An Overview of the Retinoids

ALAN S. BOYD, M.D. Lubbock, Texas

The retinoids, a group of compounds consisting

of vitamin A and its derivatives, have been the sub-
ject of intense investigation over the past 30 years.
T he retinoids constitute a class of pharmacologic
agents made up of vitamin A (retinal), vitamin A
derivatives, and closely related compounds called the
These molecules have shown beneficial effects in arotinoids. All these molecules possess vitamin A ac-
the areas of acne, psoriasis, neoplastic processes tivity to one degree or another. Clinical use of the
and, most recently, reversal of extrinsically aged retinoids have demonstrated their effectiveness in ac-
shin. Additional retinoids are currently under de- neiform eruptions, disorders of keratinization; and ne-
velopment. Adverse reactions to these drugs in- oplasia. Their use is expanding and newer derivatives
clude mucocutaneous irritation, hyperlipidemia, will undoubtedly be forthcoming. Practicing physi-
and profound teratogenicity. Appropriate patient cians should be aware of this class of compounds and
selection is imperative before beginning therapy their potential benefits to appropriate patients.
with these medications. An overview of retinoid
metabolism and the currently available compounds HISTORICAL BACKGROUND
is presented. The newest class of retinoids, the aro- In 1949, Straumfjord [l] first reported the success-
tinoids, is also discussed. ful therapy of acne vulgaris in 79 of 100 patients treat-
ed daily with 100,000 IU of vitamin A. Other investiga-
tors [2], however, were not as impressed and noted
significant side effects in patients ingesting large
amounts of the drug. Topical tretinoin (trans-retinoic
acid; Retin-A) was investigated in the early 1960s for
therapy of basal cell carcinomas, actinic keratoses, and
seborrheic warts [3]. It was not until the landmark
study by Kligman and co-workers [4] in 1969 that tre-
tinoin was shown to be an effective topical therapy for
acne vulgaris. When given orally, this drug demon-
strated a significant degree of systemic toxicity, and
enthusiasm for this method of administration waned
PI*
Retinoids with fewer deleterious side effects and
more focused therapeutic activity were clearly needed,
and extensive research was begun on synthetic ana-
logues of vitamin A. To date, more than 1,500 different
compounds have been developed and biologically test-
ed [6]. In the early 197Os, one of these compounds,
isotretinoin (13-cis-retinoic acid; Accutane) was
shown to be very effective in treating acne vulgaris [7].
This medication has recently been shown to reduce
the severity of acne when applied topically as well [B].
Etretinate (Ro 10-9359; Tegison) has been the most
recent retinoid released for use in the United States.
Synthesized in 1972, it has been available in Europe
for several years. Its predominant uses include the
treatment of psoriasis and disorders of keratinization
PI.
Acitretin (Ro 10-1670) is currently undergoing clini-
cal evaluation. This compound is the principal metab-
olite of etretinate but has the advantage of a signifi-
cantly shorter half-life. Recent clinical trials have
shown it to have a beneficial effect in the therapy of
psoriasis [lo].
METABOLISM
Vitamin A (retinol), one of the fat-soluble vitamins,

. .
From the Department of Dermatology, School of Medicine, Texas Tech is found principally in animal tissues and products. It
University Health SciencesCenter, Lubbock, Texas. This workwas support- is an essential factor in physiologic growth, visual
ed in part by Glaxo Pharmaceuticals. Requests for reprints should be ad-
dressed to Alan S. Boyd, M.D., Department of Dermatology, School of function, epithelial cell differentiation, and reproduc-
Medicine, Texas Tech Unrversity Health Sciences Center, Lubbock, Texas tion [ll]. Most vitamin A is ingested as retinyl esters,
79430. Manuscript submitted November 11,1988. and accepted in revised the storage form of retinol. Within the intestinal lu-
men, these esters are hydrolyzed to form retinol and

