Topical Retinoids

15 May

INTRODUCTION

Topical retinoids are singularly important agents in the treatment of acne vulgaris. Any  molecule having a  biological   effect  through the  binding and  activation  of retinoid receptors is considered a retinoid (1). This class  of medications includes vitamin A and all synthesized molecules that are derived from it (1). By influencing DNA  transcription, retinoids can modify cellular  growth and  differentiation, immunomodulation, and  tumor promotion. In turn,  they  improve acne  vulgaris by inhibiting microcomedone formation, diminishing the number of mature come- dones as well as inflammatory lesions, and normalizing follicular  epithelium matu- ration  and  desquamation (2).

CLASSIFICATION

Three   generations  of  retinoids exist.  First-generation  topical   retinoids  include vitamin A and  its  derivatives retinaldehyde,  all-trans-retinoic acid  (all-trans-RA) or tretinoin, and  13-cis-retinoic  acid (13-cis-RA) or isotretinoin (3). The second gen- eration retinoids comprise synthetic analogs where one aspect  of the basic vitamin A structure has  been  changed, such  as etretinate and  acitretin, though no topical forms  of these  forms  exist (3). Third-generation retinoids have  significant modifi- cation  of the original molecule, such as adapalene, tazarotene, arotinoid, arotinoid methyl sulfone,  and  arotinoid ethyl ester (3). Presently, there  are seven  topical  reti- noids:  tretinoin, adapalene, tazarotene, topical  isotretinoin, motretinide, retinalde- hyde,  and  b-retinoyl glucuronide (3). Only all-trans-RA,  adapalene, and  tazarotene are available in the United States and  are discussed in the text that  follows.

ABSORPTION

Absorption of  topical   medications  occurs   transepidermally  or  transfollicularly, influenced by the size of the particles involved (4). Molecules 3 to 10 mm in diameter penetrate the follicular  ducts,  making this size the ideal target  size for acne therapy (4). Particles  larger  than  10 mm become  trapped on the skin surface,  whereas par- ticles  less  than  3 mm disperse over  the  stratum corneum and  hair  follicles  and are, therefore, less efficacious  (4).

MECHANISM OF ACTION

Topical  retinoids act to clear  and  prevent the  formation of the  microcomedo, the precursor to acneiform lesions.  The microcomedo is formed from the occlusion of the  follicular ostium  by  the  androgen-induced  production  of  sebum  and   the

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accumulation of stratum corneum cells (5). In normal skin, the corneocytes of the hair  follicle’s infrainfundibular region  are small  and  form  a noncontinuous, inco- herent layer  of cells that  easily  desquamate individually into  the  follicular  canal (1,2,6). They  then  travel  to the  surface  of the  skin  through the  secretion of lipid- rich  sebum (6). In contrast, the  follicular  epithelium of the  microcomedo demon- strates  abnormal,  hyperactive  keratinization, resulting  in  hypergranulosis and hyperkeratosis (2,5). Corneocytes are  more  cohesive  and  less  able  to  migrate to the skin surface  and instead become lodged within the follicle, occluding the expul- sion of sebum, distending the follicular  ostia,  and  thus  forming the comedo (1,6). The anaerobic environment created therein favors  the proliferation of Proprinibac- terium acnes (1,6), which  subsequently creates  an inflammatory response by secret- ing lipase,  releasing chemotactic factors,  and  recruiting polymorphonuclear lymphocytes  (PMNs)  (1,2,6).  Bacterial  lipases   break  down sebum triglycerides into glycerol,  a growth factor for the bacteria, and  free fatty acids  that are comedo- genic  and   proinflammatory (1,6).  The  lipases   and   cytokines produced  by  the recruited PMNs each contribute to the breakdown of the follicular  wall, eventually causing microcomedo rupture. The release  of sebum, keratin, and  free fatty  acids induces an  inflammatory foreign   body   reaction, resulting  in  the  formation  of inflammatory papules, pustules, and  nodules (1,5,6). Therefore, by  targeting the microcomedo, topical  retinoids also  help  prevent the  formation of inflammatory lesions  that  have  the potential to heal  with  scarring. By preventing the formation of new microcomedones, topical  retinoids produce acne remissions that can be suc- cessfully  maintained for extended periods of time (2,7). These effects occur in what has be referred to as the “ideal  state,”  in which  retinoids could  be used  in sufficient concentrations and frequencies to obtain the desired effect. Unfortunately, for many patients, the irritant  side   effects   of  these   drugs—erythema,  xerosis,   burning, desquamation—can impede 100% adherence and improvement (2). Unlike oral reti- noids,  the topical retinoids do not decrease production of sebum, but instead act by decreasing inflammation, normalizing keratinocyte differentiation, and  increasing keratinocyte proliferation and  migration (8,9).

