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SUPPLEMENT TO THE MAY 2006
skin
&
AGING
SUPPLEMENT PROCEEDINGS FROM THE 2006
CLINICAL
DERMATOLOGY
CONFERENCE
HAWAII™
BASED ON SELECTED PRESENTATIONS FROM
THE WINTER CLINICAL DERMATOLOGY CONFERENCE TM
HELD IN MAUI, HAWAII, JANUARY 13 -17, 2006.
ORGANIZED BY
PARTICIPANTS
CONTENTS
James Q. Del Rosso, D.O., F.A.O.C.D.
Clinical Assistant Professor
Department of Dermatology
University of Nevada
School of Medicine
Las Vegas, NV
UPDATE ON THE TREATMENT OF
ROSACEA
BY JOHN E. WOLF, M.D., M.A.
PAGE 1
MANAGING ACNE VULGARIS:
TRICKS OF THE TRADE
BY JAMES Q. DEL ROSSO, D.O., F.A.O.C.D.
Mark Lebwohl, M.D.
Professor and Chairman
The Mount Sinai School of
Medicine, New York, NY
PAGE 4
WHAT’S NEW IN PEDIATRIC
DERMATOLOGY
BY LAWRENCE F. EICHENFIELD, M.D.
PAGE 7
John E. Wolf Jr., M.D., M.A.
Professor and Chairman
The Baylor College of Medicine
Houston, TX
COSMECEUTICALS IN DERMATOLOGY
BY HILARY E. BALDWIN, M.D.
PAGE 10
COMBINING DERMATOLOGIC THERAPIES:
WHAT WORKS AND WHAT DOESN’T
BY MARK LEBWOHL, M.D.
PAGE 14
Hilary E. Baldwin, M.D.
Associate Professor and
Vice Chair
State University of New York
Brooklyn, NY
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articles in this supplement are based
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held on January 13 – 17, 2006 in
maui, hawaii.
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[ WINTER
UPDATE ON THE
TREATMENT OF ROSACEA
A BASIC GUIDE TO CURRENT APPROACHES.
JOHN E. WOLF JR., M.D., M.A.
osacea is both a contemporary and an ancient disease.
It is as new as photographs
of Bill Clinton’s red nose and as
old, at least, as the excellent
depiction of rhinophyma in the
painting “Old Man and Grandson,”
which hangs in the Louvre, by
the Renaissance grand master
Domenico Ghirlandaio. Today, the
John E. Wolf Jr., M.D., M.A. number of patients with rosacea
seems to be greatly increasing, due
either to an actual increase in the
prevalence of the disorder or to an expanding awareness on the
part of both patients and dermatologists. This article will provide general information as it relates to new management
strategies and therapies for the treatment of rosacea.
R
ROSACEA BASICS
COMMON MANAGEMENT METHODS
Current FDA-approved topical therapies for rosacea include
metronidazole, azelaic acid and sulfacetamide-sulfur formulations. The “gold standard” for years has been topical metronidazole, recently challenged by topical azelaic acid. Numerous clinical studies have demonstrated the safety, efficacy and tolerability of metronidazole products ranging from 0.75% gel (MetroGel)
to 1% cream or gel formulations, which I will discuss later as an
emerging therapy. These preparations are particularly useful for
papulopustular rosacea, but may decrease erythema as well.
Several sodium sulfacetamide-sulfur products have been marketed and have demonstrated effectiveness in both monotherapy and in combination with topical metronidazole. They are safe
and generally well-tolerated. Azelaic acid as a 20% cream that
has been prescribed for both acne and rosacea, but it seems
less effective than the more recently introduced 15% gel formulation (Finacea, to be discussed as an emerging therapy).
[
Rosacea may be defined as a common, chronic, constitutional disorder of unknown etiology and uncertain pathophysiology.
Common diseases are often underestimated – patients expect a
quick cure and may be very frustrated when one is not forthcoming. Physicians, too, may be guilty of subliminal underestimation of the therapeutic challenges of rosacea. Because
rosacea is a constitutional disorder, patients must be counseled
that our therapeutic goal is control, not cure. If they do not understand this, they will “doctor shop” aggressively, wasting time and
emotional energy.
Even though we have now accumulated much interesting
information on the pathophysiology of rosacea, we still do not
understand the grand design. In the absence of a well-understood etiology and pathogenesis, therapy is, of necessity, empirical. The standard management strategy for controlling rosacea
embraces topical and systemic therapy as well as patient education regarding proper skincare regimens and the avoidance of
trigger factors.
]
BECAUSE ROSACEA IS A
CONSTITUTIONAL DISORDER,
PATIENTS MUST BE COUNSELED
THAT OUR THERAPEUTIC GOAL IS
CONTROL, NOT CURE.
A CLOSER LOOK
AT THE TREATMENT SELECTION
First-line oral therapies for rosacea are well known and include
tetracyclines (especially doxycycline and minocycline), erythromycin and ampicillin. Second-line oral agents include trimethoprim-sulfamethoxazole (Bactrim, Cotrim, various); metronidazole;
oral prednisone (Deltasone, Meticorten, various); and isotretinoin
(Accutane, Amnesteem, Claravis, Sotret); treatment of
S U P P L E M E N T T O S K I N & A G I N G • M AY 2 0 0 6 • 1
Helicobacter pylori. (The latter is controversial and lacks convincing evidence of efficacy.) All of these agents (listed in full in
“Oral Therapy for Rosacea Treatment”) have possible side
effects, so we must assess the risks and the benefits.
Often the treatment of rosacea is a two-stage process, seeking initial control with a combination of oral and topical agents,
then maintaining control with a topical agent. The soundness of
this strategy was validated in a study by Dahl, et al.1 The authors
treated patients for 3 months with tetracycline and metronidazole
gel 0.75% or vehicle and subsequently discontinued tetracycline.
Over the next 3 months, twice as many relapses were noted
among patients using vehicle alone compared to those using
metronidazole gel 0.75%.
Choosing treatments. Regardless of the choice of therapeutic
agents in rosacea, patient education is extremely important.
Patients who have rosacea often have sensitive skin that is easily irritated. We must teach them to use gentle cleansers, moisturizers and sunscreens and to avoid potentially irritating substances. As physicians, we must also inform patients of possible
trigger factors (according to surveys by the National Rosacea
Society [NRS], the three most common triggers are sunlight, heat
and stress). For a list of other common things rosacea sufferers
should avoid, see “Non-Drug Interventions.” Patient compliance
Oral Therapy for
Rosacea Treatment
First-line antibiotics for the treatment
of rosacea include:
•
•
•
•
•
tetracycline
minocycline
doxycycline
erythromycin
ampicillin
Second-line agents include:
trimethoprim-sulfamethoxazole
metronidazole
• dapsone
• prednisone
• isotretinoin
• In refractory cases, amoxicillin 500 mg q.i.d.
for 7 days, metronidazole 500 mg t.i.d. for
3 days and bismuth subsalicylate two
tablespoons or two tablets every 6 hours
for 7 days
•
•
2 • M AY 2 0 0 6 • S U P P L E M E N T T O S K I N & A G I N G
Non-Drug Interventions
The following is a list of triggers that
rosacea sufferers should avoid:
•
•
•
•
•
•
•
sun
wind
hot liquids
spicy foods
alcoholic beverages
extremes of heat and cold
any other identified triggers
in rosacea therapy is generally poor, which often leads to a high
relapse rate. I have found patient-friendly publications from the
NRS to be very helpful in patient education. I often recommend
Web sites of the NRS (www.rosacea.org) and The American
Academy of Dermatology (www.aad.org).
New treatments. Consider three emerging therapies for rosacea:
1. Anti-inflammatory dosing of doxycycline. This approach
emphasizes the anti-inflammatory as contrasted with the antimicrobial properties of oral antibiotics. Because there is no proven
and generally accepted microbial pathology in rosacea, we
employ both topical and oral agents largely for anti-inflammatory
actions. The concept of anti-inflammatory dosing of doxycycline
is based on the fact that an anti-inflammatory impact can be
achieved with a dose lower than the traditional dosing format
(i.e., < 50 mg daily). This allows for a decrease in common side
effects of doxycycline, such as photosensitivity, heart burn and
vaginal yeast infections. By staying below the minimal antimicrobial level, this approach is also likely to decrease the emergence
of resistant strains of bacteria. The clinical efficacy with such a
dosing regimen has been demonstrated first with a dose of
20 mg twice daily (Periostat), and more recently, with a single
daily dose of 40 mg. A new product containing 40 mg of
doxycycline (tentative name Oracea) is currently awaiting
FDA approval.