568 May 1989 The American Journal of Medicine Volume 86

 OVERVIEW OF THE RETINOIDS / BOYD

are absorbed, Similarly, beta-carotene and other di- decarboxylase has been shown to be intimately associ-
etary carotenoids may be biochemically modified to ated with the hyperproliferative lesions of psoriasis.
form retinol intraluminally [12]. Etretinate inhibits this enzyme and is believed to ex-
Once inside the blood stream, vitamin A is trans- ert its antipsoriatic effect by blocking the physiologic
ported bound to retinol-binding protein (RBP), a function of the protein [26]. Retinoids are also modifi-
polypeptide produced by the liver. The synthesis of ers of%the immune system. Neutrophils and eosino-
this protein is influenced by plasma retinol-RBP con- phils are inhibited in their migrations into the epider-
centrations [II]. After hepatic uptake, excess vitamin mis [27], and some investigators [27,28] believe that
A is stored as the retinyl ester [ll-131. Standard reti- these compounds have anti-inflammatory properties.
no1 plasma levels range from 20 to 50 pg/dL [12]. In summary, the retinoids are believed to exert their
Trans-retinoic acid, a metabolite of retinol, is a natu- influences at the level of the nuclear DNA. Evidence of
rally occurring retinoid and may be found in a variety altered gene expression is mounting as currently the
of tissues [12], including normal human blood [14]. production of nearly 40 proteins is known to be affect-
Retinoic acid circulates within the vasculature bound ed by the retinoids [25].
to albumin [15]. The adverse effects of excessive vitamin A ingestion
Etretinate has been extensively evaluated biochem- have been well known since their description in arctic
ically and is perhaps the most well-known synthetic explorers who had recently ingested raw polar bear
retinoid from a metabolic standpoint. Etretinate is livers. An inclusive work on the manifestations of hy-
transported intravascularly bound to lipoproteins pervitaminosis A has been published by Silverman et
and, to a smaller degree, to prealbumin [16]. Unlike al [12]. Adults who have acutely ingested large
retinol, this molecule is stored primarily in adipose amounts of vitamin A frequently experience fatigue,
tissue [17]. Glucuronidation of the parent compound malaise, anorexia, and headaches. More chronic symp-
takes place within the liver, and the newly conjugated toms include dry skin, fragile nails, cheilitis, epistaxis,
etretinate-glucuronide is excreted in the bile. A frac- weight loss, and bone and joint pain. Male patients
tion of these retinoid-glucuronide molecules are reab- may also complain of impotence. Pseudotumor cere-
sorbed in an enterohepatic-like fashion [ 181. After oral bri, although rare, may also be seen.
administration, etretinate is quickly metabolized to In children, hypervitaminosis A is most often the
acitretin (Ro lo-1670), the carboxylic acid metabolite result of well-intentioned parents who supplement
of etretinate [16]. The half-life of this retinoid (etre- their children’s diet with vitamins to an excessive de-
tinate) is unusually long (80 days), and small concen- gree. In this population, bone pain is the most preva-
trations of the drug have been detected in serum great- lent symptom of toxic retinol blood levels. Additional
er than two years after stopping the medication [19]. clinical manifestations include failure to thrive, ane-
The principal metabolite of etretinate, acitretin, has mia, poor appetite, and hepatosplenomegaly.
recently come under study as a potentially therapeutic The side effects from synthetic retinoid ingestion
retinoid, principally because of its considerably are similar to those seen with the parent compound.
shorter half-life of 50 hours. Acitretin is hydrophilic Additionally, elevation of serum lipids (particularly
(not lipophilic as is etretinate), and consequently it is triglycerides) [29], hepatic enzyme changes [30], and
not stored in adipose tissue [20]. This retinoid binds skeletal hyperostoses [31] are seen in patients under-
predominantly to prealbumin and to a lesser extent to going retinoid therapy. Adverse effects specific to cer-
lipoproteins [21]. tain retinol derivatives will be discussed under the
appropriate headings.
MECHAi’JlSM OF ACTION AND TOXICITIES
The exact mechanism by which vitamin A and the TERATOGENICIN
retinoids exert their pathophysiologic effects is un- Vitamin A and its derivatives are well-known, po-
known. Many investigators consider them to have hor- tent teratogens [32]. In addition to their embryopathic
mone or hormone-like properties. A cystosolic retinol- effects [33], these medications also lead to spontane-
binding protein has been described [22], and it is ous abortion in about one third of exposed pregnancies
known that retinoids are transported to the nucleus [34]. Lammar and co-workers (331 analyzed 154 preg-
bound to this polypeptide [23]. Increased cell turn- nancies in which there had been fetal exposure to iso-
over, protein synthesis [24], and cellular differentia- tretinoin. They described a select group of fetal abnor-
tion [25] have been associated with these binding pro- malities, including central nervous system, cardiac,
teins. and craniofacial malformations. Forty-six percent of
A prominent hypothesis regarding retinoid action the pregnancies taken to delivery resulted in the birth
maintains that these compounds influence gene ex- of a child with some abnormality. Of the 21 infants
pression at the level of the nuclear DNA 1251. In this born with major malformations, three were stillborn
model, the molecules interact with regions of the DNA and nine died after birth. More than 60 different hu-
and alter their gene sequence transcription. RNA man birth defects have been reported to be associated
polymerase affinity for the affected promoter site is with the use of isotretinoin during pregnancy and
disturbed, and transcriptional induction or repression more than 60,000 women of child-bearing potential are
ensues. An additional possibility is that the retinoids treated yearly with this drug [35]. The Food and Drug
interact with the plasma membrane and produce a Administration estimates that as many as 1,000 cases
“second messenger” that mediates their influences on of congenital deformity may be secondary to intra-
gene expression. uterine contact with isotretinoin. Similar teratogenic
Retinoids have been extensively utilized in the ther- effects have been noted with the other widely used
apy of neoplastic and hyperproliferative dermatoses, systemic retinoid, etretinate [Zl]. Topical application
most notably psoriasis. They are known to inhibit ke- of the retinoids is not believed to be associated with
ratinization and alter cell maturation [ll]. Ornithine birth defects.

