CURRENT REVIEW

Synthetic retinoids in dermatology

nes dermatoses, son emploi est Once in the lumen of the gut Elizabeth H. Heller, MD generalement interdit par des effets vitamin A palmitate is hydrolyzed Norman J. Shiffman, MD, FRCPC toxiques graves. Recemment, la syn- by pancreatic lipase to retinol, these et la mise en marche de deux which is then absorbed into the analogues relativement peu toxiques, gastrointestinal mucosa. Beta-caro- The potential of vitamin A, or reti- les retinoides, ont permis de traiter tene is hydrolyzed in two steps to nol, in the treatment of a variety of des dermatoses resistantes aux trai- retinol. Theoretically, one molecule of skin diseases has long been recog- tements habituels. 11 s'agit de l'iso- d-carotene can produce two molecules nized, but because of serious toxic tretinoine, tres efficace contre I'acne of retinol, but in humans the conver- effects this substance generally could kystique et pustuleuse, et de l'etreti- sion is inefficient, and four times as not be used. The recent development nate, fort utile dans les formes gra- much carotene as retinol is needed and marketing of two relatively non- ves du psoriasis. On obtient des to maintain the eyes' normal capaci- toxic synthetic analogues, which are resultats interessants dans certains ty for adaptation to the dark.' known as retinoids, has made it autres troubles de la keratinisation. In the mucosal cells of the gas- possible to treat some of the diseases La vitamine A et ses derives semblent trointestinal tract retinol is esterified that are resistant to standard forms posseder aussi une action antineopla- to form retinyl esters, which are of therapy. Isotretinoin is very effec- sique qui servira peut4tre un jour a then transported to the liver for tive in cystic and conglobate acne, prevenir et a traiter les epitheliomas. storage via chylomicrons in the while etretinate is especially useful in Dans beaucoup de ces maladies, les blood and lymphatic channels. Reti- the more severe forms of psoriasis. retinoides agissent en favorisant, par nol is released from the liver in Good results have also been obtained des voies encore mal comprises, la association with retinol-binding pro- in other disorders of keratinization. differenciation et la proliffration tein and circulates as a protein- Vitamin A and its derivatives appar- normale des tissus epitheliaux. Leur protein aggregate with prealbumin; ently have an antineoplastic effect as action sur les polyamines intracellu- the aggregate, in turn, binds one well and may come to be used in both laires qui regissent la synthese des molecule of thyroxine. the prevention and the treatment of acides nucleiques et des proteines In the peripheral tissues retinol epithelial cancer. In many of these serait un facteur important. Les reti- undergoes reversible oxidation to diseases the retinoids act by enhanc- noides ont peu d'effets generaux gra- retinal and then irreversible oxida- ing the normal differentiation and ves, sauf qu'ils sont teratogenes; tion to retinoic acid. Although the proliferation of epidermal tissues, comme ils persistent dans l'organis- mechanisms are poorly understood, but the exact mechanisms are not me, il faut s'en garder chez les it appears that retinol, retinal and well understood. Their influence on femmes susceptibles d'etre meres. retinoic acid all contribute in specif- the intracellular polyamines that ic ways to the biologic functions control the synthesis of nucleic acids Vitamin A, or retinol, is a fat-solu- attributed to vitamin A. and proteins may be an important ble vitamin important in reproduc- The only system in which the factor. Although the retinoids have tion, the visual cycle, and the differ- action of vitamin A is understood at few serious systemic effects, they are entiation and maintenance of epithe- a molecular level is the visual cycle. teratogenic, and because they persist lial tissues. An esterified form, vita- Retinol is metabolized to all-trans- in the body their use in women of min A palmitate, is supplied in the retinal and then to the isomer childbearing potential is limited. diet by animal sources, such as fish- 1 1-cis-retinal, which interacts with liver oil, eggs, butter and animal opsin to form the visual pigment Si on connalt depuis longtemps ce liver, and by fortified margarine. rhodopsin.' Hence, retinal is -the que peut donner la vitamine A (ou Vitamin A is also derived from the form of vitamin A important in the retinol) dans le traitement de certai- carotenoid pigments, particularly #- visual cycle, and one of the effects of carotene, which is found in many vitamin A deficiency is night blind- green and yellow vegetables. The ness.2 From the Division of Dermatology, the structures of $-carotene, retinol and Although little is known about the Wellesley Hospital, Toronto retinol's important metabolic deriva- role of vitamin A in the reproductive are Correspondence to: Dr. Elizabeth H. Heller, tives, retinal and retinoic acid (treti- tract, animals deprived of retinol 345 Victoria St., London, Ont. N6A 2C7 noin), are shown in Fig. 1. unable to maintain and deliver a

