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Clinics in Dermatology Volume 19 issue 4 2001 [doi 10.1016%2Fs0738 081x%2801%2900189 4] Marcia Ramos e Silva; Doris Maria Hexsel; Marcio Santos Rutowits Hydroxy acids and retinoids in cosmetics .pdf

Nome del file originale: Clinics in Dermatology Volume 19 issue 4 2001 [doi 10.1016%2Fs0738-081x%2801%2900189-4] Marcia Ramos-e-Silva; Doris Maria Hexsel; Marcio Santos Rutowits -- Hydroxy acids and retinoids in cosmetics.pdf
Titolo: PII: S0738-081X(01)00189-4

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Hydroxy Acids and Retinoids in


he alpha-hydroxy acid family is composed of
different compounds with wide application for
the treatment of several dermatoses. One of their
major indications is chemical peeling and their use in
creams and/or lotions also improves the manifestations
of cutaneous photoaging. Several factors influence the
efficacy of these alpha-hydroxy acids and knowledge of
them may prevent complications. Retinoids were introduced for photoaging and for the treatment of other
dermatoses more than two decades ago and were an
important advance in dermatological therapeutic resources. Risks and benefits of each treatment with these
compounds should be properly assessed and monitored by the dermatologist.

The use of drugs on the skin surface aims at the prevention of illnesses and has as its main purpose the
protection and preservation of the normality of skin.
Because in the last twenty years many patients have
also become concerned with their appearance, dermatologists now have to deal with Cosmetics as well. This
certainly arises in great part from the different information sources that exploit rejuvenation methods, including the use of vitamins A, C, and E, chemical peelings,
drugs that revitalize collagen, filling substances for
scars or expression marks, botulinum toxin and subcision, among others. The importance of vitamin A was
discovered during World War I1 and subsequent research showed that its deficiency gives rise to xerosis
and follicular hyperkeratosis, changes that quite frequently occur in various dermatological conditions. The
“retinoid project” was launched in 1968 to synthesize
compounds similar to vitamin A by chemical manipulation of its molecule to improve clinical efficacy and
From the Sector of Dermatology, HUCFF-UFRJ and School of Medicine,
Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil (MRS);
private practice, Porto Alegre, Brazil (DMH); Sector of Dermatology, Hospital dos Servidores do Estado, Rio de Janeiro, Brazil (MSR), Sector of
Dermatology, School of Medicine, Fundac¸a˜o Faculdade Federal de Cieˆncias
Me´dicas, Porto Alegre, Brazil (MZ).
Address correspondence to Marcia Ramos-e-Silva, MD, Rua Sorocaba
464/205, 22271-110, Rio de Janeiro, Brazil.
E-mail address:
© 2001 by Elsevier Science Inc. All rights reserved.
655 Avenue of the Americas, New York, NY 10010

curtail side effects.2 The use of these substances in
therapy probably dates back some 3000 years to ancient
Egypt, where liver was used to treat endemic night
blindness.3 Retinoids’ modern history, however, began
in 1909 when Steps1 discovered an essential factor for
the viability of the embryo in the fatty extract of egg
yolk, which he called vitamin A. The addition of the
synthetic retinoids to the therapeutic armamentarium
in the early 1980s marked a major advance in the treatment of certain skin diseases. Through the ages alphahydroxy acids have been used in a variety of cultures.
In Egypt, Cleopatra bathed in sour milk, and during the
French revolution the ladies of the court applied fermented wine to their faces.4 Recently, alpha-hydroxy
acids have been incorporated into a variety of creams,
lotions, and cleansers for general use. They are also
being used in a variety of chemical peelings.

Skin Structure and Function
Skin functions include protection, heat regulation, immune response, biochemical synthesis, and sensory detection; it acts as a two-directional barrier to prevent
water and electrolyte absorption and loss. The epidermis, the most superficial layer and, more specifically,
the stratum corneum, plays the major role. The stratum
corneum is formed by nonviable corneocytes, which are
cells that have lost the nucleus and cytoplasm organelles. Fibrous proteins or keratin are aligned in intercrossed disulfidic macrofibers, along with filagrine,
the main protein component of the keratolytic granule.
The cells develop a cornified involucre resulting from
the intercrossing of involucrine and keratohyaline. This
constitutes the insoluble exoskeleton that acts as a rigid
structure for the internal keratin filaments. Lamellar
lipids accumulate in the intercellular spaces, which are
strongly hydrophobic. The combination of cornified hydrophilic cells in hydrophobic intercellular material is a
barrier for hydrophilic and hydrophobic substances.5
With age, the skin’s natural rejuvenation process slows
drastically and the skin becomes thinner, drier, and less
elastic. This aging process has intrinsic and extrinsic
components.6 – 8 Intrinsic aging comprises the geneti0738-081X/01/$–see front matter