Receptor Action

Topical  retinoids regulate gene  transcription through an interaction with  nuclear retinoid receptors. Nuclear retinoid receptors are  ligand-dependent transcription factors  that  regulate the transcription of target  genes  in two ways  (10). One mech- anism  of action  is via  the  direct  binding to  retinoid receptor cognate  hormone response  elements,  direct   repeats  of  six  nucleotides, found  in  the   promoter regions of retinoid-receptive genes (10,11). The second means of transcription modi- fication  is the  antagonism of nuclear transcription factors  that  bind  to  alternate response elements (AREs), thereby preventing the  expression of genes  regulated by these AREs (10,11). For instance, when a retinoid binds  to the retinoic acid recep- tor (RAR) subtype complexed with  the jun/fos transcription factors,  it disrupts the interaction between jun/fos and  the ARE, activator protein-1 (AP-1), and  prevents transcription of AP-1 regulated genes (11). It is thought that this results in the anti- proliferative and anti-inflammatory effects seen with some of the retinoids (10 – 12).

Retinoid receptors, like thyroid hormone receptors, vitamin D receptors, and steroid receptors, are classified  as nuclear receptors (12). There  are two  classes  of nuclear retinoid receptors: RARs and  retinoid X receptor (RXRs) (12). Each  class of receptors consist  of three  subtypes: alpha, beta, and  gamma, and  in vivo, these

receptors exist as dimers (12,13). RXRs can dimerize with  RAR, thyroid hormone receptors, and  vitamin D receptors. RARs, however, can only  dimerize with  RXR (12).  RAR  alpha  subunits  are  found  ubiquitously,  RAR  gamma  subunits  are found predominantly in the skin, and RAR beta subtypes are inducible by retinoids only  in certain  tissues,  including the  skin  (6,10). RAR and  RXR subtypes bind  as heterodimers along  with  the  retinoid ligand to  the  cognate   hormone response elements. Each  retinoid holds  a different affinity  for each  receptor subtype. The clinical response to each retinoid differs on the basis of the affinity for specific recep- tors, the expression pattern of receptor subtypes, and the cognate response element (10,11). Gamma receptor is the  most  important receptor involved in  epidermal differentiation, and  tretinoin has a high  affinity  for these  receptors.

Retinoid Types

The first developed topical  retinoid was retinoic  acid, or tretinoin. Tretinoin’s flex- ible molecular structure allows it to bind all RAR and RXR subtypes, whereas tazar- otene and  adapalene are more rigid, and  therefore demonstrate receptor specificity (13). Tretinoin also  has  the  capacity to bind  cytosolic  retinoid-activating binding proteins (CRABPs) that  exist in two  forms,  I and  II, and  act as buffers  for retinoic acid by controlling free intracellular concentration (3,10,11). Retinoid potency corre- lates with  affinity  for the RARs but not for CRABPs (11).