- For prescribing information see page 1220 CAN MED ASSOC J, VOL. 132, MAY 15, 1985 1129 viable fetus, and testicular atrophy first used to treat psoriasis in Eur- have been proposed on the basis of due to loss of spermatids is ob- ope in 1973, has been used in trials experimental observations. served.3 Supplementation with reti- in the United States since 1976 and The cell growth and proliferation nol, but not retinoic acid, reverses is approved for treatment of severe that figure in many skin diseases these abnormalities. nodulocystic acne that has not re- depend in part on the intracellular Finally, vitamin A is important in sponded to standard therapy. Since polyamines that control the synthe- the growth and normal differentia- 1982 it has been marketed by Hoff- sis of nucleic acids and proteins.'0 In tion of epithelial tissues. Experimen- mann-La Roche under the trade both psoriasis"' and the early stages tally, vitamin A deficiency causes name Accutane. The aromatic reti- of cancer'2 the activity of ornithine metaplasia of glandular, ciliated, noid etretinate (Ro 10-9359) was decarboxylase, the rate-limiting en- mucus-secreting epithelium and hy- synthesized in 1972 and has also zyme in polyamine biosynthesis, is perkeratosis of keratinizing epitheli- been the subject of much study. It increased. In psoriasis etretinate um.4,5 In the human skin these was recently released as Tegison by therapy causes the levels of this changes produce a condition known the same manufacturer. enzyme to fall;'3 the retinoids also as phrynoderma, in which there are Besides being important in the block the induction of ornithine de- many minute follicular papules. treatment of disorders of keratiniza- carboxylase by tumour promoters.'4 Retinoic acid, inactive in the visual tion, including acne, the retinoids In the cell, proteins that bind and reproductive systems, can cor- are of great interest to oncologists retinol and retinoic acid carry these rect the abnormalities seen in the because of the possibility that they substances to the nucleus, where epithelial tissues of vitamin-A-defi- can be used to prevent and treat a they have an effect on RNA synthe- cient animals.6 variety of premalignant conditions. sis that is analogous to that of the We will now review the mechanisms steroid hormones.'5"6 This effect The development of retinoids of action, pharmacokinetics, side ef- may help explain how retinoids can fects and clinical applications of induce and maintain terminal differ- Because of the similarity between these two drugs in dermatology. entiation in malignant cell lines.'7 phrynoderma and many other skin Gap junctions are lost during ma- diseases involving abnormal keratin- Mechanisms of action lignant transformation; retinoids ization, it was at first thought that a stimulate their production and the deficiency of vitamin A might be The effects of vitamin A and synthesis of glycoproteins, both of involved in the pathogenesis of the retinoids on the skin are poorly which are important in cell commu- other diseases. Vitamin A was there- understood, but many possibilities nication, adhesion and growth.'8"'9 fore used orally in an attempt to treat diseases such as ichthyosis, Darier's disease (keratosis follicula- ris), psoriasis and even acne.78 The high dosages required, however, were associated with serious toxic effects (increased intracranial pres- p-carotene sure, with headache and irritability, as well as changes in the skin, mucous membranes and skeleton). Retinoic acid has been administered topically, mainly in the treatment of acne, but causes skin irritation; it is Vitamin A also impractical for conditions such (retinol) as Darier's disease in which continu- ous treatment of large areas of the body is required. The toxic effects of orally administered retinoic acid on CHO the central nervous system are simi- lar to those of vitamin A.9 A search for less toxic substitutes Retinal for vitamin A led to the develop- ment of the safer analogues known as retinoids. Retinoids are formed by modification of the vitamin A molecule at any one of its three COOH main components: the cyclic end group, the polar end group and the Retinoic acid polyene side chain (Fig. 2). The first retinoid to be synthesized, in 1955, was 13-cis-retinoic acid, also known as isotretinoin (Ro 4-3780). It was Fig. 1-Structures of vitamin A and related compounds. 1130 CAN MED ASSOC J, VOL. 132, MAY 15, 1985 Physiologic doses of retinoids also etretinate. Both etretinate and Ro of lipids and fibrosis seen in biopsy stimulate killer T-cell production 10-1670 are highly bound to plasma specimens.23 Swelling of the feet is and cell-mediated cytotoxicity, proteins. The half-life of each after common in children and often which may well be important in the a single oral dose is only 6 to 13 causes refusal to walk; cortical hy- treatment of cancer.20 hours, but the prolonged elimination perostosis may be seen on x-ray Retinoids thus act by enhancing after multiple dosing suggests that films. the normal differentiation and pro- there is a deep tissue compartment, In contrast to vitamin A, the liferation of epidermal tissues. Al- perhaps adipose tissue, where etreti- relatively nontoxic retinoids have though their mode of action is not nate was recently shown to accumu- few serious systemic side effects. Of fully known, control of polyamine late.2" In fact, the half-life is 80 to major importance, however, is their synthesis by inhibition of the rate- 100 days in patients receiving long- teratogenicity. The retinoids are not limiting enzyme appears to be an term therapy, and the drug is detect- mutagenic, but they do cause serious important factor. able in the blood 3 months after the fetal malformations, including end of treatment.22 Considering the major abnormalities of the central Pharmacokinetics teratogenicity of this class of drugs, nervous system, and cardiac and ear this persistence has important thera- defects.24 It is imperative that physi- Isotretinoin is rapidly absorbed peutic implications. cians be certain that their patients after oral administration, with peak are not pregnant before starting levels being reached in 2 to 3 hours. Toxic and side effects treatment with isotretinoin and that Virtually all of the drug is bound to the patients use reliable methods of albumin and is metabolized to Excessive vitamin A intake can birth control before and during ther- 4-oxo-isotretinoin. The elimination result in either acute or chronic apy and for a full month after half-lives with either single or