Clinics in Dermatology



cally clinical, histological, and physiologic changes that
occur in the skin throughout the body with the passage
of time. Extrinsic aging is a cumulative degenerative
process induced by decades of exposure to harmful
environmental conditions, mainly solar ultraviolet radiation.6 –9 Concurrent processes of intrinsic and extrinsic aging produce distinct skin changes, including development of fine and coarse wrinkles, leathery texture,
mottled hyperpigmentation, and dryness. There is a
marked loss of elasticity, and hyperkeratinization occurs, causing the corneocytes to adhere in excess, accounting for the thickening of the stratum corneum.6,8,9
In papillary dermis, photodamaged elastic fibers are
short and fragmented, in contrast with the appearance
of normal or nonphotodamaged elastic fibers, which are
long, wavy, and nonfragmented.6,8,9 The greater understanding of the skin structure and function has allowed
the development of efficient care products with appreciable beneficial effects,10,11 and both alpha-hydroxy acids and retinoids have a capacity of reducing cohesion
between corneocytes and, consequently, decrease the
width of the stratum corneum, especially in situations
of hyperkeratosis.3,12

Alpha-Hydroxy Acids
Alpha-hydroxy acids are a special group of nontoxic
organic acids found in natural foods and are often
commercially referred to as “fruit acids.”4,13 They are
weak organic acids and structurally all of them have
one hydroxyl group attached to the alpha position of
the acid (first carbon following the acid group). Although they are found in nature in sugarcane (glycolic
acid), sour milk (lactic acid), and fruits (malic, citric and
tartaric acids), the alpha-hydroxy acids used in dermatological and cosmetic products are usually produced

Mechanism of Action
The exact mechanism of action of these acids is still
unknown; however, it has been shown that at low
concentrations alpha-hydroxy acids decrease corneocyte cohesion at the lower levels of the stratum corneum and it has been suggested that this occurs by
interference with the formation of ionic bonds.13 Essentially, by dissolving adhesions between cells in the upper layers of the skin, alpha-hydroxy acids induce shedding of dry scales from the skin’s surface, commonly
referred to as exfoliation. In so doing, they stimulate the
growth of new skin, resulting in a rejuvenated, fresher
complexion.14,15 Analysis of experimental and clinical
data has suggested theories for the mechanism of action
of alpha-hydroxy acids topically applied to the skin.
These acids reduce the calcium ion concentration in the
epidermis and remove calcium ions from the cell adhesions by chelation. This causes a loss of calcium ions



from the cadherins of the desmosomes and from other
types of junctions (adherens and tight junctions and
also divalent metallic cation-dependent cell adhesions),
resulting in a disruption of the adherence, which results
in shedding/flaking.16 Another theory is that the protein chains are separated, that is, there are two chains
linked by hydrogen bonds, and an alpha-hydroxy acid
may adhere to them. Thus, at low concentrations, alpha-hydroxy acid forms a bond with the chains that are
then slightly separated. At high concentrations the
chains may be separated beyond a certain limit, causing
desquamation.12 A third theory involves ceramides
linked to corneocytes. The natural moisturizing factor
(NMF) in the stratum corneum is partially composed of
lipids, including ceramides. Some of these are linked to
the surface of the corneocytes by strong bonds. An ester
bond could happen between a glutamic acid chain and
the alcohol function of a carbon atom of the ceramide.
Alpha-hydroxy acid may change the ester bonds or
prevent their formation. Without the ceramide layer,
the corneocytes can desquamate more easily.12 The
main cosmetic actions of these acids on the skin are
increased exfoliation and moisturization.6,14 These and
other proposed mechanisms of action have the following effects:
1. Increased exfoliation: low concentration of alphahydroxy acids facilitates shedding of the outer layer
of the epidermis by interfering in intercellular ionic
bonding, thereby reducing corneocyte cohesion at
the lower level of the stratum corneum. Higher concentrations further reduce corneocyte cohesion and
cause the thickened, hyperkeratotic stratum corneum to shed in sheetlike fragments, becoming thinner. Very high concentrations and low pH may cause
2. Moisturization: helps diminish the appearance of
fine lines and maintain the proper moisture level of
the skin.
3. Increase of dermal thickness: in higher alpha-hydroxy acid concentrations both epidermal and dermal effects are observed.
4. Increase of dermal perfusion: alpha-hydroxy acids
have definite vascular effects, as evidenced by erythema and vasodilatation that last for hours to days
following treatment.6