Tretinoin is available as 0.025%, 0.05%, and  0.1% creams,  0.01% and  0.025% gels, and  0.05% solution, with  0.025% cream  having the  least  and  0.05% solution having the  most  irritation potential (2,3,6). Newer microencapsulated tretinoin gel and  polyolprepolymer 2 gel forms  are  less irritating than  other  formulations of  tretinoin (2,6,14). The  tretinoin microsphere, available in  0.4% and  0.1% gel forms,  encapsulates the  molecule within a porous acrylate copolyer microsphere (2,15). This packaging system allows  selective,  time-released delivery of tretinoin to the  follicle, leading to a decreased available concentration and  lower  irritation without diminishing the efficacy (2,15). In fact, the maximum comedolytic activity of tretinoin is reached at a concentration 5 to 10 times  lower  when the drug is used in a microsphere form  (15). In addition, potential percutaneous penetration to the blood  vessels  is diminished (2,15).

Similarly,   novel  vehicles  can  allow  controlled release  of  topical  retinoids. Polyolprepolymer-2 is a material designed to help  retain  drug molecules in and on  the  skin  when applied topically and  has  been  shown to  distribute tretinoin over  time  with  equivalent efficacy  to  vehicle-free analogous  formulations (16). The incorporation of tretinoin into this vehicle  prevents rapid and  excess percuta- neous  absorption of tretinoin, decreasing irritation (16). In vitro absorption studies, guinea pig irritation models, human patch test studies, and acne clinical trials of tre- tinoin  gel and  cream  containing polyolprepolymer-2 demonstrate that  the absorp- tion of tretinoin during the first six hours of delivery is significantly less than that of standard  preparations of  tretinoin,  but   becomes   similar  after   this   time   (16). Additionally, the  total  penetration of polyolprepolymer-impregnated  tretinoin is less than  vehicle-free tretinoin (16). Human patch  tests demonstrated that both tre- tinoin  gel and cream formulated with polyolprepolymer-2 resulted in less irritation when compared to their tretinoin gel and cream forms (16). Human double-blind clini- cal trials comparing tretinoin 0.025% gel and cream containing polyolprepolymer-2 to  their   commercially available  equivalents  demonstrated  diminished  xerosis, erythema, and  peeling in the tretinoin polyolpolymer gel and  cream  formulations

(16). This decrease in irritation was achieved without compromising treatment effi- cacy (16). Although the  exact  mechanism for these  actions  is unknown, one  pro- posed mechanism is that  the  degree of irritation from  tretinoin is related to the rate  of initial  penetration of drug and  while  the efficacy is more  a consequence of mean  molecular flux (16).

The second topical  retinoid developed for the treatment of acne is adapalene, a  stable  naphthoic acid  derivative with  both  significant anti-inflammatory  and comedolytic properties (6,11,17). Adapalene has been shown to have a more  favor- able sideffect  profile  than  either  tazarotene or tretinoin (6,17). It has a specific affi- nity  for  RAR beta  and  gamma subtypes in  the  terminal differentiation zone  of the  epidermis and   does  not  bind   to  CRABP  I  and   II  due   to  steric  hindrance (3,6,11,13,18,19).  Adapalene  treats   acne   by   causing  epidermal  and   follicular epithelium  hyperplasia,  increased  desquamation,  keratinocyte  differentiation, and  loosening of corneocyte connections (11,14,18).

Adapalene is available as 0.1% cream, gel, solution, and  pledget forms and  is in clinical trials as a newer 0.3% gel formulation (2,20). The 0.1% gel has been shown to be as effective  as tretinoin 0.025% gel with  decreased irritation (2,20). The 0.3% gel has  been  shown to be safe  and  well  tolerated for long-term use  with  almost doubled success over adapalene 0.1% gel without a significant increase in clinically relevant side effects (20). The release  of adapalene from solution formulations such as  lotions  and  hydroalcoholic gels  is greater than  when dispersed in  creams  or aqueous gels (18,21).