multi- toxic effects. The most prominent therapy is stopped. Because of its ple dosing are 10 to 20 hours and 24 features of chronic hypervitaminosis long half-life etretinate is generally to 29 hours for the drug and its A are dry scaling skin, cheilitis and not recommended for women of metabolite respectively. loss of hair, followed by bone pain, childbearing potential. In spite of Etretinate is rapidly hydrolyzed in anorexia, and headache and diplopia warnings, however, 13 pregnancies the gut, liver and blood to Ro due to increased intracranial pres- in Canadian women who were using 10-1670; plasma concentrations of sure. Hepatosplenomegaly often oc- isotretinoin have been reported to this metabolite far exceed those of curs, with perisinusoidal deposition the drug's manufacturer.25 One spontaneous and eight induced abor- tions resulted. The mucocutaneous side effects of retinoids are dose-related, tolerable and reversible. Most are really ex- tensions of the drugs' actions. Reti- noids impair barrier function and enhance evaporation, the results ' Cyclic Polyene side Poa being dryness of the skin and mu- end group end group cous membranes, thirst and in- creased percutaneous absorption of other topically applied compounds. Dryness of the lips occurs in almost all patients, which makes double- blind studies virtually impossible. There can be severe cheilitis and also epistaxis from dryness of the 13-cis-retinoic acid nasal mucosa. Patients may experi- (isotretinoin) ence generalized pruritus. All these COOH changes are managed with topical lubricants, and by avoiding exposure to sunlight a patient with facial dermatitis may find improvement. Paronychia, changes in hair tex- c6OOC2 H5 ture and increased skin fragility can also occur with retinoid therapy. A E tretinate more troublesome but uncommon side effect is a dose-dependent, re- versible diffuse thinning of the hair that first appears 3 to 8 weeks after CH30 the start of therapy,26 especially with Fig. 2-Modifications of vitamin A structure yielding two synthetic retinoids now etretinate.27 used as drugs. Blepharoconjunctivitis occurs in CAN MED ASSOC J, VOL. 132, MAY 15, 1985 l1131 up to half the patients treated with levels at the start of treatment and 2 side effect is the development of isotretinoin but responds to topical to 3 and 4 to 6 weeks thereafter.3' skeletal hyperostosis, in which new antibiotic ther-apy.2 Culture of con- Only if the triglyceride concentra- bone forms in areas of ligamentous junctival swabs shows Staphylococ- tion exceeds 4.50 mmol/L at 4 to 6 attachment. This occurs in long- cus aureus in a high proportion of weeks is it necessary to continue term high-dose treatment with iso- patients treated with isotretinoin; monitoring the lipid levels. Therapy tretinoin. The first report was of this may represent secondary coloni- should be stopped if the triglyceride four patients with ichthyosis who zation of a dry, susceptible cornea. level exceeds 8.0 mmol/L, because were treated with more than 2 Isotretinoin inhibits lipid production there is a risk of pancreatitis. mg/kg daily for at least 2 years.37 in the skin and may have a similar More dramatic increases in the It is currently recommended that effect on the meibomian glands.28 triglyceride level have been seen in skeletal radiologic surveys be carried Some patients have only a subjective patients who were obese, consumed out at the start and after 6 and 12 feeling of dryness of the eyes, but excessive amounts of alcohol or had months of treatment in patients this may be so troublesome that they a family history of hyperlipidemia given high doses of isotretinoin. To cannot tolerate their contact lenses. or other risk factors.3334 Eruptive date, skeletal abnormalities have not A recently reported but probatbly xanthomas33 and pancreatitis3' may been reported with etretinate thera- not uncommon side effect is the occur. Patients at risk should be put py or in acne patients treated with development of excessive granula- on a low-fat diet and have their isotretinoin. tion tissue at the site of healing alcohol intake limited in an attempt cystic acne and adjacent to nail to prevent the triglyceride level from Effects on the central nervous plates in patients treated with iso- increasing.3' The significance of an system tretinoin and etretinate respective- elevated triglyceride level and short- ly.2930 This phenomenon seems unre- term increases in the cholesterol In the central nervous system the lated to dosage and is reversible by concentration in terms of heart dis- side effects of retinoids are rare and discontinuation of treatment. It is ease is unknown,32 but no cardiac range from mild headache to visual best managed with topical applica- complications have been reported. changes and papilledema. The syn- tions of trichloroacetic acid or silver drome of pseudotumour cerebri has nitrate or with surgical excision. Hepatic effects been reported in a small number of In addition to these side effects, patients receiving isotretinoin;3' acne may temporarily become worse Unlike retinol, the retinoids are some of them were also taking either in the first few weeks of treatment, not stored in the liver, but they are tetracycline or minocycline. It is not and the oral administration of cor- metabolized there, so the liver is a known whether this representg a ticosteroids during this period may potential site of toxic effects. The drug interaction, but it would seem be indicated. mildly abnormal results of liver prudent to avoid using these antibi- Of the two compounds, etretinate function tests sometimes seen are otics concurrently with isotretinoin. seems to cause more palmoplantar often corrected while treatment con- desquamation, thinning of the hair tinues and are reversible once it is Other toxic effects and pruritus, and isotretinoin