Factors Influencing the Efficacy of Alpha-Hydroxy
Acid Products
Several factors influence the effects on the skin, such as
acid concentration, product pH, amount of free acid
present, acid type, vehicle used, duration of exposure,
and patient’s skin type.6

Clinics in Dermatology





Indications for Alpha-Glycolic Acid Peels

Higher concentrated alpha-hydroxy acid products generally deliver better results. Some studies have shown
that higher concentrations increase epidermal and dermal firmness and thickness, clinical improvement in
skin smoothness, and also the aspect of lines and wrinkles.6,10,15

Hydroxy acid products include cleansers, moisturizers,
toners, masks, age-spot removers, and other preparations.6,15 Initially, they were only used for the treatment
of ichthyosis and other dry-skin conditions.6 These
preparations moisturize dry skin on the face and body,
decrease fine lines and wrinkles, improve skin tone and
texture, and restore a radiant, youthful glow to the
skin.6,17 The cosmetic products developed as astringents
and exfoliates diminish skin scales and remove excess
skin oil.17 There are many indications for a glycolic acid
peel. Generally the most common is facial rejuvenation
or an improvement in the appearance of the skin. Also,
alpha-hydroxy acid products have been used successfully in combination with other therapeutic agents in
treating hyperpigmentation, acne, actinic keratoses, ichthyosis, xerosis, psoriasis, seborrheic keratoses, pseudofolliculitis barbae, chronic dermatitis, and erythema

Although pH and concentration are both relevant for
determining the safety and efficacy of alpha-hydroxy
acids, there is increasing evidence that pH is a more
important factor than concentration. The lower the pH,
the greater the potential for skin irritation. The higher
the pH, the more the irritation drops off.6,10,15 The pH
influences the strength of the effect: a lower pH causes
greater action.12
Free Acids
The acid in alpha-hydroxy acid preparations may be
free or it may be partially neutralized or buffered. In
solution, alpha-hydroxy acids are present partly as free
acid (neutral molecules that penetrate skin) and partly
dissociated as the anion (charged molecules that do not
penetrate skin.6
Types of Acid
The alpha-hydroxy acids include glycolic acid, lactic
acid, mandelic acid, malic acid, citric acid, and tartaric
acid, which occur naturally in sugarcane, sour milk,
apples, grapes, and citrus fruit, respectively. They are
more active in stimulating cell renewal, and others are
more irritating.6 The activity depends on the length of
the carbon chain, with longer chains showing diminished activity but greater moisturizing capacity.12
Because all commonly used alpha-hydroxy acids are
water soluble, creams and lotions of oil-in-water emulsions are usually preferred. The most appropriate vehicle for a given product will depend on the purpose of
the product and the patient’s skin type.6 The vehicles
may be: (a) hydro-alcohol-glycol solutions, indicated
for oily and acneic skins because they have greater
solvent capacity; (b) gels, also for oily and acneic skins,
but also used for dry and mature skins; and (c) creams
r creamy lotions, ideal for dry, dried and mature skins.4
Duration of Exposure
The penetration depth depends to a large extent on the
length of time the acid is in contact with the skin.6
Patient Skin Type
Variables such as skin color, thickness, oiliness, laxity,
fragility, and inflammation may also influence the effect
of alpha-hydroxy acid products on the skin.6