2. Azelaic acid 15% gel. This is a is a relatively new agent that
has direct anti-inflammatory properties. Pivotal studies showed
superiority to vehicle (57.9% vs. 39.9% and 50% vs. 38.2%). In
a comparative study with metronidazole gel 0.75%, the decrease
in lesion count was 12.9 with azelaic acid 15% gel vs. 10.7 with
metronidazole gel 0.75%. This decrease was statistically significant. Pivotal studies with the 15% azelaic acid gel showed a 33%
incidence of burning, stinging and tingling (vs. 9% with vehicle),
including 13% moderate or severe symptoms (vs. 3% with vehicle).2 I advise patients of this possibility so that they are prepared
to work patiently toward tolerance.
[ WINTER
Patient with rosacea treated with MetroGel 1%. The photo at left was taken at baseline; the photo at right was taken after 9 weeks
of treatment. Photos courtesy of Galderma Laboratories.
3. Metronidazole 1% gel. Metronidazole is notoriously difficult
to place in solution, and a 1% gel concentration (MetroGel 1%)
was not achievable until the development of a new vehicle containing 92% water and HSA-3 (a mixture of three HydroSolubilizing Agents: niacinamide, betadex and a low concentration of propylene glycol).
Phase I studies showed a low mean cumulative irritation score
(comparable to vehicle). A Phase II study of absorption demonstrated twice the absorption of metronidazole as that seen in a
[
tions could result in better patient compliance and lower cost.
I will mention only briefly that a recently concluded 15-week
study comparing once-daily metronidazole gel 1% to twice daily
azelaic acid gel 15% showed statistically equal efficacy, good tolerability and an improvement in quality of life. This study appears
in the April 2006 issue of Cutis.4
BE OPEN TO THE OPTIONS
In this article, I have concentrated on medical therapies for
rosacea; however, new and exciting applications of light-based
technologies are also being developed for the management of
rosacea. It behooves us to learn about all of the available and upand-coming rosacea therapies and management strategies so
that we may effectively treat our patients.
]
IT BEHOOVES US TO LEARN ABOUT
THE AVAILABLE AND UP-AND-COMING
ROSACEA THERAPIES AND
MANAGEMENT STRATEGIES SO
THAT WE MAY EFFECTIVELY
TREAT OUR PATIENTS.
1% cream formulation (Noritate); presumably the metronidazole
in suspension (not solution) in the cream was partially filtered out
by the stratum corneum. A large, multi-center, well-controlled
Phase III study of once daily application of 1% metronidazole gel
showed statistically significant reduction in inflammatory lesions
(median = 67% vs. 46% with vehicle alone), improvement in
investigator global severity scores (73% clear, almost clear or
mild at week 10), and excellent tolerability.3 Once-daily applica-
REFERENCES
1. Dahl MV, Katz HI, Krueger GG, et al. Topical metronidazole maintains
remissions of rosacea. Arch Dermatol. 1998;134(6):679–683.
2. Elewski BE, Fleischer AB Jr, Pariser DM. A comparison of 15% azelaic acid gel and 0.75% metronidazole gel in the topical treatment of
papulopustular rosacea: results of a randomized trial. Arch Dermatol.
2003139(11):1444–1450.
3. Torok HM. Efficacy and tolerability analysis of metronidazole
treatment. Presented as a poster at the AAD meeting in Chicago.
July 2005.
4. Wolf JE, Kerrouche N, Arsonnaud S. Efficacy and safety of once daily
metronidazole 1% gel compared with twice daily azelaic acid 15% gel
MANAGING ACNE VULGARIS:
TRICKS OF THE TRADE
NEW INSIGHTS INTO ADVANCES IN FORMULATION TECHNOLOGY,
APPLICATION TECHNIQUES AND MORE FOR MANAGING THIS
COMMON DISORDER.
BY JAMES Q. DEL ROSSO, D.O., F.A.O.C.D.
anaging acne vulgaris is an
ongoing challenge. In
practice, dermatologists
are adept at clinical evaluation and
are experienced in the use of currently
available
medications.
However, what about advances in
treatment, new techniques and
novel information regarding this condition? This article discusses new
frontiers in skin care, proper use and
compatibility of topical medications,
formulation advances and the treatment of truncal acne vulgaris.
M
James Q. Del Rosso,
D.O., F.A.O.C.D.
SKIN CARE FOR ACNE PATIENTS
Skin care is an area where dermatologists need to provide
direction for every patient. In clinical trials of medications used to
treat acne, skin care is usually specifically defined and controlled
[
]
SKIN CARE SHOULD BE GENTLE,
USING APPROPRIATE CLEANSERS AND
MOISTURIZERS TO MITIGATE IRRITATION
AND TO COUNTER DAMAGE TO THE
EPIDERMAL BARRIER CAUSED BY
SEVERAL ACNE MEDICATIONS.
and contributes adjunctively to the final therapeutic outcome. As
a result, we should not underestimate the importance of the role
of skin care. In the case of acne vulgaris, skin care should be
gentle, using appropriate cleansers and moisturizers to mitigate
irritation and to counter damage to the epidermal barrier caused
by several acne medications.
The epidermal barrier serves to maintain the functioning of the
skin through physiologic control of transepidermal water loss.
Moisture is retained within the stratum corneum by “natural moisturizing factor”. Natural moisturizing factor is a collection of small
compounds that serve as “nature's humectant” by retaining
water within the epidermis. Epidermal barrier dysfunction produced by harsh cleansing and some topical acne medications
leads to dryness, erythema, scaling and fine fissuring, predisposing the skin to symptoms of irritation that may be compounded
by the use of topical products that would not otherwise produce
an irritation reaction if the epidermal barrier were intact. In addition, decreased linoleic acid in the sebum of acne patients may
contribute to reduced barrier function by adversely affecting the
production of the intercellular lipids that comprise the lamellar
membrane component (“mortar”) of the epidermal barrier, which
is layered between corneocytes.
A recently completed, small (n=30), but important study, performed in patients with mild facial acne vulgaris emphasizes the
significance of cleansing with a gentle daily facial cleanser. Upon
entry into the study, patients were not using any acne therapy
and the clinical status of acne was stable. Researchers administered Cetaphil Liquid Cleanser to patients to use twice daily over
a 2-week period. The following parameters were evaluated:
mean percentage lesion reduction, tolerability and epidermal barrier function. By study endpoint, the investigators measured tolerability as favorable and detected no damage to the epidermal
barrier. Also, acne lesion counts decreased from a mean of 25 to
20 within the first week of use and patients reported compliance
at >99%. Hence, what we commonly describe as “vehicle effect”
during an acne trial likely includes the adjunctive benefit of proper skin care.
A 4-week study (n=50) evaluated the impact of using a gentle, synthetic detergent bar (Dove) versus a soap bar in patients
with facial acne vulgaris already maintained topically on the
combination regimen of benzoyl peroxide 5% and erythromycin
3% gel (Benzamycin Gel) and topical adapalene (Differin). Simply
changing to the gentle synthetic detergent cleansing bar signifi-
[ WINTER
cantly lessened several irritation and tolerability parameters
including erythema, peeling, dryness, stinging and burning by
study endpoint.
COMPATIBILITY OF TOPICAL MEDICATIONS
What about the chemical compatibility of applied medications?
Is this important in clinical practice? Studies evaluating retinoid
stability data indicate rapid degradation of tretinoin formulated in
conventional vehicles when combined with benzoyl peroxide or
upon exposure to light. Adapalene (Differin) and tazarotene
(Tazorac) do not exhibit this degradation, and in fact, adapalene
has been shown to not degrade in the presence of the tube gel
formulation of benzoyl peroxide 5%-clindamycin 1% (Duac Gel).
Importantly, the microsponge vehicle of tretinoin microsphere gel
0.04% and 0.1% (Retin -A Micro) significantly protects the
tretinoin from degradation upon light exposure or concomitant
admixture with benzoyl peroxide.