May 1989 The American Journal of Medicine Volume 86 569

 OVERVIEW OF THE RETINOIDS / BOYD

-
that the patient understand in no uncertain terms the
Retid consequences surrounding possible fetal exposure to
(Vitamin A) that compound and all options available to her should
that occur.

Trerinoin
TRETINOIN
(tram-retinoic acid; Tretinoin (trans-retinoic acid) was one of the first
R&n-A@)
synthetic retinoids produced and represents the prod-
uct of chemical manipulation of the polar end group of
Isotretinoin vitamin A (Figure 1). Oral preparations have been
(134s+2*inoic
ACCUtNleO)
acid:
used in the treatment of dermal neoplasms and hyper-
keratotic conditions [5]. Considerable toxicity, how-
ever, was a frequent side effect and currently only the
topical form of this drug (Retin-A) is available.
The landmark paper by Kligman et al [4] demon-
strating the efficacy of topical tretinoin in the therapy
of acne vulgaris disclosed a powerful new tool with
which to combat this disorder. Tretinoin application
Acitretin was shown to loosen the horny cells within the follicu-
(Ra 10.1670)
lar canal. This keratolytic effect on abnormal desqua-
mation is believed to be responsible for the therapeu-
tic effect of this medication. Bazzano and co-workers
[36] investigated topical retinoic acid 0.025% alone
and in combination with topical minoxidilO.5% in the
treatment of androgenetic alopecia. Modest hair re-
growth was demonstrated.
CMlH Ro 13-7410
Recently, the use of this drug in the treatment of
extrinsically aged skin has been examined. An initial
investigation by Kligman et al [37] demonstrated his-
tologic changes in tretoin-treated areas. Specifically,
these investigators noted a partial reversal of chronic
Figure 1. Chemical characteristics of the retinoids. ultraviolet exposure-induced structural damage in the
dermis of patients treated with 0.05% tretinoin cream.
Weiss et al [38] performed the first purely clinical
Recommendations for the systemic use of these evaluation of topical tretinoin in the therapy of pho-
medications in women of child-bearing age are differ- toaged skin. In this vehicle-controlled, double-blind
ent for each retinoid. Isotretinoin has a relatively short study, 0.1% tretinoin cream was applied nightly for 16
half-life. Birth control must be continued for at least weeks to the face and dorsal forearms. At the conclu-
one month after discontinuing this drug or until after a sion of the treatment period, 14 of 15 patients who had
normal menstrual period. Etretinate has been detect- been given the active ingredient demonstrated evi-
ed in serum samples two years after the drug has been dence of improvement in their facial wrinkling. Long-
stopped. In women treated with etretinate, pregnancy term effects of this therapy, whether beneficial or det-
should be prevented for at least 24 months posttreat- rimental, are currently unknown. Topical tretinoin is
ment and preferably longer if possible. Acitretin, a clearly effective in augmenting repair of ultraviolet-
metabolite of etretinate, has a significantly shorter damaged connective tissue in hairless mice [39]. In
serum half-life than its parent compound. Pregnancy humans, histologic changes associated with use of this
prevention recommendations for this medication will drug include new collagen formation, eradication of
likely approximate those of isotretinoin. atypical keratinocytes, exfoliation of follicular corneo-
Exactly what constitutes adequate birth control is a cytes, and new blood vessel formation [37]. More in-
matter of some debate. However, there is general vestigational work must be undertaken before tretin-
agreement that oral contraceptives represent the most oin is presented as a definitive therapy in actinically
effective method of pregnancy prevention when used damaged skin; however, the results of early studies are
appropriately. Perhaps of even greater importance in encouraging.
the prevention of retinoid-induced congenital malfor- A considerable benefit for patients in whom tretin-
mations is patient selection. Strauss and colleagues oin is being used to treat extrinsically aged skin is the
[35] have published a brief guideline outlining appro- early detection of skin cancers [40]. Although this
priate measures for making such decisions. medication has shown a salutary effect on actinic kera-
Clearly, the use of these medications places a wom- toses [37], Robinson and Kligman [41] noted that the
an of child-bearing potential and her physician in a combination of tretinoin with 5-fluorouracil demon-
precarious situation. Many patients with fulminant strated greater efficacy than either agent used as
acne, psoriatic erythroderma, and disabling disorders monotherapy. Individuals may become better educat-
of keratinization will respond to no other type of medi- ed regarding skin care and neoplasia and may begin to
cation. Likewise, physicians often become frustrated detect skin cancers on their own. An excellent outline
in their attempts at more conventional therapies for of practical management for patients treated with top-
such patients. It is therefore imperative that if a clini- ical tretinoin is available [40].
cian wishes to begin treatment with one of these drugs Unpleasant side effects of this medication are gener-

