene are effects. without polar group and almost devoid of hypervitaminosis A syndrome and Acknowledgements: teratogenic effect which is the major draw back of retinoid therapy. Topical retinoids are being rapidly developed at present and The authors express their heartful thanks to seems promising for the future; their clinical Dr.M.Sumakanth Principal, RBVRR application includes acne, aging, photo Women’s College of Pharmacy for her damage, precanceroses, skin cancer and constant support and for providing necessary disorder s of skin pigmentation. The facilities.

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References: [18] Blumberg B, Evans RM. Orphan nuclear [1] Gudas LJ, Sporn MB, Roberts AB. The receptors- new ligands and possibilities. Genes Retinoids. Newyork, NY Raven Press, 1994: Dev 1998; 12:3144-3155. 443-520. [19] Gerard J.Gendemenico, James A.Mezick. [2] Orten JM, Neuhaus OW. Human Bio-chemistry. Pharmacological effects of Retinoids on Skin 10th ed. Mosby, St Louis, 1982: 735-746. cells. Skin Pharmacol 1993; 6: 24-34. [3] Wolbach SB, Howe PR. Tissue changes [20] Fulton Jn, MD. Acne following deprivation of fat soluble A vitamin. Vulgaris[online].2009[cited 2009 Aug 6]. J Exp Med 1925; 42: 753-778. Avilable from: URL: [4] Bern HA, Elias JJ, Pickett PB et al. The http://emedicine.medscape.com/article/106980 influence of vitamin A on the epidermis. Am J 4-overviewJames Anat 1955; 96: 419-447. [21] Cunliffe WJ, van de Kerkhof PC, Caputo R, et [5] Thompson JN, Howell JM, Pitt GAJ. Vitamin A al. Roaccutane treatment guidelines. Results of and reproduction in rats. Proc R Soc Lond [ an international survey. Dermatology 1997; Biol] 1964; 159: 510-535. 194: 351. [6] Dowling JE, Wald G. Vitamin A deficiency and [22] Shalita AR, Cunnigham WJ, Leyden JL, et al. night blindness. Proc Natl Acad Sci .U.S.A. Isotretinoin treatment of acne and related 1958; 44: 648-661. disorders: an update. J Am Acad Dermatol [7] Zile M, DeLuca HF. Retinoic acid:some aspects 1983; 9:629-638. of growth-promoting activity in the albino rat. [23] Plewig G, Nikolowski J, Wolff HH. Action of J Nutr 1968; 94: 302-308. isotretinoin in acne rosacea and gram-negative [8] Elizebeth H. Heller, Norman J.Schiffman. folliculitis. J Am Acad Dermatol 1982; 6: 766- Synthetic retinoids in Dermatology. Can Med 785. Assoc J 1985; 132(10):1129–1136. [24] Leyden JJ, Tanghetti EA, Miller B, Ung M, [9] Bershad S. Developments in topical retinoid Berson D et.al. Once daily tazarotene 0.1% gel therapy for acne. Semin Cutan Med Surg versus once-daily tretinoin 0.1% microsponge 2001; 20: 154-161. gel for the treatment of facial acne vulgaris; A [10] Wiegand UW, Chou RC. of double-blind randomized trial 2002; 69:12-19. acitretin and etretinate. J Am Acad Dermatol [25] Prystowsky JH. Topical retinoids. Philadelphia: 1998; 39:S25. W.B.Saunders Company; 2001. [11] Joseph B. Bikowski. Mechanisms of the [26] Lassus A. Systemic treatment of psoriasis with comedolytic and anti-inflammatory properties an oral retinoic acid derivative (Ro 10-9359). of topical retinoids. Drugs Dermatol 2005; Br J Dermatol 1980; 102: 195-202. 4(1):41-47. [27] Pettit JH. Oral retinoid for psoriasis. A report of [12] Altucci, L. Gronemeyer H. Nuclear receptors in a double blind study. Acta Derm Venereol cell life and death. Trends Endocrinol. Metab 1979; 59: 133-136. 2001; 12: 460-486. [28] Lassus A, Lauharanta J, Juvakoski T, et al. [13] Chambon P. A decade of molecular biology of Efficacy of etretinate (Tegison) in clearing and Retinoic acid receptors. FASEB J 1996; 10: prevention of relapse of palmoplantar 940-954. pustulosis. Dermatologica 1983; 166: 215-217. [14] Sporn MB, Roberts AB, Goodman DS. The [29] Dicken CH, Bauer EA, Hazen PG et al. retinoids. Newyork: Raven Press; 1994: 319- Isotretinoin treatment of Darier’s disease. J 350. Am Acad Dermatol 1982; 6:721-726. [15] Xie W, Evans, R.M. Orphan nuclear receptors: [30] Christiansen JV, Holm P, Moller R, et al. the exotics of xenobiotics. J.Biol.Chem 2001; Treatment of dyskeratosis follicularis Darier 276: 37739-42. with the retinoic acid derivative Ro 10-9359 [16] Ben-Shushan, Sharer H, Pikarsky E, Bergman (Tegison). Dermatologica 1982; 165: 204-207. Y. A dynamic balance between ARP-1/COUP- [31] Di Grovanna J, Robinson Bostom L. TF 11, EAR-3/COUP-TFI and retinoic acid Ichthyosis: Etiology Diagnosis, and receptor:retinoid X receptor heterodimers Management. Am J Clin Dermatol 2003; 4 (2): regulates Oct-3/4 expression in embryonal 81-95. carcinoma cells. Mol Cell Bio 1995; 15:1034- [32] Traupe H. The Ichthyosis. Berlin:Springes- 1048. verlag; 1989:232-243. [17] Mangelsdorf DJ, Evans RM. The RXR [33] Duvic M, Martin AG, Kim Y, et al. Bexarotene heterodimers and orphan receptors. Cell 1995; is effective and safe for treatment of refractory 83: 841-850. advanced-stage cutaneous T-cell lymphoma:

382 Archana J et al, /J. Pharm. Sci. & Res. Vol.2 (7), 2010, 376-383

Multinational phase II-III trial results. J Clin [38] Ertl GA. Levene N, Klingman. AMA Oncol 2001; 19: 2456. Comparision of the efficacy of tretinoin and [34] De Sevaux RGL,.Smit JV,.de Jong EMGJ, Van low dose oral isotretinoin in rosacea. Archives PCM, De Kerkhof, Hoitsma AJ. Acetretin of Dermatology 1994; 130(3): 19-24. treatment of premalignant and malignant skin [39] Verschoore M. Bouclier M, Czenielewski J, disorders in renal transplant recipients: Hensby C. Topical retinoids-their uses in Clinical effects of a randomized trial dermatology. Dermatologic Clinics; 11(1): comparing two doses of acetretin. J Am Acad 107-113. Dermatol 2003; 49(3): 407-412. [40] Debabrata Bandyopadhyay. Topical treatment [35] Dicken. C, Powell S, Spear K. Evaluation of of melasma. Indian J Dermatol 2001; 54:303- isotretinoin treatment of hidradentis 309. Suppurativa, J Am Acad Dermatol 1984; [41] Anders Vahlquist, Madeleine Duvic. Retinoids 11(3):500-502. and , informa health care USA, Inc, [36] Gilliam JN, Sonthumer RD. Distinctive Newyork: 2007; 249-260. Cutaneous Subsets in the spectrum of lupus [42] Benke PJ. The isotretinoin teratogen syndrome. erythmatoses; J Am.Acad Derm 1981; 4: 471- JAMA 1984; 251: 3267-3269. 475. [43] Orfanos CE. Oral retinoids- present status. Br J [37] Graham RR, Ortmann WA, Langefeld et al. Dermatol 1980; 103: 473-481. Visualizing human leukocute antigen class II [44] Pittsley RA, Yoder FW. Retinoid hyperostosis. risk haptotypes in human systemic lupus N Engl J Med 1983; 308: 012- 1014. erythmatosus. Am J Hum Genet 2002; 71: [45] Parker Margin, Wayne Smith. Isotretinoin, 543-53. depression and suicide: a review of evidence. Br J Gen Pract. 2005; 55(511):134-138.

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