The anti-inflammatory effects of adapalene result  from  inhibition of the oxi- dative metabolism of arachidonic acid by the 5 and 15 lipoxygenase pathways and through the inhibition of PMN  chemotactic and  chemokinetic responses (3,11). As such,  adapalene has  demonstrated superiority when compared to reference anti- inflammatory agents such as indomethacin and betamethasone valerate (22). Other contributing factors  for the lower  skin irritation induced by adapalene include its different RAR  subtype-binding pattern  and   more   neutral  molecular structure, which  makes  it less likely  to nonspecifically interact with  cell membrane function (3). Its high  melting point  and  low  solubility result  in low  flux through the  skin, leading to high  concentrations in the  stratum corneum and  hair  follicle, where it can best act to prevent and treat acne (11).

Tazarotene is a topical  retinoid that has demonstrated superior efficacy when compared with  other  topical  retinoids in the treatment of acne (23). Tazarotene is

available in 0.05% and  0.1% cream  and  gel formulations (2). Tazarotene is selective for RAR beta and gamma subtypes (13). Although tazarotene does not directly bind to the RXRs, it does isomerize to 9-cis-RA, which  weakly binds  all RXRs leading to a degree of transactivation (21). The  precise  mechanism of action  of tazarotene  is unknown, however, it is postulated that  through the  activation of retinoid recep- tors,  retinoid responsive genes  are  upregulated impacting the  differentiation   of keratinocytes.  Similarly,   by  inhibiting  proinflammatory  transcription                                     factors, tazarotene causes  decreased cell proliferation and  inflammation (21). Tazarotene penetrates  the  skin  but  accumulates  in  the  upper  dermis (24).  The  molecule remains concentrated here   with   very   little   absorption  into   blood   vessels   or lymphatics (24).

The topical retinoids induce specific changes in the structure and morphology of the skin. Normal epithelial cell differentiation is a vitamin A-dependent process (25). The presence of vitamin A alters  the size of the keratin molecules synthesized by keratinocytes (25). When small keratin molecules are produced, a secretory-type

epithelium is generated. A stratified squamous epithelium is induced when larger keratin molecules are synthesized (25). In the absence  of vitamin A, cells differen- tiate toward keratinizing epithelium (25).

Keratinocytes within each layer of epidermis possess a distinct set of proteins unique to their  stage  of differentiation (26). As undifferentiated basal  cells mature and  migrate up through the epidermis, their  pattern of protein expression changes (26). Once  these  cells arrive  at the  stratum corneum, the  intracellular organelles have  been  catabolized and  cytoplasmic and  membrane proteins altered so as to produce a  layer  of  dead  corneocytes with  thick  keratin fibrils  within a  dense matrix (26). As a group, the retinoids alter this process by inducing dose-specific ker- atinocyte proliferation  and   reversing the  abnormal keratinocyte desquamation found in  acne  (26).  This  helps   form  a  thicker   layer  of  suprabasal cells,  but  a thinned, loose stratum corneum (2,3,26). Topical retinoids increase the rate of kerati- nocyte turnover resulting in an increased rate of follicular proliferation and differen- tiation  (24). This results in decreased follicular  occlusion and faster microcomedone clearance (3,24). Specifically, topical retinoids cause basal and spinous epithelial cell proliferation and reduce the size and adhesion of corneocytes by decreasing filaggrin expression and  suppressing the  normal proteolysis of keratins 1 and  14 (1). In addition, retinoids thin  the  stratum corneum by  causing desmosomal shedding, decreasing tonofilaments, and  increasing keratinocyte autolysis (1,8,27).

Epidermal cell commitment to proliferation and differentiation can be altered by the topical retinoids. Normal keratinocyte differentiation involves the expression of keratins K1 and  K10 (26). An alternative pathway of differentiation compatible with  hyperproliferation occurs  upon suprabasal expression of K6, K16, and  K17 (26). Cells  expressing K6 and  K16 enlarge as they  migrate to the  surface  and  do not produce keratohyalin granules or lose their  nuclei  before desquamating (26).