One 24-hour stability study specifically evaluated benzoyl peroxide 6% (Triaz) admixed with adapalene or tretinoin microsphere
1
gel 0.04% and 0.1%. Testing of the retinoid concentration in the
admixture was completed after 8 hours and 24 hours. Adapalene
remained fully stable over the entire 24-hour study period, whereas both tretinoin microsphere gel strengths retained >97% stability over 8 hours, with retention of approximately 70% by 24 hours
(Table 1). Why is this study important? Topical drugs that are
chemically compatible may be applied consecutively, allowing for
a once-daily application session, thus enhancing potential for
better compliance. This approach warrants consideration of possible skin irritation, and it may be prudent to separate use initially for the first few weeks to allow the skin to accommodate to
each of the medications.
APPLICATION TECHNIQUES FOR
TOPICAL MEDICATIONS
Another important aspect of acne therapy is education with
regard to how much medication to apply and how to properly
apply topical product diffusely and uniformly to the region requir-
TABLE 1
Benzoyl Peroxide Compatibility
with Adapalene or Tretinoin Microsphere
Benzoyl Peroxide 6% (Triaz) +
Formulation
8 Hours
24 Hours
Adapalene 0.1%
100%
100%
Tretinoin Micro 0.1%
97.8%
68.4%
Tretinoin Micro 0.04%
97.0%
71.5%
ing treatment. This is important with all topical medications,
especially antibiotics, which necessitate achieving a critical concentration to attain antibiotic activity; that is, levels above the
minimum inhibitory concentration of the targeted microorganism.
In the case of acne vulgaris, the targeted bacterium is
Propionibacterium acnes, which proliferates within follicles of
acne lesions contributing to the stimulation of an inflammatory
cascade and possibly to comedogenesis.
Application technique must ensure widespread and even distribution. Patients who are not properly educated on medication
application to the face are inclined to apply centrally, with feathering toward the periphery. This is likely to result in inconsistent
application, especially along the lateral face and hairline.
[
]
TOPICAL DRUGS THAT ARE
CHEMICALLY COMPATIBLE MAY BE
APPLIED CONSECUTIVELY,
ALLOWING FOR A ONCE-DAILY
APPLICATION SESSION.
A study completed by the author in 2005 evaluating a specific
method of application with a defined distal fingertip unit con2
firmed diffuse distribution using fluorescence technique. The
study also evaluated product consumption based on vehicle
type, and confirmed efficacy of treatment. This study did not use
the classic definition of a fingertip unit (from the distal volar crease
to the tip); rather it defined the unit as confined to the distal tip
(pulp region).
Patients applied a fingertip unit to each of nine designated
facial sites once daily for 7 days with results extrapolated to
28 days of use. Using weighing at baseline and at 7 days, consumption of product in grams was calculated for lotion, cream,
thick cream, gel in a tube and gel in a jar. This approach allowed
for determination of how long a given quantity of product should
last. For example, a 45-g tube gel formulation of benzoyl peroxide 5% and clindamycin 1% gel applied once a day should last a
patient approximately 2 months (using the described facial application technique).
The use of benzoyl peroxide pads (Triaz Pads), a leave-on formulation, has been shown to facilitate even drug distribution with
many patients expressing preference for pads and cloths. A
newer benzoyl peroxide pad cleanser (Zoderm RediPads) is also
available, as is a sulfacetamide 10% and sulfur 5% open-weave
cleansing cloth (Plexion Cloths) for the treatment of rosacea,
acne vulgaris and seborrheic dermatitis.
TRUNCAL ACNE: THE FORGOTTEN TERRAIN
Data on the treatment of truncal acne vulgaris is scarce. The
trunk is a treatment challenge, as it is difficult for patients to apply
and evenly distribute medication, especially on the back.
Fortunately, a new formulation is adaptable for truncal acne vulgaris: clindamycin phosphate foam, 1% (Evoclin). A major advantage of this particular patented VersaFoam formulation is that it’s
a “slow-break” foam. In contrast, the available corticosteroid
VersaFoam formulations of betamethasone valerate 0.12%
(Luxiq) and clobetasol propionate 0.05% (Olux) utilize “quick-
[
]
... PRACTITIONERS MAY MODIFY
CURRENT [TREATMENT] APPROACHES
BASED ON NEW DATA THAT SUPPORT
THE INTEGRAL INVOLVEMENT OF
CONTROLLED, GENTLE SKIN CARE ...
break” foam technology, which liquifies immediately upon contact
with skin, penetrating rapidly without residue. Clindamycin foam
liquifies at a 5˚ higher temperature, so it remains as a mound on
the skin until it is actively rubbed in.
The importance of using a benzoyl peroxide cleanser in combination with clindamycin foam for treatment of truncal acne is
based on additive therapeutic value with combination therapy
and reduction of emergence of antibiotic-resistant P. acnes
strains. The use of a quality benzoyl peroxide cleanser avoids
bleaching of fabric, which is much more likely to occur with
“leave-on” formulations and mitigates the risk of the emergence
of antibiotic-resistant bacterial strains that may occur with chronic antibiotic therapy.
In an open-label, proof-of-concept trial, Dr. Joseph Bikowski
and the author treated 40 patients with moderate truncal acne
vulgaris with clindamycin phosphate foam 1% once daily in combination with either benzoyl peroxide 9% cleanser or benzoyl peroxide 8% (Brevoxyl Creamy Wash).3 By the 8-week study endpoint, 30% were completely clear or almost clear, 60% were at
least markedly improved, and 92% were at least moderately
improved (Table 2). In patients with more severe involvement, an
oral antibiotic such as doxycycline or minocycline may be added
to the combination of topical clindamycin foam and benzoyl peroxide cleanser.
PURSUING NEW OPTIONS
Although there has been a conspicuous absence of new
chemical entities available for the treatment of acne vulgaris,
practitioners may modify current approaches based on new
data that support the integral involvement of controlled, gentle
skin care into the acne treatment regimen; chemical compatibility data, which may simplify treatment by allowing for a single
topical application session; and the use of medication application techniques that maximize the distribution of medication to
the skin as well as product consumption. In addition, practitioners are directing new attention to truncal acne vulgaris, with
efficacy demonstrated in cases of moderate severity using a
combination of clindamycin phosphate foam and a quality benzoyl peroxide cleanser.
REFERENCES
TABLE 2
Truncal Acne Vulgaris Clindamycin 1% Foam + Benzoyl
Peroxide 8% Creamy Wash or 9% Cleanser
of a Patented Pad Formulation of Benzoyl
Peroxide in Combination With a Topical Retinoid:
Chemical Stability, Efficacy, and Tolerability.
Open-label, observational trial
Cosm Dermatol. 2006;19(2):93-97.
40 patients ~ age range 15 to 28 years (mean – 21 yrs)
8-week trial ~ moderate truncal acne
BP 8% Creamy Wash (n=22) / BP 9% Cleanser (n=18)
2. Del Rosso JQ. A Qualitative and Quantitative
Assessment of the Application and Use of
Response
Complete Clearance
Almost Clear
Markedly Improved
Moderately Improved
No Improvement
Worsening
1. Del Rosso JQ. Bench Top to Bedside Evaluation
2.5%
27.5%
30%
32.5%
7.5%
0%
1/40
11/40
12/40
13/40
3/40
0/40
Topical Acne Medication by Patients. Cutis.
2005;76(2):109–113.
3. Del Rosso JQ, Bikowski J. Poster presentation.
Summer AAD, Chicago, 2005. Skin & Aging.
September 2005.
[ WINTER
WHAT’S NEW IN
PEDIATRIC DERMATOLOGY
A REVIEW OF PRACTICAL INFORMATION RELEVANT
TO THIS SPECIALTY.
BY LAWRENCE F. EICHENFIELD, M.D.
s part of practicing dermatology, we deal with children.
In doing so, we sometimes
approach treatment differently than
we would in our adult patients. I will
present some common and uncommon pediatric cases, including treatment considerations. I will also discuss some new “tricks and trends”
in pediatric dermatologic care.
A
Lawrence F. Eichenfield, M.D.
CASE 1: STERNAL CLEFT
The child had a sternal cleft malformation and an umbilical
raphe, the name for a line of midline tissue, extending superiorly
from the umbilicus. No hemangioma was present at the time,
though my experience and referenced articles suggest that the
physical findings are usually associated with the development of
facial hemangiomas.1 Two weeks later, the child developed a
[
A pediatrician in the community
called because a child was born with a “line coming up from the
belly button to the chest” (Figure 1). Over the phone, I asked
whether a defect of the sternum was present, and the pediatrician answered “yes”. I then inquired whether he could see the
heart beating through it, and he said “no”. That’s when I figured
we were dealing with a sternal cleft malformation, which made
me concerned that the infant would develop a potentially serious
facial hemangioma. Several days later, after discharge from the
hospital, the family came to my office.