570 May 1989 The American Journal of Medicine Volume 86

 OVERVIEW OF THE RETINOIDS / BOYD

ally minor and center around irritation of treated creased endogenous production of lipids coupled with
areas. When used in the treatment of acne, patients a diminished utilization and degradation [57].
should be counseled that an initial worsening of the Since Pittsley and Yoder’s [58] description in 1983
lesions may occur before improvement is seen. A typi- of an association between this drug and the develop-
cal irritant dermatitis of treated areas commonly oc- ment of skeletal hyperostosis, much attention has
curs after about seven days of use. Weiss et al [38] been focused on this medication’s effects on bones and
noted that greater than 90% of tretinoin-treated pa- tendons. Recently, Ellis et al [59] examined patients
tients experienced some degree of dermatitis. A tem- for skeletal changes after long- and short-term isotre-
porary burning sensation of the eyes has also been tinoin therapy. They found the radiographically de-
reported [40]. tectable hyperostosis to be of little clinical signifi-
cance. Premature closure of the epiphyses in a child
ISOTRETINOIN receiving isotretinoin has also been described [60].
Ro 4-3780, or isotretinoin, was synthesized in 1955. The long-term importance of these musculoskeletal
Initial testing of the drug showed it to be highly effica- effects is presently unknown and should be borne in
cious in the therapy of disorders of keratinization (e.g., mind when beginning therapy.
Darier’s disease, ichthyosis) [42]. Peck et al [43] were Two critical ingredients to successful therapy with
the first investigators to demonstrate this drug’s value this drug include a physician well versed in its intrica-
in the treatment of severe acne, and in September cies and good communication between doctor and pa-
1982 it became the first systemic vitamin A derivative tient. Clinicians who dispense this medication should
to be released for general use in the United States. be aware of its toxicities, and potential patients must
Since that time, it has become clear that 13&s- be thoroughly screened for compliance, insight, and
retinoic acid may be of considerable benefit to patients responsibility.
with severe, recalcitrant acne. Most dermatologists
now consider it to be the drug of choice for this condi- ETRETINATE
tion. It is believed that oral administration of isotre- Etretinate (Ro 10-9359; Tegison) is the most recent-
tinoin leads to a diminished production of sebum [44] ly available synthetic retinoid. Synthesized in 1972, it
and a subsequent lessening of the inflammation and has found its major success in the treatment of psoria-
cyst formation. Doses of isotretinoin of 0.5 to 1.0 mg/ sis [61]. Although this drug is effective in the therapy
kg/day typically produce a 70% to 90% reduction in of chronic plaque psoriasis, its predominant indica-
sebum production at one month [ll]. Oddly, patients tions are its use in the erythrodermic [62] and pustular
may remain free of their disease after discontinuing variants [63]. These latter two types of psoriasis are
the drug despite subsequent development of sebum more responsive to the medication than are other
excretion rates that approximate those of pretreat- forms of the disease [64]. Ellis and Voorhees [21] treat-
ment values [15]. Isotretinoin has also been shown to ed 57 patients with etretinate for greater than three
effect epidermal desquamation, diminish neutrophil months. More than 90% experienced a minimum of
and eosinophil motility, alter cellular differentiation 50% clearing, and half the treated patients showed
and, perhaps, inhibit 5lipoxygenase [ll]. Levels of greater than 75% clearing. Etretinate may be com-
Proprionibacterium acnes, the etiologic agent of bined with more traditional therapies for psoriasis in
much of the inflammatory component in acne, are di- order to limit the patients’ contact with potentially
minished in isotretinoin-treated patients [45], proba- detrimental therapeutic modalities. Examples of this
bly as a result of nutrient deprivation. Topical applica- include etretinate’s use in conjunction with oral psora-
tion of this drug has also been shown to be effective lens and ultraviolet A (PUVA) [65], ultraviolet light B
when treating acne of moderate severity [8]. [66], and topical corticosteroid preparations [67]. It
Isotretinoin has been found to be of help in a num- has proven to be a useful adjunctive therapy to metho-
ber of other disorders including pityriasis rubra pilaris trexate in the treatment of recalcitrant pustular psori-
[46], rosacea [47], gram-negative folliculitis [47], hi- asis [68]. Etretinate as monotherapy [64] or when used
dradenitis suppurativa [15], lichen planus [48], and with ultraviolet light therapy [69] has been reported to
cutaneous sarcoidosis [49]. Considerable interest in have a beneficial effect on psoriatic arthritis.
this drug centers around its usefulness in the therapy This retinoid, like isotretinoin, has been successful-
of various neoplastic conditions. It has demonstrated ly used in the therapy of many other diseases including
favorable results in the therapy of basal cell carcino- disorders of keratinization such as Darier’s disease
mas [50] and cutaneous T-cell lymphoma (mycosis [70], pityriasis rubra pilaris [71], and the ichthyoses
fungoides) [51]. Flynn and co-workers [52] have de- [72]. Acne vulgaris will respond to etretinate; however,
scribed the use of isotretinoin in the therapy of acute treatment outcomes are clinically inferior to those of
promyelocytic leukemia. isotretinoin.
Although the therapeutic response to this drug is The therapy of neoplastic disorders has become the
high, it is not without side effects. Cheilitis, epistaxis, most recent area of interest. Etretinate has been asso-
and facial erythema are seen in more than 50% of pa- ciated with the regression of bronchial metaplasia [73]
tients taking the drug. Gastrointestinal upset has been and has been of benefit in the treatment of mycosis
reported to develop in as many as 20% of treated pa- fungoides [74]. Cutaneous neoplasia such as actinic
tients [53]. Sixteen percent will experience myalgias keratoses [75], arsenical keratoses [76], and basal cell
and arthralgias [54]. Additional symptoms include carcinomas [77] have also responded favorably to sys-
headache, paronychia, and ocular irritation [55]. Char- temic therapy.
acteristic of retinoids in general, isotretinoin elevates The precise means by which etretinate works is cur-
serum lipids, particularly triglycerides [56]. Animal rently unclear. Inhibition of the enzyme ornithine de-
studies suggest that this compound induces an in- carboxylase [26], normalization of epidermal cell dif-