The  dose-dependent  epidermal acanthosis results from  increased number of cell layers,  not  from  hypertrophy of individual cells (9). There  is no change  in structure or  size  of sebaceous glands after  treatment with  topical  retinoids (9). All  of  the  above  factors  demonstrate that  comedolysis is  retinoid-specific, not simply secondary to desquamation (3).

Retinoids also have  secondary effects that  facilitate  acne clearance. By weak- ening  and  loosening the cornified layer and  decreasing the number of corneocytes, skin  permeability is increased (2). This  facilitates the  absorption of other  topical agents, such  as  antimicrobials or  benzoyl peroxide (2). Increased cell  turnover

within the follicular epithelium also allows  more oral antibiotic to enter  the follicu- lar  canal  where P. acnes is concentrated (2). This  increases antimicrobial activity, lowering the  potential for  antibiotic resistance from  inadequate concentrations (2). By increasing the rate of acne clearance, the overall  duration of antibiotic treat- ment  and  chance  for  antibiotic resistance can  be reduced (2,6). In addition, this modification of skin morphology creates a more aerobic environment and decreases the ability  of P. acnes to proliferate (2).

USE AND SIDE EFFECTS

Proper selection  and  usage  of the topical  retinoids is crucial  to maximize efficacy and  patient adherence and  satisfaction. Treatment should begin  with  the  lowest concentration of medication, usually in a cream-based form if available (21). Appli- cation   should occur  at  night   to  dry  skin,  20  to  30  minutes after  the  face  has been  washed with  a mild,  nonsoap cleanser (21). A pea-sized amount should be

dispensed and  equally divided over  two  index  fingers,  which  then  dab  the medi- cation  evenly  onto  opposite sides  of the  face  and  spread the  medication into  a thin  layer  until  no  visible  product remains (21). Hands should be washed after- wards to  avoid   retinoid dermatitis (21).  Application should  first  occur  every other  night  for one  to two  weeks  depending on the  skin  type  so as to minimize the  initial  irritation that  may  otherwise discourage adherence to  the  treatment regimen (1,21). Oily skin  is better  able to tolerate the potential irritating effects of the  retinoids and,  as  such,  a  shorter introductory period may  be  utilized (21). Non-comedogenic moisturizers can  be used  to minimize xerosis,  erythema, and stinging (2). Patients should be instructed that  as long as four  to six weeks  of use may  be required before  the  onset  of efficacy and  that  an initial  flare in acne  may occur  following two  to four  weeks  of use  due  to an accelerated evolution of pre- existing   microcomedones (3). Periodic encouragement  and  reassurance may  be necessary. Four  to six weeks  of nightly application should occur,  after  which  the concentration may  be  increased if the  desired results are  not  obtained (21). An additional benefit  to topical  retinoid use  is the  potential to improve and  prevent the  postinflammatory hyperpigmentation often  seen  in darker skin  types  as acne lesions  heal.

MINIMIZING SIDE EFFECTS

Side   effects   of  topical   retinoid  use   include  initial   local   irritation,  including erythema, burning, stinging, peeling, and  xerosis  (1). These  symptoms usually peak  after  two  weeks  of use,  and  subsequently diminish and  then  resolve  once the  skin  adapts to the  use  of the  product (1,3,18). Factors  influencing the  extent and  duration of irritation include concentration of the  medication used,  vehicle of delivery, frequency and  amount of application, skin  type,  and  environmental factors   such   as  use   of  abrasive  cleansers  or  other   topical   alcoholic   agents, ambient xerosis,  and  exposure to  the  sun  (1,6,14,18,28). Higher concentratations or  use  of  a  gel  or  solution vehicle   predisposes to  the  most  irritation. Topical retinoids produce more  irritation when used  by patients with  eczema,  rosacea,  or other  conditions of skin  sensitivity, including exposure to extreme weather (2,14). In  these  patients and   during the  winter, lower   concentrations and   the  milder forms   and    vehicles    should  be   utilized  (2,28).   Individual  patient  variation does,  however, occur  and  some  patients may  actually tolerate gels  better  than creams,  perhaps because they are more  difficult  to apply. Adapalene and  tretinoin are photoirritants, not photosensitizers, meaning that  there  is an increased susceptibility  to  irritation upon  sun   exposure,  and   therefore minimizing sun exposure through sun  avoidance and  the use  of sunscreen or physical blockers  is imperative (14,28).