]
WITH FIVE OR MORE HEMANGIOMAS,
YOU SHOULD WORRY ABOUT SYSTEMIC
HEMANGIOMATOSIS. SOME COME UP
IN CONSISTENT PATTERNS OR
SEGMENTAL LESIONS, WHILE OTHERS
ARE INDETERMINATE.
facial hemangioma, which was aggressively treated before it
could have an impact on function or become deforming. The
findings of this child are consistent with a sternal cleft malformation with association of facial hemangiomas and are part of the
spectrum of what has been called PHACES syndrome.
CASE 2: SEGMENTAL PATTERN HEMANGIOMA
FIGURE 1. Sternal cleft with supra-umbilical abdominal raphe.
Hemangioma of lip/chin developed 2 weeks later.
This case involves a child noted to have an erythematous area
overlying the right side of the face and extending over the right
eye (Figure 2). Despite the distribution, the diagnosis was actually a hemangioma, not a port wine stain, because of the presence of elevated areas. This child presented with a lesion that
mimicked a port wine stain but clearly was a segmental patterned hemangioma of the face. We now know about the subtypes of hemangiomas. Some are localized, some segmental,
some indeterminate and others are multiple. With five or more
hemangiomas, you should worry about systemic hemangiomatosis. Some clearly come up in consistent patterns or segmental
lesions, while others are indeterminate.
temic corticosteroids and/or intralesional steroids; occasionally
laser, which can help with the surface component of hemangiomas as well as ulcerated hemangiomas. Occasionally, other
treatment modalities are used, including surgical excision.
CASE 3: LICE
FIGURE 2. Segmental pattern hemangioma overlying the right
side of the face, as described in Case 2.
A group of investigators performed an excellent study of data
on more than 2,300 hemangiomas.2,3 This study discussed risk
factors of hemangiomas. There is approximately 2.5 to 1 female
predominance, with hemangiomas more common in white nonHispanics than in African-Americans. Prematurity is a known risk
factor for hemangiomas, and this study showed an average gestational age of 36.3 weeks. Twins are more commonly seen with
hemangiomas than non-twins, though if corrected for prematurity, it’s uncertain if the twinning is an independent risk factor. Two
new observations were made:
1. Advanced maternal age is a risk factor for hemangiomas.
2. There appears to be a higher incidence of placental abnormalities in mothers of children with hemangiomas.3
A paper in Pediatric Dermatology summarizes these observations and also discusses the results of a National Institutes of
Health research workshop on infantile hemangiomas, which
included a dialogue on the placental theory of hemangiomas.
Some strong evidence exists that there is an association of placenta and hemangioma tissue, including hemangiomas expressing bio-markers similar to placental stains, and recent work
showing similar gene expression of hemangiomas and placentas.
Interestingly, hemangiomas usually present themselves, have
generally a 6- to 9-month proliferation phase and then stop growing and undergo apoptosis, involuting over time. A placenta has
a somewhat similar timeframe in terms of its phases of development. A new article evaluates total gene analysis. Using total
gene expression analysis, the authors looked at the similarity of
hemangioma tissue with placental tissue. And the degree of correlation in terms of genetic material is as close as the relationship
between lung cancer and lung tissue.4
A take-home point for those of us who manage hemangiomas
is that, for most hemangiomas, reassurance is all that is necessary; we don’t have to treat unless there’s a risk of functional
compromise or deformation. The mainstays of therapy are sys8 • M AY 2 0 0 6 • S U P P L E M E N T T O S K I N & A G I N G
An adolescent patient presents with an itchy rash on the base
of her neck (Figure 3). The diagnosis is lice. In fact, this was a lice
infestation presenting with an eczematous dermatitis. Which
would be the most effective topical treatment: Lindane (also
known as benzene hexachloride or gamma hexachlorocyclohexane), Cetaphil, malathion (Ovide) or permethrin? Many therapeutic agents are available to treat this problem. Most of us know
that Lindane generally has poor efficacy rates and high therapeutic risk, so there’s not much use of it in the United States anymore. Permethrin used to be highly effective and still is — but
there is some resistance to standard permethrin in products.
Malathion has low resistance rates in the United States, though
resistance does exist in areas where it’s commonly used.
Dr. Dale Pearlman began using a non-toxic, dry-on, suffocation
pediculicide to treat lice. He smeared this lotion on affected areas,
then used a blow dryer to shrink-wrap it (the “Nuvo method”). He
conducted two open clinical trials, one with 93 subjects who had
lotion and physical removal of the nits, and the other with 40 subjects who only had the lotion without nit removal, and had a 97%
cure rate and 95% in the second trial. With a 6-month follow-up,
remission was maintained in 94% and 95% of subjects, respectively.5 It was subsequently reported that the lotion he used was
Cetaphil cleanser. So I guess Cetaphil is an option if you want to
use something other than Nix or malathion for resistant lice cases.
Quell your urge to use Lindane because we don’t use it anymore.
Permethrin is the standard first-line agent, malathion is an alternative, but remember that it’s flammable, so advise families to avoid
smoking when using this treatment.
FIGURE 3. This 12-year-old girl presented with itching on her
neck and scalp. The diagnosis: head lice infestation.
[ WINTER
CASE 4: MOLLUSCUM CONTAGIOSUM
A 4-year-old child presents with 70 molluscum contagiosum
on the trunk and extremities (Figure 4). Should you:
• give her some topical anesthetic and schedule for curettage
with one of your partners?
• send immunologic studies for HIV serology because you are
worried about immunosuppression and HIV as a risk factor associated with molluscum?
• reassure the family that these lesions will resolve in a few
months?
• give her some Cetaphil?
None of these are my choice for this particular case.
A recent paper published in The Journal of the American
Academy of Dermatology looked at the epidemiology of molluscum.6 The study represented 300 patients from each of three
pediatric dermatology clinics. They found that 63% of children
younger than 8 years of age presented with greater than 15 molluscum lesions. Of the patients, 24% had atopic dermatitis.
Another interesting thing we looked for is whether immunosuppression was seen in the population, and only one patient had
immunosuppression. So while HIV and molluscum are commonly associated in adults, in pediatrics, molluscum are generally
seen in immunocompetent patients.
Most molluscum lesions occur on the trunk and the extremities;
only 18% appear on the face. When it comes to treatment, I keep
it simple. Some people perform curettage, some use imiquimod
(Aldara), liquid nitrogen or other treatments. But my mainstay of
therapy is 4-hour application without occlusion of cantharidin
(Cantharone). I apply small amounts of the liquid with the wooden
tip of a cotton-tipped applicator and require that it be washed off
in 4 hours. Patients generally tolerate this well. I limit it to about 30
lesions per treatment. So in this patient, it may take two to four
treatments to ensure that the child is well taken care of.
FIGURE 4. Molluscum lesions in a 4-year-old female patient.
ment area and starting a movie, children tolerate 20 minutes to
half an hour of incisional surgery quite well. Relevant to more
aggressive surgeries, which cannot be done under local anesthetic, is a recent paper showing the utility and safety of general
anesthesia for pediatric dermatologic procedures. This study
reviewed more than 881 procedures performed on 269 patients
at Children’s Hospital, San Diego and Children’s Memorial
Hospital in Chicago. It showed that the children tolerated general anesthesia for pediatric dermatologic procedures quite well,
with no serious events and no mortality.
EVOLVING FIELD
Clearly, pediatric dermatology is an evolving field. We continue
to learn from our patients, as well as from studies on pediatric
dermatology conditions.
IDENTIFYING NEW TRENDS
REFERENCES
As far as new “tricks and trends” in pediatric dermatology, we
should be aware of two in particular:
Wart treatment with Candida antigen immunotherapy. The use
of Candida antigen injections is clearly a trend in pediatric dermatology, although a good number of people still aren’t using it. We
probably have an approximate 40% response rate using 0.1 cc to
0.2 cc of Candida antigen injected into one to two warts. Patients
can opt for a topical anesthetic before receiving the injections, and
we do three or four treatments at about 3- to 4-week intervals. If the
lesions don’t respond after that, we’ll go on to another treatment.