more stopped.28 Although liver biopsy has conjunctivitis, facial scaling and shown deterioration in patients pre- A recent update on the side ef- cheilitis.27 Dryness of the skin and disposed to liver damage and receiv- fects of isotretinoin reported the mucous membranes is so strongly ing etretinate, the changes were not occurrence of hyperuricemia (twice associated with both drugs that its consistent and were not seen if the in association with symptomatic absence raises the question of pa- pretreatment biopsy had shown nor- gout), regional ileitis and, in pa- tient compliance. mal histologic features.35 Kanigs- tients with cystic acne, corneal opac- berg and DesGroseilliers36 reported ities.38 Other abnormalities that Effects on lipid metabolism a case in which a full course of seem to have had no clinical signifi- isotretinoin therapy was given des- cance include increases in the per- A mild, dose-dependent increase pite a mild but persistent elevation ipheral blood platelet count and in the serum triglyceride level, usu- of the patient's hepatic enzyme lev- total protein level and in the urine ally to between 2.25 and 4.50 els during treatment; the results of a specific gravity and leukocyte mmol/L, occurs commonly with iso- subsequent liver biopsy were normal. count.3' tretinoin therapy and less frequently Serious hepatotoxic effects, such as with etretinate therapy.27'3' It is are seen with vitamin A, have not Clinical applications rarely of clinical significance. Over been reported with the retinoids. the first 4 weeks of treatment the concentrations of low- and very-low- Musculoskeletal effects Psoriasis density lipoproteins and cholesterol increase and the level of high-densi- Arthralgias and myalgias occur in The common type of psoriasis, ty lipoprotein decreases. The levels up to 16% of patients receiving iso- psoriasis vulgaris, is characterized then stabilize, but after treatment is tretinoin for acne and are usually by erythematous plaques with a sil- stopped they return to normal with- easily managed with analgesics or very scale. This chronic disease may in 8 weeks.32 Hence, the current nonsteroidal anti-inflammatory evolve to a more severe form in recommendation is to check the lipid drugs.3' However, a more serious which an erythematous, scaling 1132 CAN MED ASSOC J, VOL. 132, MAY 15, 1985 eruption covers almost the entire Other disorders ofkeratinization against that of the p I g- body. In addition, there are various term side effects for ach p pustular forms of psoriasis, which Several other disorders of keratin- may be either localized or acute and ization, previously alnost untreata- Acne generalized, with high fever, system- ble, have responded well to treat- ic toxic effects and a poor prognosis. ment with retinoids, particuarly Vitamin A has been used in the Erythrodermic psoriasis, general- etretinate. treatment of sever acne simc the ized pustular psoriasis and pustular The ichthyoses, a group of disor- 1940s, when the similarity bdtween psoriasis of the palms and soles, all ders characterized by fish-like scal- acne comndoncs and the filr of which have been difficult to treat, ing and hyperkeratosis, with or hyperkeratosis of vitamin A defi respond particularly well to etreti- without erythema, can be treated ciency was ottct1 iuis nate therapy.3"-4 Psoriasis vulgaris, with either retinoid.&"0 The results has now boen shown to be vay however, responds less well, and al- have been especially good in lamel- effective in sever cystic. though etretinate therapy is about lar ichthyosis and epidermolytic hy- acne (Fig. 3). In 1979 and as effective as treatment with an- perkeratosis. Although few patients coworkers9 t c e ldear- thralin, the Goeckerman regimen have had complete clearing of these ingin l3of14tns with (the use of tar ointments plus ultra- disorders, their tolerance of heat and 2 mg/kg daily for 4 mths og- violet radiation of short wavelength ability to sweat has increase, and term folow-up shw that the ro- [UVB; 290 to 320 nmn) or photo- they have had a much improved missn persisted for up to 5 ycr.° chemotherapy (the use of a psoralen appearance. Similar rasult wer ained in a plus ultraviolet radiation of long In Darier's disease, an autosomal doubi-bid crss L" Sie wavelength [UVA; 320 to 400 nml, dominant condition characterized by the relea of isotrtioin for ue in also known, therefore, as PUVA a defect in the tonofilament-des- severe cystic acne 2 yes ago, mny therapy) it is unlikely to replace mosome complec that connects epi- studies and cli cal - these standard forms of treatment, thelial cells in the epidermis, frm, perience have testified to its dfec- because they have fewer side ef- greasy papules develop in seborrheic tiveness.31 fects.42 areas. These can become generalized A generally cffective r The response to etretinate is dose- and complicated by a foul odour with isotretinoin seems to be I dependent,43 and the best results are from secondary infection. Treatment mg/kg daily for 4 m ths, with a seen with daily rather than alter- was poor in the past because the scond course given if nate-day or alternate-week treat- vitamin A used was too toxic for the after a wait of at last 2 moths. ment." However, this retinoid does continuous treatment needed to pre Lower doses do not geat not seem to alter the natural history vent relapse. Isotretinoin5' and the incidence of side cffcs and of the disease, and relapses may etretinate,52 however, have both result in higher rates of relapIe." occur while maintenance treatment been shown to be effective: in one Improvement can begin after I to 2 continues, as well as when it ends. study over 85% of 98 patients months of treatment but usuall The combination of etretinate showed definite improvement in 5 to does not appear before 3 to 4 with other forms of treatment has 8 