Dramatic improvement of the fine lines and skin discolorations shown by the hard and thickened sun-exposed epidermis occurs with skin care that incorporates
alpha-hydroxy acid products. With regular application,
the outer signs of intrinsic and extrinsic aging decrease.
Exfoliating dead cells makes wrinkles appear less
deep.6 The long-term effects of alpha-hydroxy acids on
the rate of exfoliation are not known, but research
shows that the skin does become used to the simulatory
activity of alpha-hydroxy acids, with respect to measures of cell shedding.6,10
Melasma is a genetic condition characterized by the
appearance of brown patches, most commonly on the
cheeks and/or forehead. Bleaching agents, such as hydroquinone (2%), are prescribed with good results for
this type of hyperpigmentation, and combination therapy with glycolic acid (10%) has been found to be more
effective than hydroquinone (2%) alone.6
Although acne results from multiple factors, an abnormal pattern of keratinization is believed to be one of the
more important mechanisms. The ability of alpha-hydroxy acids to diminish corneocyte cohesion and keratinocyte plugging addresses this mode of acne pathogenesis. Lower concentrations reduce follicular
corneocyte cohesion, thereby dislodging comedones
and preventing their formation; higher concentrations
cause unroofing of pustules and loosening of the keratinocytes that line the follicular epithelium.6,18 Acne
responds quite well to short application of serial gly-

Clinics in Dermatology



colic acid peels, which can be an important adjunct to
therapy with topical and oral antibiotics.
Other Indications
Precancerous conditions, such as actinic keratoses, respond well to treatment with alpha-hydroxy acids, especially with glycolic acid peels. It can be applied in
combination to 5-fluorouracil (5-FU).6 Flat warts, as
well as mild acne scarring, may be treated with this
peel. Superficial rhytides may also improve with the
use of serial glycolic acid peel, depending on the skin
type and individual patient response. Ichthyosis is a
congenital disorder of keratinization characterized by
dryness and fishlike scaling of the skin. It is effectively
treated with formulations containing up to 12% glycolic
acid, lactic acid, and their derivatives.6 Hyperkeratosis
palmaris et plantaris can be successfully treated with
short-term 70% glycolic acid application to the palms
and soles.19 Xerosis is a common dermatologic condition in which the skin becomes rough and covered with
fine, white scales. Studies have shown that alpha-hydroxy acid preparations at higher pHs (those that have
been partially neutralized) reduce dry skin somewhat
better and faster than lower pH preparations.6

There are many potential complications seen in any
kind of chemical peel. These include, in order of severity: scarring, infection, post-inflammatory hyperpigmentation, post-inflammatory hypopigmentation, and
persistant erythema.20 –22

Retinoids include natural and synthetic compounds derived from retinol that show vitamin A activity.5 The
importance of this vitamin became manifest many years
ago, when xerophtalmia was widely observed in people
with a diet poor in this vitamin. Some experiments on
animals showed that dietary deficiency of vitamin A
causes, among other things, an increase in epidermal
keratinization and desquamating metaplasia of the mucous membranes.1 The therapeutic action of vitamin A
was tested on acne and psoriasis. In 1943, acne treatment was instituted with this substance. In 1952, Frey
and Schoch23 reported initial findings on the effects that
this substance has in psoriasis because subtoxic doses of
the vitamin induced peeling of the stratum corneum. In
1962, it was demonstrate that a physiologic acid derivate of vitamin A, all trans-retinoic acid, can be used as
therapeutic agent in dermatology. In 1955, isotretinoin,
or 13-cis-retinoic acid, was synthesized but its therapeutic use only began in 1976. Etretinate was synthesized in
1972 and is used in the treatment of conditions associated with keratinization disorders.24 Kligman and colleagues published the first study suggesting that topical



tretinoin was effective in the treatment of human photoaging.24,25 More recently, trials have been conducted
with acitretin, the active metabolite of etretinate, a substance with fewer side effects because it does not accumulate in the deep compartments of the body and is
therefore more rapidly eliminated.24 Vitamin A is essential for normal skin-cell proliferation and regulation.
The introduction of topical and then oral retinoids in
the treatment of skin disorders two decades ago began
a new era in dermatological therapy.17 Natural vitamin
A is known as retinol, an alcohol that is converted to
retinal, an aldehyde, which in turn is converted into
retinoic acid. Retinal can be converted to retinol again,
but retinoic acid is a dead-end metabolite and can not
be recycled back up the chain. Retinal is an essential
part of rhodopsin, the optic chromophore.18 Retinoids,
such as isotretinoin (13-cis retinoic acid), etretinate, and
acitretin, can be given orally for the treatment of skin
diseases that cover large surfaces or areas not responsive to local treatment. Topical retinoids currently available include retinol, retinaldehyde, retinoic acid,
isotretinoin, adapalene, and tazarotene.26 –28