Several papers support the use of Candida antigen for this purpose.
Making surgical procedures more bearable. Have you ever
seen a young child in front of a television? They totally ignore
everything else. A breakthrough for dermatologic surgery in the
office is the use of personal DVD players. After numbing the treat-
1. Chan YC, Eichenfield LF, Malchiodi J, Friedlander SF. Small facial haemangioma and supraumbilical raphe — a forme fruste of PHACES
syndrome? Br J Dermatol. 2005;153(5):1053–1057.
2. Haggstrom AN, Lammer EJ, Schneider RA, et al. Patterns of infantile
hemangiomas: new clues to hemangioma pathogenesis and embryonic facial development. Pediatrics. 2006;117(17):698–708.
3. Frieden IJ, Haggstrom AN, Drolet BA, et al. Infantile hemangiomas:
current knowledge, future directions. Proceedings of a research workshop on infantile hemangiomas, April 7-9, 2005, Bethesda, Maryland,
USA. Pediatr Dermatol. 2005;22(5):383–406.
4. Barnes CM, Huang S, Kaipainen A, et al. Evidence by molecular profiling for a placental origin of infantile hemangioma. Proc Natl Acad
Sci. USA. 2005;102(52):19097–19102.
5. Pearlman DL. A simple treatment for head lice: dry-on, suffocationbased pediculicide. Pediatrics. 2004;114(3):e275–279.
COSMECEUTICALS IN
DERMATOLOGY
THOUGHTS OF A SKEPTIC AND A HYPOCRITE.
BY HILARY BALDWIN, M.D.
am a skeptic regarding most of the
hype surrounding cosmeceuticals.
Having said that, I am also a hypocrite, since I personally use two cosmeceuticals every day, and I recommend them to my patients when
asked. This article will review the
background of cosmeceuticals and
examine their role in the field of
dermatology.
I
Hilary Baldwin, M.D.
COSMECEUTICALS:
THEN AND NOW
THE SEARCH FOR THE IDEAL ANSWER
In 1938, the FDA defined the
words “drug” and “cosmetic” with a clear-cut distinction.
Dermatologists used drugs to treat and prevent disease,
whereas they used cosmetics to change the appearance of,
adorn and ornament the skin. These definitions provided an
adequate distinction between the two terms until recent con-
[
]
ALBERT KLIGMAN COINED THE TERM
“COSMECEUTICALS” IN 1984 AS AN
ILL-DEFINED REALM BETWEEN
COSMETICS AND PRESCRIPTION
CARE PRODUCTS.
cepts of skin functioning became known. Albert Kligman,
M.D., Ph.D., coined the term “cosmeceuticals” in 1984 as an
ill-defined realm between cosmetics and prescription care
products.
The word “cosmeceutical” means different things to the various interested parties. The FDA doesn’t recognize the class of
1 0 • M AY 2 0 0 6 • S U P P L E M E N T T O S K I N & A G I N G
cosmeceuticals. The cosmetic companies believe that a cosmeceutical is composed of well-studied active ingredients with
proven efficacy. We as dermatologists see cosmeceuticals as
products that may or may not live up to claims. Dermatologic surgeons view them as adjunctive products that may alter wound
healing. Our patients see them as miracle cures, which leads to
the purpose of this article.
The luxury skincare market is the fastest growing of the entire
cosmetic industry. Sales for 2003–2004 were 6.4 billion, and
are projected to be $7.2 billion by 2008. And all of this is driven by the aging U.S. population.1
Most women are concerned about wrinkling and skin discoloration and loss of elasticity, and many are unaware that this is
largely due to sun exposure. The fear of wrinkles, as well as
procedures, has stimulated women to look for new alternatives.
Even if we are skeptical about cosmeceuticals’ efficacy, we
need to be well-versed in their existence. Why should we care
about cosmeceuticals? We care because patients like to use
cosmeceuticals; therefore, we need to know how to address
patients and how to discuss the available options with them.
Women want to feel beautiful, and they are confused by the
vast array of products available. They want specific information
and brand name recommendations from us. They are equally
seduced by cosmetic claims, cosmetic salespeople and by dermatologists. We need to be the most knowledgeable about
these products. We also need to know about cosmeceuticals
because they can make retinoids more tolerable and they can
improve the protocols and the procedures that we’ve done to
start the anti-aging process.
THE COSMECEUTICAL AIM
The goals of cosmeceuticals include:
• Preventing ultraviolet (UV) damage
• Reducing free radical formation
• Improving the skin lipid barrier
[ WINTER
• Brightening and unifying skin tone and color
• Smoothing texture
• Reducing pore size
• Reducing fine lines and wrinkles.
These goals are attainable, to a limited extent. We have to
remember that cosmeceutical science is really about using biologically active ingredients that were proven in vitro. In vitro success does not necessarily mean in vivo success. Putting two
proven actives together in a cream and applying it to the skin
does not guarantee its success, and few of these ingredients
have actually been tested in the finished marketed formulation.
The effectiveness of a cosmeceutical must be proven visually.
Histopathologic evidence of the success of a cosmeceutical
doesn’t help us much, unless it translates into clinical efficacy.
We need results to be compared to baseline or the patient’s routine regimen, positive control, split face or placebo. We need a
long study duration. Most of the studies published are not long
enough to show a difference between the cosmeceutical and
the vehicle. It may well be that there is no such thing as a placebocontrolled trial with a cosmeceutical. The vehicles used are
excellent moisturizers that will improve the quality of the skin.
The active ingredient adds only a small advantage (if any) to the
final product. A placebo-controlled trial may therefore show no
difference between vehicle and product.
AVAILABLE ACTIVE INGREDIENTS
Numerous elements and molecules exist. More than 70
botanicals are currently being added to what we refer to as cosmeceuticals. Cosmeceuticals can be categorized by their
chemical descriptions (retinoid, peptide, vitamin), by their activity, or based on their class (antioxidants, neurotransmitters, collagen stimulators or exfoliates). This article will review antioxidants, the collagen-stimulating cosmeceuticals and botanicals.
Retinoids and hydroxy acids have been omitted, as good evidence-based medicine exists to support their use.
ANTIOXIDANTS
Many agents belong in this category. This article will only discuss
vitamins C and E, niacinamide, alpha lipoic acid and idebenone.
Vitamin C is a powerful antioxidant. It scavenges UV lightinduced free radicals, reduces UV light-mediated phototoxicity
and is essential for collagen biosynthesis. The problem arises in
trying to get the vitamin C to penetrate into the dermis. It has
erratic penetration and is unstable. When it is able to get down
into the dermis, it has been shown to increase collagen synthesis. There is also some photoprotection for both UV-A and UV-B,
an effect that is improved by the addition of a vitamin E.2,3 As a
result, there is a modicum of visible improvement in skin texture, and a reduction in hyperpigmentation.
Vitamin E as a solitary agent is probably ineffective. The ini-
tial claims that it was able to reduce scar formation have not
been demonstrated. In combination with vitamin C, it may
enhance the antioxidant activity of vitamin C. The addition of
both vitamins C and E to sunscreens has been shown to
increase the photo-protective potential of the sunscreen, and
the addition of both to hydroquinone and sunscreen has been
shown in one study to hasten the resolution of melasma.4
Additionally, the initial claims of a high incidence of allergic contact dermatitis to vitamin E are probably unfounded.
Niacinamide (vitamin B 3) has a theoretical benefit of prevention
of photo-immunosuppression and photocarcinogenesis, as well
as a clinical loss of collagen. In a recent split-face study with niacinamide in Derm Surgery in 2005, the side treated with the active
[
]
WE HAVE TO REMEMBER THAT
COSMECEUTICAL SCIENCE IS
REALLY ABOUT USING BIOLOGICALLY
ACTIVE INGREDIENTS THAT WERE
PROVEN IN VITRO.
showed a reduction in fine lines, hyperpigmentation, blotching
and improved elasticity.5 Bissett, et al were impressed by how well
patients tolerated the niacinamide and compared it to their experience with tretinoin. They felt that niacinamide, although somewhat effective in the split-face study, was one-third to one-fifth
less effective than tretinoin (Renova, Retin-A, Avita).
Alpha lipoic acid is a potent antioxidant that’s both fat- and
water-soluble. It therefore penetrates well through the epidermis. It’s protective of both vitamins C and E within cells and it
has been shown (as a solo ingredient) to decrease fine lines and
scars.6 As such, it is a common additive to cosmeceuticals.