weeks.5' months. PNck and colagues" found met with more success. For example, Good results with retinoid therapy that the mean time to e when etretinate and PUVA therapy have been seen in pityriasis rubra dearing after the cad of treatnmt were combined, the number of irra- pilaris,53 porokeratosis,M4 subcorneal in 18 patients given a single cowe diation sessions required was re- pustular dermatosis" and verrucous was 6 months n ws duced by 40%, and the cumulative epidermal nevus.5'6 The retinoids better and faster on the face than on dose of UVA radiation, the factor have also been used in the more the trunk, and lsions on the ltle most related to carcinogenesis, was severe forms of keratosis almris et may require higher dosag reduced by two thirds.45 Etretinate plantaris,"5 which interfere with Although a recet report has sug- has similar advantages when used daily work or walking. gested using n cass of with UVB radiation.'" Lichen planus is generally fairly inflammatory n c ac wc The combination of etretinate and benign and often remits spontae- extcnsive sn,3 the dr is cr- anthralin has given better results ously. However, chronic lichen pla- rently aveonly for tretna than either agent alone,47 and the nus of the skin and mucous mem- of sv ol acme me- combination of etretinate in low branes can be severe, pinflul and sponsive to aonventioal tl , daily doses (0.50 to 0.66 mg/kg) and difficult to treat. Etretinate therapy which shoul include a full tl of corticosteroids administered topical- has been successful in over 75% of systemic antibiotic tpy. ly has given good results with few patients, with the best results occur- In acne, tretment with thc effec- side effects,48 thus proving to be a ring in the erosive-atrophic form of tive retinoi, isrENoin,der-ases good form of treatment for outpa- the disease.-n sebum productio by 80% to 90% in tients with mild to moderate psoria- In the keratinizing disorders, reti- 8 week.2 There is a co o sis. Adding etretinate therapy to noids seem to suppress but not cor- reduction in the sie of thecsea- PUVA, UVB or anthralin treatment rect the discase, and maintenance ceous ands.3 After treat is often effective in patients who treatment with a reduced dseage is ends, th.o sebum have become resistant to a single necessary. The probability of clinical tend to return to norma ecn wile form of therapy. improvement must be weighed clinical Son pst alo, CAN MED ASSOC J, VOL 132, MAY 15, 19S5 lm a few m io as cancr apairedin rats fed a vita- and was found to induce differenta- hae -od wdxt there bhing min-A-deficient diet.'7 Further tion of py locyas in a patient a coTemdiing clini calponse.""2 sti, guinea pigs, showed that with acute promyeocytic leuke- Therfo other such a diet defrient in vitamin A resulted mi.'9 Preliminary fnding suggest a ali of keratiization or in heratinization, squamous that isotretinoin may be useful in inhibiion ofthe growth of Pro- metaplasia and tumour formation in adjuvant treatment of squamous epi- pp&te am, are being the epithelial tissues of the larynx, thelial malignant diseases.U) considered. Isotretinoin's anti- trachea, lungs, salivary glands, nflnuntory effects may be in- stomach and bladder." CeucIim voled Itoo.'5 Experimentally, vitamin A has Isotretinoi us effective in related prevented chemically induced lung The retinoids are drugs of great dis_rd ansa! -s to be the treat- cancer," and mtiic acid has potential in dermatology and oncolo- mat of dcic in gam-negtive caused dose-dependent regression of gy. They are defitely effective in foliculitis,3A'M a coication of pro- chemically induced skin papillo- severe acne, certain forms of psoria- longe anibiotic tratment for acne. mas.7" A high intake of vitamin A in sis and other disorders of keratiniza- In is dider the anrr nares the diet has also been associated tion - all diseases for which there become heavily oozd with with a decreased incidence of lung has been no satisfactory treatment. gramnegative bactria, which then cancer in humans.7 In psoriasis vulgaris etretinate is case ser in tio of the Over the past decade retinoids very useful in combination therapy, skin and are difficult to eradicate. have been used in the prevention but further clinical trials and better 1oretnoi fis y effective in acne and treatment of vanous premalig- knowledge of the long-term side ef- _ , which re like acne nant and malignant skin conditions fects will determine its exact role. vgari3' Ih the teatmet of hi- in humans. In three patients with There is evidence that the reti- drdenits suppurativa the drug is a multiple basal-cel carcinomas17 and noids are of value in the prevention useladj , bat it cannot cause another with multiple keratoacan- and, to a lesser extent, the treatment reoluion of the dieas onc under- thomas72 isotretinoin had varied ef- of premalignant and malignant con- unning sinus tracts have forme; fects on existing tumours but pre- ditions of skin and epithelial tissue. Shalita and auoCiaes3' sgested a vented the development of new le- In addition, retinoids with greater 4- to 5-m th e ofisOte sions until treatment was discontin- specificity for target organs and teray in addition to treatment ued. Although the major role of fewer systemic side effects are being wit aniot, intrasional appli- retinoids soems to be preventive, developed by means of modification cation of s and surical exci- etretinate has been used with some of the basic structures.-' Whether a sio when necsr. success in the treatment of actinic daily regimen could decrease the Meratoses,73 warts,74 leukoplakia,75 incidence of cancer in high-risk pa- epidermodysplasia verruciformis7' tients awaits the outcome of large and cutaneous T-ell lymphoma clinical trials. Tle fascinating sty of retinoids (mycosis fungoides).7 Isotretinoin ad cancer bgan in the 1920s, has also been of benefit in patients We thank Dr. W.C. McMurray, Depart- when a high i1 nc of gastric with cutaneous T-ell lymphoma7 ment of Biochemistry, University of Western Ontario, for his help in the preparation of this paper. Refedces