For patients who  are unable to tolerate even  the gradual introduction of the mildest topical   retinoids, short   contact   therapy can  be  utilized. Short   contact therapy is a safe  and  effective  method that  involves applying the  topical  agent for a brief period and then washing it off (13). Patients should initially  leave the reti- noid  on the skin for two minutes each day, increasing by one minute at least every three days as tolerated and without causing adverse effects (13). If irritation occurs, time of exposure should be decreased by 30 seconds for at least three days and then incremental increases can be resumed (13). Studies  have  demonstrated somewhat diminished efficacy than overnight tazarotene, but overall good results without irri- tation  in patients who  otherwise would be unable to benefit  from  topical  retinoid therapy (13).

VEHICLES

The  type  of  vehicle  used   to  deliver the  retinoid  influences the  degree of  skin penetration, the  clinical  effect, and  the  side  effect profile,  including the  degree of photoirritance (1,6). Future formulations suspending topical  retinoids in  a foam vehicle  could  potentially create  a nongreasy, no-residue, less-drying formulation to more  effectively  deliver the medication over hair-bearing sites such  as the back and  chest  (29).

EFFICACY

Acne  vulgaris is an  almost  ubiquitous condition. When  antimicrobials are  used alone,  there  is a risk  of creating widespread, multidrug resistance of P. acnes as well as other  skin flora such  as Staphylococcus aureus (2,5,30). This potential resist- ance can be limited by combining agents that  act on different steps  in the mechan- ism of acne pathogenesis. When topical  retinoids are used  in combination with oral or topical  antimicrobials, excessive  ductal cornification, P. acnes proliferation, and inflammation can  be  simultaneously targeted for  increased efficacy,  faster  onset of effects, decreased total  antibiotic use and  risk of resistance, and  shorter overall duration of treatment (2). The combination tretinoin with  topical  or oral antibiotics has been shown to be superior to either  alone in decreasing lesion count,  increasing rate  of improvement, and  decreasing levels  of P. acnes and  free fatty  acids  (8,14). Similarly,  the  combination of adapalene with  topical  doxycycline or clindamycin shows  increased efficacy in improving total,  inflammatory, and  noninflammatory lesions  including a faster  onset  of action  without an augmentation in side  effects (17).  In  addition,  combination  use   of  adapalene  offers   an   anti-inflammatory benefit, which  minimizes the increased risk of irritation that occurs upon increasing the number of topical  treatments (17).

Similar results were found upon combining retinoic acid and antibiotics, with a reduction in the initial retinoid-induced flare of lesions  through the antibiotic use (3). When combined with a benzoyl peroxide oxidizing wash—which demonstrates an effective bacteriostatic concentration after only 20 seconds of use—tretinoin 0.1% micro  gel decreased P. acnes counts without increasing irritation (6,31).

With  long-term use,  however, overall  improvement is similar with  combi- nation  therapy as compared with  topical  retinoid use  alone  (14,23,32). Increased reductions in  open  and  closed  comedones, papules, and  pustules were  demon- strated when tazarotene or  tretinoin creams  were  combined with  clindamycin/ benzoyl peroxide as compared to either  retinoid alone  (14,32).

Finally,  it has been  shown that  combining topical  retinoid therapy with  oral antibiotics for inflammatory acne is more  cost-effective than  using  an oral retinoid alone when accounting for pretreatment and  treatment laboratory tests, pregnancy tests, and  diagnostic fetal tests after a potential unintended pregnancy (33).