Idebenone is an active ingredient that has been shown in an
industry-based study to be a superior antioxidant compared to
those listed above. In clinical studies, it was demonstrated to be
capable of improving fine lines, smoothing texture, decreasing
sunburn cells, and down-regulating matrix metalloproteinases.7
COLLAGEN-STIMULATING COSMECEUTICALS
There is much less clinical evidence to support the use of collagen-stimulating cosmeceuticals, but considerable scientific
rationale exists. This category includes peptides, copper and
growth factors.
Cumulative UV exposure causes dermal changes in collagen,
elastin and glucosaminoglycans. Histologically, sun damaged skin
can be viewed as a large, chronic wound. Any agent that can
stimulate wound-healing pathways could be potentially helpful.
S U P P L E M E N T T O S K I N & A G I N G • M AY 2 0 0 6 • 1 1
Fibroblast stimulation might improve the thickness of the dermis
and could theoretically reduce fine lines and reduce pore size.
Peptides. The FDA consider peptides to be food, so there is
little scrutiny about their addition to cosmeceuticals. These are
charged moieties that penetrate poorly through the epidermis.
As such, they must be linked to a lipophilic tail such as palmitic
acid or incorporated into liposomes to penetrate the epidermis.
Once they get to the dermis, they have three theoretical activities. They can act as:
1. signal proteins to increase collagen production
2. carrier peptides to allow copper to get to the dermis
3. neurotransmitters that might be capable of destabilizing
the SNARE complex.
Signal peptides modulate collagen breakdown. They are
fragments of collagen type I. When placed into the dermis, they
signal that cellular damage has occurred in the dermis.
Fibroblasts could respond by increasing collagen and by
decreasing collagenase, thereby (theoretically) improving fine
lines and wrinkles. Secondly, peptides could act as carrier proteins. Some products contain a tri-peptide complex that stabilizes and delivers copper to the superficial dermis. Theoretically,
topically applied peptides could also act as neurotransmitters.
Argireline, a hexapeptide, has been added to some cosmeceuticals. It mimics part of the SNARE complex at the neuromus-
[
BOTANICALS
We use nearly 70 botanicals, but only six have clinical trials of
any sort. There has been a sharp increase in the use of these
agents because the concept of “natural” appeals to patients.
But for many botanicals, there is a lack of sound scientific
rationale, a lack of proof of any objective affects and a paucity
of human clinical studies. Furthermore, because entire plants
are used, it is unclear what active compounds are present in
each plant, how they interact with each other and their metabolites, and whether or not they get through the skin. Having said
that, some actives are theoretically able to decrease inflammation, decrease erythema and sunburn cells, and might thereby
improve skin tone and texture.
Active ingredients in soy include bioflavons and phytoestrogens. Alone and in combination with avocado and pentapeptides, creams have been shown to decrease sunburn cells and
crow’s feet, increase elasticity in skin thickness and visually
improve skin tone and texture.
All types of tea are the same species, but black tea is fermented and green tea is not, resulting in different active molecules. Recently, Chiu in Derm Surgery showed an increase in
elastic tissue on H&E, but was unable to show any clinical
improvement.11 This is the only double-blinded, placebo-controlled trial in green and black teas.
The concentration of actives in the final product determines
its efficacy. Quality assurance with botanicals is nearly impossible because numerous edaphic, climatic and manufacturing
variables exist. Changes in the soil and water, climate, how the
plant is harvested, how it is cared for during transport, whether
it freezes, rots and desiccates are all important. All of these fac-
]
SOME ACTIVES ARE THEORETICALLY
ABLE TO DECREASE INFLAMMATION,
DECREASE ERYTHEMA AND
SUNBURN CELLS, AND MIGHT THEREBY
IMPROVE SKIN TONE AND TEXTURE.
cular junction. Products with argireline advertise that they
“extend and potentiate Botox”. There is no evidence that topically applied neurotransmitters have any ability to reach the
SNARE complex. This requires injection.
Copper. Copper is an important trace element that is a cofactor in the cross-linkage of elastin and collagen. Copper has
been shown to be important in wound healing and other enzymatic processes. Data supporting its use in cosmeceuticals
were extrapolated from the use of copper in open wounds and
in tissue cultures.8,9 It is not at all clear at this time that this
extrapolation was appropriate.
Growth Factors. Similarities between the pathophysiology of
photodamage and acute and chronic wound healing exist. If
photodamaged skin is analogous to a chronic wound, then
growth hormones might be useful in improving skin appearance. Data are available that support the importance of growth
factors in the healing of open wounds.10 These are extraordinarily large molecules, and there is no evidence that they are
capable of penetrating through intact epidermis.
Hundreds of growth factors have been identified. It is likely
that the most important for aging issues will be the cytokines
involved in immune response and phagocytosis, as well as
those that up-regulate collagen, elastin and glucose immunoglycans. Marketed products include various growth factors
alone and in combination.
If topically applied growth factor can reach the dermis, they
could potentially induce epidermal thickening, cause new collagen formation and decrease wrinkles. There is a theoretical
concern about growth factor stimulation of melanomas
because vascular endothelial growth factor receptors are seen
in some melanomas. Another potential concern might be an
increase in hypotrophic scar formation because of the use of
transforming growth factor beta.
[ WINTER
tors substantially alter the solubility and stability of actives in the
final product, the ability of the product to work and potential
toxicity. The result is marked bottle-to-bottle variation.
SUNSCREEN: IMPORTANT, YET OVERLOOKED
Most women ask for the best wrinkle cream, but what they
really should be asking is, “What sunscreen should I be using?”
Nothing is more important than the obsessive-compulsive use
of a well-formulated sunscreen. Most patients don’t know how
to shop for them. Not all sunscreens are created equal and
patients don’t realize that UV-A protection is at least as important as UV-B. Patients need specific brand name recommendations based on their skin color, their skin type and their vehicle preference. Dermatologists need to acquaint themselves
with multiple products so they make the right recommendation
for each individual patient. A new formulation (Helioplex from
Ortho-Neutrogena) stabilizes avobenzone and is now available
in the United States.
appearance of wrinkles. Those looking for proven efficacy at
this point in time are limited to the use of tretinoin or tazarotene
with a sunscreen.
Whether or not a clinician believes in cosmeceutical efficacy,
patients are still going to ask for recommendations. We need to
be educated about them because patients are. The patient
comes to us for our opinion, so we have to have one. Those of
us who are skeptics have grounds for this belief. However, dismissing the entire group of products as ineffective because
there are no placebo-controlled, double-blind studies is unhelpful and probably ultimately untrue. We look forward to more rigorous trials in the future that will demonstrate the efficacy of
cosmeceuticals as we help our patients in their quest for the
fountain of youth.
REFERENCES
1. Household & Personal Industry, April 2004, pg. 14, www.happi.com.
THE MOISTURIZER SIDE OF COSMECEUTICALS
As we know, moisturizers are composed of emollients and
humectants. Emollients are film-forming agents that retard water
loss. Humectants absorb water that evaporates from the skin
and from the environment to moisturize the skin. Many emollients are available, from heavy petrolatum to silicones, which are
light and non-acnegenic. Humectants include glycerin, sorbitol,
lactic acid, urea and propylene glycol. When there is a paucity of
water in the air, such as in arid climates (e.g., the desert),
humectants may sting. Moisturizers are combinations of emollients and humectants. They are then formulated into a variety of
bases including oleaginous products (somewhat greasy), and
“oil-free moisturizers” which are usually silicone-based.
2. Darr D, Combs S, Dunston S, et al. Topical vitamin C protects porcine
skin from ultraviolet radiation-induced damage. Br J Dermatol.
1992;127:247–253.
3. Lin Jy, Selim MA, Shea CR, et al.UV photoprotection by combination
topical antioxidants, vitamin c and vitamin e. J Am Acad Dermatol.
2003;48:866–874.
4. Guerara I, Pandya A. Safety and efficacy of 4% hydroquinone combined with 10% glycolic acid, antioxidants and sunscreen in the treatment of melasma. Int J Dermatol. 2003;42:966-972.
5. Bissett D, Oblong J, Berge C. Niacinamide: a B vitamin that improves
aging facial skin appearance. Dermatol Surg. 2005;31:860-865.