1. Orten JM, Neuhaus OW: Human Bio-

.... .l- chemistry, 10th ed. Mosby, St Louis, 1982: 735-746 .5 i- l : 2. Dowling JE, Wald G: Vitamin A defli- ciency and night blindness. Proc Nail Acad Sci USA 1958; 44: 648-661 3. Thompson JN, Howell JM, Pitt GAJ: Vitamin A and reproduction in rats. Proc R Soc LondIBiolI 1964; 159: 510-535 4. Wolbach SB. Howe PR: Tissue changes following deprivation of fat-sduble A vitamin. J Exp Med 1925; 42: 753-778 5. Brn HA, Elias JJ, Pickett PB et al: The influenc of vitamin A-on the qidermis. Am J Anat 1955; 96: 419-447 6. Zile M. DeLuca HF: Retinoic acid: some ..& _-h* w se* mm .ew(kt d wmo aspects of growth-promoting activity in the albino rat. J Nuir 1968; 94:302-308 7. Porter A>. Vitamin A in somecougeui- tal anomalies of the sktin. Br J Dermatol 1951; 63: 123-127 8. Peckc SM, Chargin 1, Sobotkca H: Kera- 11u CAN MED ASSOC J. VOL. 132, MAY 15, 1985 tosis follicularis (Darier's disease), a vita- Dermatol 1982; 6: 675-682 dinical evaluation of the effects of an min A deficiency disease. Arch Dermatol 28. Toxicity of oral retinoid therapy (panel aromatic retinoid (Tegison), cm Syphilol 1941; 43: 223-229 discussion). Ibid: 688-691 of retinoid and PUVA, and PUVA aone 9. Stuttgen G: Oral vitamin A acid therapy. 29. Exner JH, Dahod S, Pochi PE: Pyogenic in severe sis Br JlDernatl 1981; Acta Derm Venereol 1975; 55 (suppl 74): granuloma-like acne lesions during iso- 104: 325-332 174-179 tretinoin therapy. Arch Dermatol 1983; 46. Orfanos CE, Ste GK, Pllman H 10. Russell DH, Durie GM: Polyamines as 119: 808-811 et al: Oal retinoid and UVB tion: a Biochemical Markers of Normal and 30. Campbell JP, Grekin RC, Ellis CN et al: ncw, alternative treatment for po Malignant Growth, Raven, New York, Retinoid therapy is associated with ex- on an out-paticnt basis Aa D Vea- 1978 cess granulation tissue response. J Am ereol (Stockh) 1979; 59:241-244 11. Lowe NJ, Kaplan RP, Breeding J: Etreti- Acad Dermatol 1983; 9: 708-713 47. Orfanos CE, Goerz G: Oalc Psoriasis1 nate treatment for psoriasis inhibits epi- 31. Shalita AR, Cunningham WJ, Leyden Therapie mit einem nenen atisAh dermal ornithine decarboxylase. J Am JL et al: Isotretinoin treatment of acne Rctinoid. Dsck Med Wocheascr 1918; Acad Dermatol 1982; 6: 697-698 and related disorders: an update. Ibid: 103:195-199 12. O'Brien TG: The induction of ornithine 629-638 48. Polano MK, Van der Rhoe HJ, Van da decarboxylase as an early, possibly oblig- 32. Zech LA, Gross EG, Peck GL et al: Schroeff JG: A three-year follow-np atory, event in mouse skin carcinogenesis. Changes in plasma cholesterol and tri- study of psoriasis patients treated with Cancer Res 1976; 36: 2644-2653 glyceride levels after treatment with oral low dosages of etrctinate orally and cor- 13. Kaplan RP, Russell DH, Lowe NJ: isotretinoin. Arch Dermatol 1983; 119: ticosteod topically. Aeta Derm VKa/ol Etretinate therapy for psoriasis: clinical 987-993 (Stockh) 1982; 62: 361-364 responses, remission times, epidermal 33. Dicken CH, Connolly SM: Eruptive xan- 49. Vigiogli PA: Therapentic evaluation of DNA and polyamine responses. J Am thomas associated with isotretinoin thc oral retinoid .Ro 10-9359 in seeral Acad Dermatol 1983; 8: 95-102 (13-cis-retinoic acid). Arch Dermatol non-psoriatic dermatoses. Br J Denuatol 14. Boutwell RK: Retinoids and inhibition of 1980; 116: 951-952 1980, 103: 483-487 ornithine decarboxylase activity. J Am 34. Gollnick H: Elevated levels of triglycer- 50. Baden HP, Buxam MM, Weinstn GD Acad Dermatol 1982; 6: 796-798 ides in patients with skin disease treated ct al: Treatmcnt of ichthyasis with is- 15. Ong DE, Chytil F: Retinoic acid-binding with oral aromatic retinoid. The signifi- tretinoin. J Am Acad Dermatol 1982; 6: protein in rat tissue: partial purification cance of risk factors. In Orfanos CE, 716-720 and comparison to rat tissue retinol-bind- Braun-Falco 0, Farber EM et al (eds): 51. Dickcn CH, Baucr EA, Hazen PG et al- ing protein. J Biol Chem 1975; 250: Retinoids - Advances in Basic Research lsotretinoin trcatment of Darie's disease 6113-6117 and Therapy, Springer-Verlag, New Ibid: 721-726 16. Jetten AM, Jetten MER: Possible role of York, 1981: 503-505 52. Christinsen JV, Holm P. Moller R et al: retinoic acid binding protein in retinoid 35. Glazer SD, Roenigk HH, Yokoo H et al: Treatment of dyskcratoss foliculris stimulation of embryonal carcinoma cell A study of potential hepatotoxicity of Darier with the retinoic acid deia-tive differentiation. Nature 1979; 278: 180- etretinate used in the treatment of psori- Ro 10-9359 (Tegison). Dermatokogk 182 asis. J Am Acad Dermatol 1982; 6: 683- 1982; 165:204-207 17. Peck GL, Gross EG, Butkus D et al: 687 53. Gokismith LA, Weinrich AE, Shupack J: Chemoprevention of basal cell carcinoma 36. Kanigsberg N, DesGroseilliers J-P Use Pityriasis rubra pilaris response to with isotretinoin. J Am Acad Dermatol of 13-cis-retinoic acid in cystic acne. Can 13-cis-rctinoic acid (isotrtiin). J Am 1982; 6: 815-823 Med Assoc J 1983; 129: 224, 228 Acad Dermatol 1982; 6: 710-715 18. Prutkin L: Mucous metaplasia and gap 37. Pittsley RA, Yoder FW: Retinoid hyper- 54. Kariniemi AL, Stubb S, Lassus A: Trcat- junctions in the vitamin A acid-treated ostosis. N Engl J Med 1983; 308: 1012- ment of disseminated superficial actinic skin tumor, keratoacanthoma. Cancer 1014 porokceratosis with a new aromatic reti- Res 1975; 35: 364-369 38. Adverse effects with isotretinoin. FDA noid (Ro 10-9359). Br J Denaol 1980; 19. DeLuca LM, Sasak W, Adamo S et al: Drug Bull 1983; 13: 21-23 102:213-214 Retinoid metabolism and mode of action. 