May 1989 The American Journal of Medicine Volume 86 571

 OVERVIEW OF THE RETINOIDS / BOYD

ferentiation [2i], and diminishment of desmosomal found in psoriatic patients treated for six to 18 months
size [78] are thought to play a role. Through these with etretinate. Currently, most clinicians believe that
mechanisms, the aberrant, cell cycling and accumula- this side effect is not of major concern in short-term
tion of scale that characterize psoriasis might, be sub- therapy.- A recent report on the use of electromyo-
sequently returned to normal in patients undergoing graphic studies in etretinate-treated patients by Da-
etretinate therapy. This drug has anti-inflammatory vid.et a2 [89] has suggested that this retinoid may
properties [27] and immunomodulatory activity via its cause subclinical muscle damage.
interaction with the arachidonic acid cascade [79]. The Before and during etretinate therapy, standard lab-
leukotrienes and hydroxyeicosatetraenoic acids have oratory evaluations are mandatory (e.g., fasting SMA,
been implicated in the pathogenesis of psoriasis, and complete blood cell count, urinalysis, pregnancy test).
agents that interact with this cascade are known to Treatment is usually begun with 0.5 to 1.0 mglkglday
affect the disease [80]. Etretinate may exert its influ- in divided .doses, although Dubertret [90] has stated
ence by altering the production of these proteins. Re- that doses as low as 10 to 20 mglday (0.14 to 0.28 mg/
search into the cell-mediated immunity aspects sur- kg/day) may be effective for beginning therapy. Pa-
rounding this medication has shown a normalized tients are encouraged to adopt a low-fat diet in antici-
neutrophil chemotactic capacity in the serum of etre- pation of the retinoid-induced hyperlipidemia. Alco-
tinate-treated patients with psoriasis [81] and no ef- hol, in moderate doses, has not been proven to pose the
fect on antibody-dependant cell-mediated cytotoxici- same degree of risk in etretinate therapy as in metho-
ty in monocytes [82]. Dubertret and Touraine [83] trexate administration. Regardless, alcohol consump-
have suggested that neutrophil accumulation in le- tion is discouraged. Of paramount importance is the
sions of psoriasis may be an important event in the careful tabulation of the total dose of etretinate ad-
pathogenesis of the disease. Modulation of the chemo- ministered to the patient and pregnancy-prevention
tactic capabilities of neutrophils and their subsequent counseling given to any female of childbearing age who
clearance from the skin in etretinate-treated patients is about to start taking the drug. Ellis and Voorhees
has been proposed as a possible etiologic mechanism of ave authored an excellent overview of etretinate
the drug [84]. Continuing investigation into etretin- 9 !ts administration.
ate’s mechanism of action is ongoing and continues to
yield much needed information. ACITRETIN
The realized and potential adverse reactions to etre- The most recent retinoid to be subjected to clinical
tinate are both numerous and varied. Virtually all pa- trials is acitretin (Ro lo-1670), the carboxylic acid me-
tients experience some of the mucocutaneous side ef- tabolite of etretinate. Initial investigations have cen-
fects commonly associated with this drug such as dry tered around its use in psoriasis. Gollnick and collabo-
lips and mucous membranes, hair loss, nail dystrophy, rators [lo] studied 175 patients with psoriasis in a