6. Beitner H. Randomized, placebo-controlled, double-blind study on the
clinical efficacy of a cream containing 5% alpha-lipoic acid related to
photoaging of facial skin. Br J Dermatol. 2003;149:841-849.
THE BOTTOM LINE
With our current level of understanding of cosmeceuticals,
combination protocols are most advisable. It’s unlikely that we
will be recommending the use of only one active in the future.
The combination of cosmeceuticals with cosmetic procedures is
most beneficial. Alster showed that by using vitamin C, zinc and
tyrosine combination cream after resurfacing, she could reduce
the amount of erythema.12 Another attractive concept would be
combining resurfacing techniques with growth factors.
If a clinician insists on evidence-based medicine and pure
science, cosmeceuticals are not yet available for use. There is
little real science with the finished products. Even fewer adequate, placebo-controlled, double-blind trials exist. Whether
cosmeceutical actives are effective, the final products are at
the very least well-made moisturizers that feel good on the skin
and make a woman feel beautiful. As moisturizers, they do
improve the texture and feel of the skin while decreasing the
7. www.prevage.com, Annual meeting of the American Academy of
Dermatology; February 6–11, 2004; Washington, D.C.
8. Pollard J, Ovan S, Kang T, Koch R. Effects of copper tripeptide on the
growth and expression of growth factors by normal and irradiate
fibroblasts. Arch Facial Plast Surg. 2005;7:27-31.
9. Canapp S, Farese J, Schultz G, et al. The effect of topical tripeptidecopper complex on healing of ischemic open wounds. Vet Surg.
2003;32:515–523.
10. Cohen M, Eaglestein W. Recombinant human platelet-derived growth
factor gel speeds healing of acute full-thickness punch biopsy
wound. J Am Acad Dermatol. 2001;45:857-862.
11. Chiu A, Chan J, Kern D, et al. Double-blinded, placebo-controlled
trial of green tea extracts in the clinical and histological appearance
of photoaging skin. Dermatol Surg. 2003;149:841-849.
12. Alster T, West T. Effect of topical vitamin C on postoperative
carbon dioxide laser resurfacing erythema. Dermatol Surg.
1998;24:331-334.
COMBINING DERMATOLOGIC
THERAPIES: WHAT WORKS
AND WHAT DOESN’T
EXAMINING THE TREATMENT INTERACTIONS BETWEEN VARIOUS
TOPICAL AND SYSTEMIC AGENTS.
BY MARK LEBWOHL, M.D.
t is common practice in dermatology to combine or layer therapeutic agents, but knowing the effects
of these combinations is prudent,
especially if they lead to adverse
results. I’ll discuss the top interactions between topical and systemic
dermatologic agents.
I
Mark Lebwohl, M.D.
METHOTREXATE +
TMP/SMZ
Avoid
the
combination
of
methotrexate (Rheumatrex, Trexall) and trimethoprim-sulfamethoxazole (Bactrim, Septra), as it is deadly in a high number of patients.
Many other methotrexate interactions exist, so we should take care
to avoid these. A lot of the nonsteroidal anti-inflammatory drugs
(NSAIDs) reduce the renal excretion of methotrexate; by this mechanism, acetylsalicylic acid (aspirin), ibuprofen (Advil, Motrin) and
naproxen (Aleve, Naprosyn) all raise methotrexate levels.1 Wallace
and colleagues have shown that not only do methotrexate levels
increase when you administer naproxen, but naproxen levels
increase when you administer methotrexate.
The nontraditional NSAIDs that we can safely administer with
methotrexate are ketoprofen (Actron, Orudis, Oruvail), piroxicam
(Feldene), flurbiprofen (Ansaid) and celecoxib (Celebrex). None of
the other cyclooxygenase type II (COX-2) inhibitors, which are no
longer available, affect methotrexate levels.
men and post-menopausal women won’t take acitretin because
the package insert says not to take it with alcohol. I tell these
patients just not to drink alcohol 1 or 2 days before they come in
for a blood test, so as not to elevate their liver function tests.
BEXAROTENE + GEMFIBROZIL
Never use bexarotene (Targretin) with gemfibrozil (Lopid).
Bexarotene is a useful treatment for patients who have mycosis
fungoides, but, as one of its main side effects, it elevates triglycerides, the usual treatment for which is gemfibrozil (Lopid).
However, gemfibrozil raises bexarotene levels and causes a
marked elevation of triglycerides. And there have been patients
who developed pancreatitis as a result of that interaction. Plenty
of other lipid-lowering agents are available, such as atorvastatin
calcium (Lipitor).
[
ACITRETIN + ETHANOL
The package insert for etretinate (Tegison) stated that physicians should never administer it to a woman who ever planned to
become pregnant at any point in her life because of its long period of teratogenicity. Etretinate in the body converts to its active
metabolite, acitretin (Soriatane). And when acitretin combines
with alcohol, the acitretin turns back to etretinate, which would
again prolong the period of teratogenicity in women of childbearing potential. This is not a reason not to prescribe it. Many
]
CYCLOSPORINE HAS MANY DRUG
INTERACTIONS3 AND AMONG ITS
SIDE EFFECTS ARE HYPERTENSION,
REDUCTION IN RENAL FUNCTION ...
NAUSEA AND LOSS OF APPETITE.
CYCLOSPORINE TOXICITY
Cyclosporine has many drug interactions3 and among its side
effects are hypertension, reduction in renal function, paresthesia,
nausea and loss of appetite. Rather than monitor cyclosporine
levels, we look for side effects to determine whether patients are
developing cyclosporine toxicity as a result of drug interactions. In
particular, we look at serum creatinine, and blood pressure. If
those are okay, then the drug you’ve given them with cyclosporine
is okay. We also, of course, look at clinical response.
With the interaction of cyclosporine and aminoglycosides,
many of us worry about additive nephrotoxicity. Drugs that inhib-
[ WINTER
it the cytochrome P450 3A enzymes, such as
erythromycin, actually raise cyclosporine levels.
Some agents (such as the following four) actually
induce the enzymes that metabolize cyclosporine,
lowering levels.
1. Carbamazepine
(Atretol, Carbatrol, Tegretol)
2. Phenytoin (Dilantin, Phenytek, various)
3. Rifampin (Rifadin, Rimactane)
4. Pentobarbital (Nembutal).
Lowering cyclosporine levels is of particular
importance in transplant patients because you
don’t want to endanger their transplanted organ.
ERYTHROMYCIN + THEOPHYLLINE
Many interactions exist with erythromycin
Past and present officers of the American Academy of Dermatology had a
and theophylline. The combination causes an
chance to meet Joe Torre, Manager of the New York Yankees, at the
Winter Clinical Dermatology Conference. Pictured from left to right are:
elevation in theophylline levels, which can
Raymond L. Cornelison Jr., M.D., Stephen P. Stone, M.D., Diane R. Baker, M.D.,
make patients jittery, increase their heart rate
Darrell S. Rigel, M.D., Joe Torre, Clay J. Cockerell, M.D., Roger Ceilley, M.D.,
and even cause myocardial infarctions. With
and Boni E. Elewski, M.D. Photo courtesy of Darrell Rigel, M.D.
lovastatin (Mevacor, Advicor, Altoprev), you
need to worry about the risk of rhabdomyolysis, so it is advisable to check creatinine phosphokinase levels in those patients, and probably avoid combin- beta blockers is a much bigger problem for plastic surgeons than
ing lovastatin with erythromycin as well.
for dermatologists. We seldom use the amounts of epinephrine
In general, erythromycin interacts with other agents that with lidocaine that they do, so we don’t get into trouble with this.
inhibit the cytochrome P450 3A enzyme system. It prolongs the
The combination of retinoids and tetracycline cause an
QT interval on electrocardiograms (EKGs), so it results in an increase in pseudotumor cerebri. The combination of allopurinol
increase in cardiac arrhythmias. And what Ray reported in The (Aloprim, Zyloprim) and ampicillin (Omnipen, Polycillin, Principen)
New England Journal of Medicine last year is that the frequen- is interesting because a hospital study examined patients who
cy of sudden death goes up in patients on erythromycin.4 These had received the two drugs and the frequency of drug rash in
agents that inhibit cytochrome P450 3A double erythromycin these patients was 22.5%. Needless to say, we should probably
levels, so be particularly cautious. These authors looked at the avoid this combination. The same holds true for amoxicillin
frequency of sudden death in patients taking erythromycin and (Amoxil, Augmentin, Prevpac).