Vitamin A is a 20-carbon molecule that consists of a
cyclohexenyl ring, a side chain with four double bonds
(all arranged in trans configuration), and an alcohol end
group (all-trans retinol). The oxidation of the alcohol
end group of all-trans retinol results in the formation of
an aldehyde (all-trans retinaldehyde), which can be
further oxidized to carboxylic acid (all-trans retinoic
acid ⫽ tretinoin).28 All-trans retinol cannot be synthetized in the body and is thus an essential nutrient.
Retinyl esters and beta-carotene are the two major precursors of retinol in our diet. They are converted to
all-trans retinol in the intestine and stored in the liver
after reconversion to retinyl esters. Meals, particularly
those with fat content, improve retinoid absorption.
Because of its lipid solubility, etretinate has extensive
and prolonged storage in fat resulting in a serum halflife of 80 –160 days.27 Upon discontinuing the drug, a
low level may be detected in the blood for 2 years or
more.29 Retinol released from the liver is carried in the
circulatory system by plasma retinol-binding proteins.
It is removed apparently through passive diffusion.28
Retinol is a hydrophobic molecule and it associates
intracellularly with the cellular retinol-binding protein
(CRBP). Thus, retinol can be metabolized to at least four
important products: retinyl esters, all-trans retinoic
acid, 14-hydroxy-4,14-retro retinol, and all-trans 3,4didehydroretinol, and also its esters.28

Mechanism of Action
The mechanism of action of retinoids has not been
completely elucidated, but these substances have profound effects on the modulation of cellular proliferation

Clinics in Dermatology


and differentiaton.5,26,30,31 Retinoids have been demonstrated to exert anti-inflammatory effects in cutaneous
diseases.26 They are also considered as mediators of
morphogenesis and development. These pleiotropic effects are known to be mediated by the interaction of
retinoids with specific nuclear receptors that belong to
the steroid/thyroid/vitamin D receptor superfamily.30
There are specific retinol and retinoic acid receptors: the
retinoic acid receptors (RAR␣, RAR␤, and RAR␥) are
ligand inducible trans-acting factors that heterodimerize with the 9cisRA receptors (RXR␣, RXR␤, and RXR␥)
and interact with specific DNA sequences or retinoic
acid response elements contained in the promoter region of target genes.28,30 –32

Types of Retinoids
Oral Retinoids
Isotretinoin, etretinate and acitretin are used for skin
diseases unresponsive to topical treatment or that affect
large areas.26,27



cogen deposition.5,16 In the epidermis, they increase the
thickness of the granular layer, decrease the strength of
the tonofilaments and desmossomes, decrease melanocyte activity, and increase secretion of a substance similar to glycosaminoglycans in the intercellular space. In
the dermis, blood vessel dilation was reported along
with angiogenesis and increase in collagen synthesis in
dermal papillae.25,26
Retinol is used for the treatment of skin aging in a
concentration of 0.075%. There are no studies comparing its effectiveness with that of of retinoic acid, although retinol does not appear to be as effective. There
are indications that its beneficial effects would be
greater at higher concentrations.
Retinoic Acid
Retinoic acid is used at 0.025%, 0.05%, and 0.1% concentrations for acne and photoaging treatment.

Topical Retinoids


Topical retinoids include retinol, retinaldehyde, retinoic
acid, isotretinoin, adapalene, and tazarotene.26,27

Retinaldehyde is used at a 0.05% concentration for photoaging treatment. Its efficacy is similar to that of retinoic acid. It can be used for the treatment of acne,
rosacea, seborrheic dermatitis, and also for the prevention of topical-steroid-induced atrophy.

Isotretinoin acts in the normalization of the keratinization process of the follicular epithelium, reduces the
number of sebocytes with decrease in sebum synthesis
and reduction of the population of Propionibacterium,
a microorganism that produces inflammation in

Topical Isotretinoin
Topical isotretinoin is available in concentration of
0.05% for the treatment of acne. Its efficacy is similar to
that of retinoic acid, producing less irritation.