A new combination clindamycin 1%/tretinoin 0.025% gel, Velac, has demon- strated greater and  faster treatment success  in initial  clinical trials when compared to clindaymycin or tretinoin gel alone  and  provides a convenient means of appli- cation,  which  may  improve patient adherence (12). The side  effect profile  of Velac was  similar to that  of tretinoin gel alone,  with  only  slightly  higher irritancy than clindamycin gel alone  (12).

And  as previously discussed, the use of topical  retinoid in combination with oral antibiotics can decrease time of use of antibiotics, decreasing risk of resistance, adverse response, or drug interaction.

SYSTEMIC ABSORPTION AND TERATOGENICITY

The  teratogenic effects  of  oral  retinoid therapy are  well-documented. Tretinoin penetrates the skin and accumulates in the upper dermis with very little absorption into blood  vessels  or lymphatics (24). Several  studies have  evaluated the systemic effects  of topical  retinoid therapy. Tretinoin 0.1% to  0.2% applied for  extended periods demonstrates minimal to no increase in tretinoin levels above  endogenous and   these   level  changes  have   not   been   associated  with   teratogenicity  (1,21). Worobec   et  al.  (34) studied the  percutaneous absorption of  0.05% tretinoin by using   radioactive  labeling   and   measuring the  levels  of  retinoid found  in  the urine,  stool, and  plasma, after repeated applications. An absorption level of 1.38% to  2.13% was  found, correlating to  an  insignificant increase in  the  endogenous level of tretinoin and  a very low risk of systemic toxicity (34). When  0.1% tretinoin cream, 0.1% Tazarotene gel, and 0.1% adapalene gel were applied over 26 days,  the respective mean  maximal plasma levels of were 4.7, 0.14, 0.04 ng/mL, which  are all well below  the mean  endogenous level of 6.6 ng/mL of all-trans-,  13-cis- þ 13-cis-4- oxo-RA (21). Other  studies have also found that overnight tazarotene use produces levels  of tazarotene and  tazarotenic acid  levels  lower  than  endogenous, with  the highest rate of absorption shown to occur after tazarotene was applied under occlu- sion  for 10 hours resulting in ,6% absorption of total  applied dose  (13). In fact, diurnal and  nutritional factors  alter  endogenous plasma levels  of retinoids more than  widespread topical  use  of all-trans-RA  (35). Buchan  et al. (35) evaluated the daily  use  of radiolabeled 0.025% all-trans-RA over  the  face, shoulder, and  upper chest  and  demonstrated a percutaneous absorption in the  range  of 0.1% to 7.2%, considered to be an insignificant increase in endogenous levels. Daily ingestion of the 50,000 IU of vitamin A, however, tripled the endogenous level of all-trans-RA, doubled the  level  of 4-oxo-13-cis-RA, and  increased 13-cis-RA six times  (35). The recommended daily  allowance of vitamin A for male  adults is 900  mg/day  and fornonpregnant, nonlactating women 700 mg/day of vitamin A, with the recommended dosage actually increasing to 770 mg/day in preganancy and to 1300 mg/day in lactation (36). On the basis of this information, it is very  unlikely that  topical  retinoid use could cause systemic toxicity.

Although  there   is  a  lack  of  studies  on  humans,  topical   retinoids  have not  demonstrated teratogenic effects in animals (24,37,38). Nevertheless, tretinoin should be used  cautiously in pregnancy and  lactation while  tazarotene is contraindicated.

CONCLUSIONS

Topical retinoid therapy is a safe, effective, economical means of treating all but the most  severe  cases of acne vulgaris. The retinoids serve  as the cornerstone of treat- ment  and should be the initial therapeutic step, either  alone or in combination with topical   or  oral  antibiotic therapy  and   benzoyl  peroxides.  Once  a  patient  has achieved adequate results, the topical  retinoid should be continued alone as main- tenance therapy to maintain lesion  remission (2,20,33).

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