The combination of azathioprine (Azasan, Imuran) and allopurifound it was double compared to patients formerly on erythromycin (the same as the general public). But the patients who nol results in bone marrow destruction and pancytopenia and is
took cytochrome P450 3A inhibitors and erythromycin experi- deadly.5 If you do use azathioprine, be aware that a test for this
enced an increase in the frequency of sudden death by five- enzyme is available from every lab. Before I put any patient on
fold. These researchers recommend avoiding this combination azathioprine, I always check their levels of this enzyme.6 A patient
of erythromycin with agents that increases cytochrome P450 deficient in this enzyme is at a much higher risk of bone marrow
3A, such as ketoconazole (Nizoral).
destruction and pancytopenia.
Other macrolides have better coverage for organisms than
erythromycin. Clarithromycin (Biaxin, Prevpac) rarely causes CONTRACEPTIVES + ANTIBIOTICS
negative drug interactions, and azithromycin (Zithromax)
In one study, 1.6% of patients who received the combination
doesn’t inhibit the enzyme, so there’s no reason why you can’t of antibiotics and oral contraceptives became pregnant comtreat the same patients with either of these antibiotics instead.
pared to 0.96% who received oral contraceptives alone.7 (The
authors deem this statistically insignificant.) In this study, the
authors reported on 281 acne patients who became pregnant
GENERAL CAUTIONS WITH EPINEPHRINE,
RETINOIDS AND ALLOPURINOL
while on oral contraceptives; 42 of them were on antibiotics at
The combination of epinephrine in local anesthesia and the same time. In reviewing the results, they advise us to warn
patients, especially those on low estrogen oral contraceptives,
about the risks of antibiotic interaction.
BEWARE OF SOME TOPICAL COMBINATIONS
Anthralin (Drithocreme, Micanol, Dritho-Scalp) works for psoriasis, but it’s irritating. A paper showed that adding tar to anthralin
diminishes irritation.8 Another paper explained why the irritation
diminished: because coal tar degrades the anthralin.9 We have
shown something similar with calcipotriene (Dovonex), which, on
contact with salicylic acid is immediately degraded.
In this study, we added sodium hydroxide to get any stability at
all, and even then, it degraded over a period of hours. I won’t mix
calcipotriene with anything unless I know in advance that both
agents are compatible, and there are a few products that have
actually gone up and been mixed with calcipotriene and been
shown to be effective and stable (clobetasol foam [Olux],
betamethasone valerate foam [Luxiq] and optimized fluocinonide
cream [Vanos]), and these are certainly stable for enough hours
to be effective. Some degradation occurs with the cream, but
probably not enough to have a major impact on efficacy, yet certainly the ointment is stable.
with local irritation, you would expect some of the irritation from
calcipotriene to be ameliorated by the combination, and it was.
The combination calcipotriene and betamethasone dipropionate
is as effective once a day as when given twice daily. It is fast-acting as well, with significant improvement noticed in 1 week and
80% of its improvement in Psoriasis Area and Severity Index
score occurs within the first 2 weeks. Additionally, it is superior to
each of its individual components. It is unique in that calcipotriene is inactivated by an acid pH and betamethasone dipropionate requires an acid pH. Both medications co-exist in stable
form in a unique anhydrous vehicle.
KNOW THE RISKS AND REWARDS
Many positive and negative drug interactions exist in the world
of dermatology. That’s why, when dealing with systemic combinations, physicians must consider additive toxicities as well as
the additive beneficial effects. As for topical drug combinations,
physicians must be cognizant of whether individual ingredients
are compatible with one another and whether they enhance the
penetration of one another.
REFERENCES
COMPATIBILITY OF IMMUNOMODULATORS
The topical immunomodulator tacrolimus (Protopic) appears to
be compatible with just about everything with which it has been
studied. It is stable with desoximetasone (Topicort) and in terms of
efficacy, the combination of tacrolimus and desoximetasone is a little bit better and there’s particularly less pruritus or local irritation
when you combine it with desoximetasone. The same has been
shown with clocortolone pivalate (Cloderm), which has been used
effectively with tacrolimus ointment, and fluticasone (Cutivate).
Tacrolimus ointment and pimecrolimus cream have each been
used with hydrocortisone butyrate (Locoid). In a study at Mt. Sinai,
patients with irritation from tacrolimus (only those with the most irritation were studied) experienced dramatically minimized irritation
when they added the hydrocortisone butyrate.
Pimecrolimus (Elidel) has been combined with hydrocortisone
butyrate with very good efficacy.10 The stability of pimecrolimus
with various betamethasone valerate preparations was studied
and the combinations are quite stable. Apparently the combination of tacrolimus ointment with betamethasone valerate foam
enhances the penetration of tacrolimus through the skin.
1. Stewart CF, Fleming RA, Germain BF, et al. Aspirin alters methotrexate disposition in rheumatoid arthritis patients. Arthritis Rheum.
1991;34(12):1514–1520.
2. Wallace CA, Smith AL, Sherry DD. Pilot investigation of
naproxen/methotrexate interaction in patients with juvenile rheumatoid
arthritis. J Rheumatol. 1993;20(10):1764–1768.
3. Lebwohl M, Ellis C, Gottlieb A, et al. Cyclosporine consensus conference: with emphasis on the treatment of psoriasis. J Am Acad
Dermatol. 1998;39(3):464–475.
4. Ray WA, Murray KT, Meredith S, et al. Oral erythromycin and the risk
of sudden death from cardiac causes. N Engl J Med.
2004;351(11):1089–1096.
5. Venkat Raman G, Sharman VL, Lee HA. Azathioprine and allopurinol: a
potentially dangerous combination. J Intern Med. 1990;228(1):69–71.
6. Kurzawski M, Dziewanowski K, Ciechanowski K, Drozdzik M. Severe
azathioprine-induced myelotoxicity in a kidney transplant patient with
thiopurine S-methyltransferase-deficient genotype (TPMT*3A/*3C).
Transpl Int. 18(5):623–625.
7. Helms SE, Bredle DL, Zajic J, et al. Oral contraceptive failure rates and
oral antibiotics. J Am Acad Dermatol. 1997;36(5 Pt 1):705–710.
8. Schulze HJ, Schauder S, Mahrle G, Steigleder GK. Combined tar-
THE SUM IS BETTER THAN ITS PARTS
A twice-a-day study compared a new combination of calcipotriene and betamethasone dipropionate (Taclonex) to its individual ingredients, and the combination product was superior to
calcipotriene and betamethasone dipropionate alone. In terms of
adverse reactions, the combination product had fewer adverse
reactions than each of the individual ingredients. And particularly
anthralin versus anthralin treatment lowers irritancy with unchanged
antipsoriatic efficacy. Modifications of short-contact therapy and
Ingram therapy. J Am Acad Dermatol. 19987;17(1):19–24.
9. Whitefield M. Degradation of anthralin by coal tar. J Am Acad
Dermatol. 1987;16(3 Pt 1):629.
10.Diruggiero DC, Smith J. Atopic dermatitis: employing a new treatment
paradigm. Skin & Aging. 2004;12(5):58–59.
Yesterday… Stiefel Laboratories was founded in Europe in 1847 as a
family business with a global mission. The founders were determined to
provide quality skin care products and promote healthy skin throughout
the world. The popularity of Stiefel Laboratories in Europe prompted
August Stiefel’s move to the United States in 1910 to make Stiefel
products equally successful on both sides of the Atlantic.
Yesterday,
Today
and
Tomorrow
Today… Stiefel Laboratories is the world’s largest privately owned
pharmaceutical company specializing in dermatology. Our products are
marketed in over 100 countries with the support of over 30 subsidiaries,
including manufacturing plants in six countries and research and
development facilities on three continents. Our commitment extends
to our philanthropic support of organizations and institutions dedicated
to the advancement of dermatology.
Tomorrow… Stiefel Laboratories will continue to partner
with dermatologists and patients worldwide to create
innovative, therapeutic and aesthetic skin care products
for a lifetime of healthy skin.
Duac, Brevoxyl, ROSAC and Rose with sunray design, SARNA and Zeasorb are registered trademarks of Stiefel Laboratories, Inc.
MimyX and Research in Dermatology are trademarks of Stiefel Laboratories, Inc. Claripel is a registered trademark.
©2006, Stiefel Laboratories, Inc.
STI-01-2006-USA
www.stiefel.com

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