39. Lassus A: Systemic treatment of psoria- 55. Folkers E, Tafelkruyer I: Subloeal Environ Health Perspect 1980; 35: 147- sis with an oral retinoic acid derivative pustular dermatosis (Sneddon-Wilkison 152 (Ro 10-9359). Br J Dermatol 1980, 102: disease) - therapcutic Br J 20. Lotan R: Effects of vitamin A and its 195-202 Dermatol 1978; 98: 681 -684 analogs (retinoids) on normal and neo- 40. Pettit JH: Oral retinoid for psoriasis. A 56. Happle R, Kastrup W, Macher E: Sys- plastic cells. Biochim Biophys Acta 1980; report of a double blind study. Acta temic rctinoid therapy of systematized 605: 33-91 Derm Venereol (Suppli (Stockh) 1979; vcrrucous epidermal ncvus. Der- 21. Rollman 0, Vahlquist A: Retinoid con- 59: 133-136 matologica 1977; 155: 200-205 centrations in skin, serum and adipose 41. Lassus A, Lauharanta J, Juvakoski T et 57. Bergfeld WF, Derbes VJ, Elias PM et al: tissue of patients treated with etretinate. al: Efficacy of etretinate (Tegison) in The treatment of kcratosis palmaris et Br J Dermatol 1983; 109: 439-447 clearing and prevention of relapse of plantaris with isotretinoin. J Am Aad 22. BrazzelL RK, Colburn WA: Pharmacoki- palmoplantar pustulosis. Dermatologica Dermatol 1982; 6: 727-731 netics of the retinoids isotretinoin and 1983; 166: 215-217 58. Hersle K, Mobacken H, Slobers K a al: etretinate. J Am Acad Dermatol 1982; 6: 42. Cram DL: Psoriasis: current advances in Severe oral lichen planus: trcatmcnt with 643-651 etiology and treatment. J Am Acad Der- an aromatic retinoid (etretinate). Br J 23. Russell RM, Boyer JL, Bagheri SA et al: matol 1981; 4: 1-14 Dermatol 1982; 106: 77-80 Hepatic injury from chronic hypervita- 43. Fredriksson T, Pettersson V: Severe 59. Peck GL, Olsen TG, Yoder FW ct al: minosis A resulting in portal hyperten- psoriasis - oral therapy with a new Prolonged remissions of cystic and con- sion and ascites. N Engl J Med 1974; retinoid. Dermatologica 1978; 157: 238- globate acne with 13-cis-retinoic acid. N 291: 435-440 244 Engl J Med 1979; 300: 329-333 24. Benke PJ: The isotretinoin teratogen syn- 44. Dominguez-Soto L, Hojyo-Tomoka HT, 60. Isotretinoin (Accutane) for acnc. Med drome. JAMA 1984; 251: 3267-3269 Armas JJ: Intermittent dose schedules of Lett Drugs Ther 1982; 24: 79-81 25. Zarowny DP: Accutane' Roche®: risk retinoids (Ro 10-9359) for long-term 61. Peck GL, Olsen TG, Butkus D ct al: of teratogenic effects [C]. Can Med follow-up on psoriasis (preliminary re- Isotretinoin vcrsus placebo in the treat- Assoc J 1984; 131: 273 port). In Orfanos CE, Braun-Falco 0, ment of cystic acne. J Am Acad Der- 26. Orfanos CE: Oral retinoids - present Farber EM et al (eds): Retinoids - matol 1982; 6: 735-745 status. Br J Dermatol 1980; 103: 473- Advances in Basic Research and Thera- 62. Goldstein JA, Socha-Szott A.- Thosn 481 py, Springer-Verlag, New York, 1981: RJ et al: Comparative effect of iso- 27. Windhorst DB, Nigra T: General clinical 175-183 tretinoin and etretinate on acne and seba- toxicology of oral retinoids. J Am Acad 45. Lauharanta J, Juvakoski T, Lassus A: A ceous gland secretion. Ibid: 760-765 CAN MED ASSOC J, VOL. 132, MAY 15, 1985 1135 63. Landthaler M, Kummermehr J, Wagner A et al: Inhibitory effects of 13-cis-retinoic acid on human sebaceous EASY D TAKE glands. Arch Dermatol Res 1980; 269: 297-309 0 64. Stewart ME, Benoit AM, Stranieri AM et al: Effect of oral 13-cis-retinoic acid at three dose levels on sustainable rates of sebum secretion and on acne. J Am Acad (enternc-coated ketoprofen) Dermatol 1983; 8: 532-538 65. Plewig G, Wagner A: Anti-inflammatory effects of 13-cis-retinoic acid. An in vivo PRESCRIBING INFORMATION apy because of these local reactions. Central Ner- study. Arch Dermatol Res 1981; 270: vous S7stem: headache, fatigue, dizziness, tension, 89-94 INERAPEUTIC CaIfICTION: anxiety, depression and drowsiness. Skin: rashes, Anti-inflammatory agent with analgesic pruritus, flushing, excessive perspiration and loss 66. Plewig G, Nikolowski J, Wolff HH: of hair. Alergic: urticaria, angioedema and asth- Action of isotretinoin in acne rosacea and INDICTONS: Tiatment of rheumatoid ar- ma. Cardiovascular: mild peripheral edema, pal- gram-negative folliculitis. J Am Acad and osteoarthritis. pitation and bruising. Auditory system: tinnitus. tlritis, ankyloing spondylitis Mouth: ulcers, sore tongue, inflammation of the Dermatol 1982; 6: 766-785 CNAINDIC TIONS: Active peptic ulcers mouth and gums. 67. Fujimaki Y: Formation of carcinoma in or actien disease of the gastroin- Laboratory TDst: Abnormal alkaline phospha- albino rats fed on deficient diets. J Can- testunal tract; s esshould not be used in tase, lactic dehydrogenase, glutamic oxaloacetic cer Res 1926; 10: 469-477 with any inflanmatory lesom of retum transaminase and blood urea nitrogen values were or anus, or a recent hiuory of rectal or anal found in some patients receiving Orudis therapy. 68. Wolbach SB, Howe PR: Vitamin A defi- The abnormalities did not lead to discontinua- ciency in guinea pig. Arch Pathol Lab IHypesseitivity to the drug- Because of the exis- tion of treatment and, in some cases, returned to Med 1928; 5: 239-253 tence of cim .i,t Orudis should not be normal while the drug was continued. There have give to patiens in whom actyli id and been sporadic reports of decreased hematocrit and 69. Saffioti U, Montesano R, Sallakumar othr no-steroidal anti-inflammatory drugs in- hemoglobin values without progressive deteriora- AR et al: Experimental cancer of the duce symptoms of asthma, rhinitis or urticaria. tion on prolonged administration of the drug. lung. Inhibition by vitamin A of the WARNINGS: In pregnancy - Safety in preg- SYMP1'OMS AND TREATMENT OF OVER- induction of tracheobronchial squamous nant or nung wmmen has not been determined DOSAGE: Sympm.: At this time, no overdosage metaplasia and squamous cell tumors. and thdreke is not r_c ed. Pregnant rats has been reported. Treatment: Administer gas- Cancer 1967; 20: 857-864 whorecei ketopwrokn 6 and 9 mg/kg/day p-o. tric lavage or an emetic and treat symptomatical- fnun day 15 of gesation. showed dystocia and ly: compensate for dehydration, monitor urinary 70. Bollag W: Therapy of chemically in- inrasd pup motlity- excretion and correct acidosis if present. duced skin tumors of mice with vitamin In childre - The conditions for safe and ef- DOSAGE AND ADMINISTRATION: A palmitate and vitamin A acid. Experi- fectiwe ue in children under 12 years of age have Adults: Oral: The usual dosage for enteric-coated entia 1971; 27: 90-92 not been esablshed and the dnrg is therefore not tablets or capsules is 150 to 200 mg per day in 3 r m d in this ae group or 4 divided doses. 