and peeling of the palms and soles. Patients also often double-blind, randomized trial in Germany. No signif-
complain of a “sticky” sensation to the surface of their icant differences in disease response were noted in
skin. In addition, as many as half of all etretinate- patients treated with 50 mg of etretinate daily com-
treated patients with psoriasis develop a “retinoid pared with patients given 50 mg of acitretin daily. The
dermatitis” that may, at times, be difficult to delin- toxicity profile for acitretin was essentially the same as
eate from underlying psoriasis [21]. These side effects for etretinate. Hepatic effects of both drugs are also
are readily reversible as soon as the drug is discontin- thought to be similar [91]. A key difference between
ued; however, there seems to be no immunity to a the two substances concerns their half-lives. The ter-
recrudescence of such adverse reactions if etretinate is minal elimination half-life of etretinate is approxi-
given again. mately 80 days [19], whereas that of acitretin is ap-
Some of the more significant toxicities involving proximately 48 hours [91]. This may be of considerable
etretinate administration are of a metabolic nature. significance in the therapy of females of childbearing
Half of all treated patients will develop serum triglyc- age. Currently, dermatologists are reluctant to pre-
eride levels in excess of 250 mg/dL, and serum choles- scribe etretinate for this segment of the populace due
terol will exceed 300 mg/dL in one patient in five. to the need for extended pregnancy prevention (per-
High-density lipoprotein will fall below the normal haps years) once the medication has been discontin-
limits in a third of patients with psoriasis undergoing ued. Acitretin may help avoid this problem.
treatment. Discontinuing etretinate therapy has been
recommended in any patient whose serum triglyceride MISCELLANEOUS RETINOIDS
level exceeds 800 mg/dL because of the associated risk Ongoing research in the field of retinoids has pro-
of developing pancreatitis [21]. Recently, Lowe and duced a class of compounds known as the arotinoids.
co-workers [85] have demonstrated a lowering of etre- These molecules are chemical “cousins” to the retin-
tinate-induced hypertriglyceridemia in patients treat- oids and are composed of heterocyclic rings. The ini-
ed with oral fish oil supplements. tial arotinoid to be introduced was Ro 13-6298. It has
An additional adverse reaction to this drug is that of proven effective in the treatment of psoriasis [92] and
liver enzyme elevations [64]. Hepatotoxicity may be Darier’s disease [20] but is less sebosuppressive than
seen in up to 20% of etretinate-treated patients [21], isotretinoin [20]. The free carboxylic acid of this com-
and significant liver disease is thought to occur in 1% pound is Ro 13-7410 and, like acitretin, it has a shorter
[86]. Currently, a pretreatment liver biopsy is not rec- elimination half-life than its parent molecule. Prelimi-
ommended. nary studies have shown its spectrum of efficacy to be
Etretinate, like isotretinoin, has been shown to be similar to that of Ro 13-6298 [20]. Arotinoid Ro 15-
responsible for the development of tendinous and liga- 0778 was initially thought to be promising in acne
mentous calcifications [87]. Gilbert et al [88], however, therapy based on pilot studies in an animal model.
note that radiographic skeletal changes were not Human trials, however, have not been as successful