Etretinate is used to treat psoriasis and is stored in
adipose tissue. It probably promotes the terminal differentiation, normalizing the expression of keratin in
epidermal cells; suppresses chemotaxis; decreases the
cohesiveness of the stratum corneum; and may interfere
with cytokine function.5

Adapalene is a synthetic product analogue to retinoic
acid. It belongs to the naphtoid acid derivatives family,
which possesses high stability toward light and oxygen.
Used in a concentration of 0.1%, its activity for moderate acne is similar but much less irritant than 0.025%
retinoic acid.



Acitretin has a plasmatic life of 50 hours. Similarly to
etretinate, it does not accumulate in the adipose tissue
or in the hepatic cells, where they show fat degeneration. It is better absorbed when ingested with a high fat.
Tretinoin is a derivative of vitamin A called all-trans
retinoic acid. Its primary effect is the reduction in hyperkeratinization that leads to the formation of microcomedones, the initial acne lesions. The bonds between
the follicular corneocytes become looser as a result of
the loss of desmossomes, decrease in tonofilaments,
increase in keratinocyte autolysis, and intracellular gly-

Tazarotene is a synthetic product that is also analogue
to retinoic acid and belongs to the family of acetylenic
retinoids. It has a specific binding profile to RAR-beta
and gamma and is available at a concentration of 0.05%
in a gel formulation for the treatment of mild psoriasis.

Retinoid Indications
Creams are more appropriate for sensitive skin and gels
are appropriate for oily skin. The disadvantages of
these products are that they may cause desquamation,
burning and erythema, exacerbate preexisting lesions,
and cause photoirritation with sunlight.14,16

Clinics in Dermatology



Some complications may be associated with retinoids,
especially if used as oral an treatment.
Generalized xerosis, scaling, retinoid-induced dermatitis, excessive growth of fine hair and kinking of the hair,
nail changes, and others.26,33,34
Conjunctivitis, night blindness, myopia, and corneal
Serum Lipids
Increase in triglycerides and plasma cholesterol.26,35
Elevation of transaminases, bilirubin and lactic dehydrogenase, decrease of albumin levels, toxic hepatitis.26,35
This is the most important side effect of retinoids, and
all physicians must be aware of it. Some authors have
shown that pregnancies coinciding with retinoid treatment may result in normal births, spontaneous abortion, premature births, and congenital malformations.
The site of action of the teratogenic effect may be the
cells of the neural crest, indicating that the malformations are probably not related to the dose of the drug
but to the gestation phase in which the embryo is
exposed to the substance.35 Maternal ingestion of retinoids early in pregnancy can lead to fetal abnormalities,
and exposed infants seem to have a characteristic appearance. It is important that women are not pregnant
before starting treatment31 and also that there is effective contraception during the therapy. The manufacturers recommend that conception should not occur for
1 month after isotretinoin therapy and 2 years after
cessation of acitretin therapy,31,35 but there are recommendations for a total of 3 years after etretinate and
acitretin.29 There are no reports of impairment of spermatogenesis with isotretinoin or etretinate. They do not
damage the human germinal epithelium when administered in therapeutic doses. Some males treated with
etretinate have complained of impotence, but it is not
clear whether the drug was responsible for this disturbance.35 Man can safely father children when they are
taking the drug.31

Glycolic acid and other members of the alpha-hydroxy
acid family occur naturally in foods and have been used
for centuries as cutaneous rejuvenation therapy. Recently, glycolic acid has proved to be a versatile peeling



agent and it is now widely used to treat many defects of
the epidermis and papillary dermis in a variety of
strengths, ranging from 20% to 70% depending on the
condition being treated. The introduction of retinoids in
the treatment of skin disorders two decades ago began
a new era in dermatology therapy. Oral and topical
tretinoin are widely used in the treatment of acne and
photoaging. Research on acne pathogenesis has provided a rational basis for its use. Before instituting
treatment with retinoids, the dermatologist must weigh
the risks and benefits in each case. Though certain mild
conditions may improve under retinoid therapy, the
use of these drugs may not be advisable if the side
effects are likely to outweigh the benefits. On the other
hand, retinoids may have a more rapid effect on certain
pathological processes than long-term treatment with
other substances. Both drugs have multiple therapeutic
indications when well prescribed. An excellent efficacy
can be obtained in the treatment of many dermatoses
using derived products that have been the subject of
much research in recent decades.

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