71. Bjelke E: Dietary vitamin A and human Orudis-E tablets provide an alternative presenta- lung cancer. Int J Cancer 1975; 15: 561- PRECAUIMONS: Use with caution in patients 565 with a hisory of g inflammatory tion for those who may prefer this dosage form. disoders or uleiration. No difference in toxicity profile was documented. 72. Haydey RP, Reed ML, Dzubow LM et Rectal: Orudis suppositories offer an alternative Orudis tabklt capsul and suppositories can route of administration for those patients who al: Treatment of keratoacanthomas with caine upper g is toxcity, including prefer it. Administer one suppository morning and oral 13-cis-retinoic acid. N Engl J Med evening or one suppository at bedtime sup- 1980; 303: 560-562 Supprinsories should be n with caution to pa- plemented as needed by divided oral doses. The 73. tients with any rectal or anal pathology. total daily dose of Orudis (capsules, tablets and Moriarty M, Dunn J, Darragh A et al: The drug should be gnen under close medical suppositories) shold not exceed 200 mg. Etretinate in treatment of actinic kerato- Se in paients with impaired liver or When the patient's response warrants it, the dose sis. A double-blind crossover study. Lan- may be decreased to the minimum effective lev- cet 1982; 1: 364-365 Onudis may mask signs of infectious disase This el. In severe cases, during a flare-up of rheumat- 74. Fritsch P: Oral retinoids in dermatology. should be kept in mind so that any delay in diag- ic activity or if a satisfactory response cannot be nosing and tTeating infection may be avoided. obtained with the lower dose, a daily dosage in Int J Dermatol 1981; 20: 314-329 Use in ra Oru- excess of 200 mg may be used. However, a dose 75. Koch HF: Effect of retinoids on precan- pasims saig ulants: of 300 mg per day should not be exceeded. dis has been shown to depres platelet aggrega- cerous lesions of oral mucosa. In Orfanos tion in anumalis hwever, in twenty patients Children: Orudis is not indicated in children un- CE, Braun-Falco 0, Farber EM et al u goig thrapywith counsarin, Orudis failed der 12 years of age because clinical experience in to deuonsrate p of anti-coagulant ef- this goup of patients is insufficient. (eds): Retinoids: Advances in Basic Re- feat Neverthelw caution is when Availability: Capsules of 50 mg, bottles of 100 search and Therapy, Springer-Verlag, Orudis is given concomitantly with anti- and 500. New York, 1981: 307-312 os-xs Tablets (enteric-coated) of 50 mg, bottles of 100 76. Jablonska S, Obalek S, Wolska H et al: The presence of Orudis and its metabolites in and 500. Ro 10-9359 in epidermodysplasia ver- ume h been shown to inerferewith certain tests Suppositories of 100 mg, boxes of 30. Store be- which are used to dtect albumin, bile salts, low 305C. ruciformis. Preliminary report. Ibid: 17-k troidsk or 17-hyoxorroids in 401-405 urine and which rely upon acid precipitation as Product information as of Jan. 7, 1983. an end point or upon color reactions of carbonyl Product Monograph available on request. 77. Claudy AL, Rouchouse B, Boucheron S groqs. No infne ws seen in the tests for et al: Treatment of cutaneous lymphoma ptinuria using Albustix, HemaCombistix or Referen : with etretinate. Br J Dermatol 1983; 109: Lb Reaget Strips. 1. Milbr,Fabender, H.,etal., X V Int. Congr Rheumatol-, Paris, 1981. 49-56 ADVERSE REACTIONS: Gastro-intestial: 2. Willans, M.J., et al., Curr Theer Res., 78. Kessler JF, Meyskens FL Jr, Levine N et they wer the most frequently observed and were 23,1,35, 1979. al: Treatment of cutaneous T-cell lym- seen in apprxmately 22% of patients. Ulcera- 3. Russel, A.S., et al., Cur Ther Res, 33,2, tion and a l bleeding have been noted 1983. phoma (mycosis fungoides) with ina ewpnis(appoxrn 0.8%). Other ad- 4. Vrbeeck, R.K., et al., Ckinical Pharnacoki- 13-cis-retinoic acid. Lancet 1983; 1: vee reactin i order of decreasing frequency netics of Non-Steroidal Anti-Inflammatory 1345-1347 were: n pa, nausea, constipation, Druga 8:297-331, 1983. vomiting, dyspepsia and flatulence, diarrhea, 5. CaillH, G., 5th Scapal Congress ofRheuma- 79. Flynn PJ, Miller WJ, Weisdorf DJ et al: anorexia and bad taste in mouth. Rectal adminis- tology, Bangkok, 1984. Retinoic acid treatment of acute promye- tration was asocated with a lower incidence of 6. Greenblatt, D.J., et al., The New England locytic leukemia: in vitro and in vivo uppeg t reaction (12%) with the e- Journal ofMedicine, lb'. 306, No. 18, 1083, observations. Blood ceptno of ulceration, the incidence ofwhich was 1982. 1983; 62: 1211-1217 the sane. 80. Meyskens FL Jr: Studies of retinoids in Hlowever anorectal reactions presenting as local the prevention and treatment of cancer. J pain, burning, pruritus, tenesnus and rare in- Rhone-Pbulenc Pharma Inc. 8580 Esplanade Am Acad Dermatol 1982; 6: 824-827 stances of rectal bklding occurred in 16.5% of I,HOEPOILEENr Montreal, Quebec PA subjects 5% of patients discontinued rectal ther- mPP 81. Moon RC, McCormick DL: Inhibition of Authorized user chemical carcinogenesis by retinoids. Ibid: 809-814 1136 CAN MED ASSOC J, VOL. 132, MAY 15, 1985