572 May 1989 The American Journal of Medicine Volume 86

 OVERVIEWOF THE RETINOIDS / BOYD

[XI]. Finally, administration of Ro 15-1570 to ham- retinoids: experimental findings and clinical experience. Br J Dermatol 1983; 109:
55-60.
sters has shown evidence of a reduction in the size of 28. Plewig G, Wagner A: Anti-inflammatory effects of 13-cis-retinoic acid. Arch
the sebaceous glands [93]. Dermatol Res 1981; 270: 89-94.
29. Zech LA, Gross EG, Peck GL, Brewer HB: Changes in plasma cholesterol and
SUMMARY triglyceride levels after treatment with oral isotretinoin. Arch Dermatol 1983; 119:
987-993.
The retinoids may be of significant benefit to pa- 30. Shalita AR: Mucocutaneous and systemic toxicity of retinoids: monitoring and
tients with acne and psoriasis. Early indications are management, Dermatologica 1987; 175: 151-157.
that they may also have a role in the therapy of extrin- 31. Kilcoyne RF: Effects of retinoids in bone. J Am Acad Dermatol 1988; 19: 212-
sically aged skin. As additional synthetic molecules 216.
are developed and tested, it is anticipated that some of 32. Kamm JJ: Toxicology, carcinogencity and teratogenicity of some orally admin-
istered retinoids. J Am Acad Dermatol 1982: 6: 652-659.
the significant toxicities associated with this class of 33. Lammar EJ, Chen DT, Hoar RM, efa/:Retinoicacid embryopathy. N Engl J Med
compounds will be diminished and their efficacies en- 1985: 313: 837-841.
hanced. Use of these compounds in neoplastic pro- 34. Shalita AR: Lipid and teratogenic effects of retinoids. J Am Acad Dermatol
1988; 19: 197-198.
cesses is a broad, new area of interest. Clearly, the 35. Strauss JS. Cunningham WJ, Leyden JJ, Pochi PE, Shalita AR: lsotretinoin and
retinoids will have a lasting impact on dermatology teratogenicity. J Am Acad Dermatol 1988; 19: 353-354.
specifically and medicine in general. 36. Banano GS, Terezakis N. Galen W: Topical tretinoin for hair growth production.
J Am Acad Dermatol 1986; 15: 880-883.
37. Kligman AM, Grove GL, Hirose R, Leyden JJ: Topical tretinoin for photoaged
ACKNOWLEDGMENT skin. J Am Acad Dermatol 1986; 15: 836-859.
I wish to thank Mark Naylor, M.D.. for his helpful suggestions and Bryan Stadigfor 38. Weiss JS, Ellis CN, Headington JT, Tincoff T, Hamilton TA, Voorhees JJ: Topical
his excellent technical suggestions in the preparation of this manuscript. tretinoin improves photoaged skin: a double-blind vehicle-controlled study. JAMA
1988; 259: 527-532.
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