DERMATOLOGY PHARMACOLOGY - … nursece4less.com nursece4less.com nursece4less.com nursece4less.com 1 DERMATOLOGY PHARMACOLOGY Jassin M. Jouria, MD Dr. Jassin M. Jouria is a medical

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DERMATOLOGY

PHARMACOLOGY

Jassin M. Jouria, MD

Dr. Jassin M. Jouria is a medical doctor,

professor of academic medicine, and medical

author. He graduated from Ross University

School of Medicine and has completed his

clinical clerkship training in various teaching

hospitals throughout New York, including

King’s County Hospital Center and Brookdale

Medical Center, among others. Dr. Jouria has

passed all USMLE medical board exams, and

has served as a test prep tutor and instructor for Kaplan. He has developed several medical

courses and curricula for a variety of educational institutions. Dr. Jouria has also served on

multiple levels in the academic field including faculty member and Department Chair. Dr.

Jouria continues to serves as a Subject Matter Expert for several continuing education

organizations covering multiple basic medical sciences. He has also developed several

continuing medical education courses covering various topics in clinical medicine. Recently,

Dr. Jouria has been contracted by the University of Miami/Jackson Memorial Hospital’s

Department of Surgery to develop an e-module training series for trauma patient

management. Dr. Jouria is currently authoring an academic textbook on Human Anatomy &

Physiology.

Abstract

Skin diseases range in types, onset and severity in individuals. Healthcare

providers need to be informed of the varied conditions and pharmacology

treatments in order to provide comprehensive care. Dermatology treatment

may be directed toward the treatment of an inflammatory process, co-

morbid medical condition, or it may be cosmetic to achieve a patient desire

outcome involving a change in physical appearance. The practice of

dermatology is a blending of traditional and market factors, which health

providers should be aware of when guiding patients in their health

management and medication treatment choices.


Continuing Nursing Education Course Planners

William A. Cook, PhD, Director, Douglas Lawrence, MA, Webmaster,

Susan DePasquale, MSN, FPMHNP-BC, Lead Nurse Planner

Policy Statement

This activity has been planned and implemented in accordance with the

policies of NurseCe4Less.com and the continuing nursing education

requirements of the American Nurses Credentialing Center's Commission on

Accreditation for registered nurses. It is the policy of NurseCe4Less.com to

ensure objectivity, transparency, and best practice in clinical education for

all continuing nursing education (CNE) activities.

Continuing Education Credit Designation

This educational activity is credited for 5 hours. Nurses may only claim credit

commensurate with the credit awarded for completion of this course activity.

Pharmacology content is 5 hours.

Statement of Learning Need

The skin is an important body organ to understand, especially while

considering the many factors that influence percutaneous medication use

and efficacy. Many factors ultimately affect therapeutic efficacy of

dermatology pharmaceuticals. Knowledge of the different forms and

properties of dermatology medication is essential to patient care outcomes;

and, of the market influences on patient cost and compliance.


Course Purpose

To provide nursing professionals with knowledge of dermatology

pharmacology to support medication efficacy for varied skin conditions and

to improve patient understanding and compliance with medication use.

Target Audience

Advanced Practice Registered Nurses and Registered Nurses

(Interdisciplinary Health Team Members, including Vocational Nurses and

Medical Assistants may obtain a Certificate of Completion)

Course Author & Planning Team Conflict of Interest Disclosures

Jassin M. Jouria, MD, William S. Cook, PhD, Douglas Lawrence, MA,

Susan DePasquale, MSN, FPMHNP-BC – all have no disclosures

Acknowledgement of Commercial Support

There is no commercial support for this course.

Activity Review Information

Reviewed by Susan DePasquale, MSN, FPMHNP-BC

Release Date: 1/1/2016 Termination Date: 10/18/2018

Please take time to complete a self-assessment of knowledge, on

page 4, sample questions before reading the article.

Opportunity to complete a self-assessment of knowledge learned

will be provided at the end of the course.


1. _____________ is defined as the decrease in drug response due to the

use of a drug over a prolonged period of time.

a) Tapering down

b) Rebound effect

c) Tachyphylaxis

d) Topical nonadherence

2. There are two fields in dermatology:

a) medical and cosmetic dermatology.

b) surgical and cosmetic dermatology.

c) dermatology and general medicine.

d) dermatology and surgery.

3. ____________ are at an increased risk of absorbing topical

corticosteroids.

a) Infants

b) Individuals who are underweight

c) Women

d) The elderly

4. True/False: Cosmetic dermatologists are required to fulfill residency

requirements before they may offer cosmetic procedures.

a) True

b) False

5. Which of the following is a topical dermatologic treatment:

a) Oil

b) Liquids

c) Anti-infective agents

d) Powders


Introduction

In the course of a day, dermatologists see a wide variety of patients with

concerns ranging from serious medical conditions like cancer to cosmetic

issues that impact the patient's physical and emotional health. As with most

other specialties, pharmacological agents can be a useful resource for

treating dermatological concerns involving the hair, nails, and skin. There

are a wide variety of pharmacological agents that can be utilized in treating

dermatological issues, and they are typically delivered either topically or

percutaneously. As with any medical treatment, the purpose of these

pharmacological agents is to provide relief for the patient's issue with a

minimal amount of pain and other side effects.

Medical And Cosmetic Dermatology

There are two fields in dermatology: medical dermatology and cosmetic

dermatology. Dermatologists are physicians trained in the medical, surgical,

and cosmetic care of the skin. To become a dermatologist, physicians must

spend an additional year of internship in general medicine, and then another

three years training in the specialty of dermatology after they complete

medical school.1 This training includes medical, surgical, and cosmetic

dermatology. Regardless of their career goals, all dermatologists receive

training in the following specialties:2

Medical dermatology: Diagnose, treat, and prevent diseases that affect

the skin, hair and nails.

Dermatopathology: Diagnose diseases that affect the skin, hair, and

nails by removing a sample and examining the sample with a

microscope.


Surgical dermatology: Treat diseases that affect the skin, hair, and

nails by using a surgical procedure.

Cosmetic dermatology: Treat the skin, hair, or nails using a treatment

that is meant to improve a patient's appearance rather than treat a

disease.

Many dermatologists do not specialize in one area; instead, they choose to

practice in all of these areas.

It is important to note that providers who do not receive training in cosmetic

procedures during their residency may also offer cosmetic procedures. There

are no residency requirements for cosmetic dermatologists. Even

aestheticians are able to offer some basic cosmetic procedures.

When a dermatologist chooses to specialize in cosmetic dermatology, he or

she will likely perform the following treatments:3

Surgery to diminish acne scars.

Injecting fillers and botulinum toxins to give an aging face a more

youthful appearance.

Laser surgery to diminish or remove small veins, age spots, tattoos,

or wrinkles.

Dermatology Treatment: Topical Agents

Topical dermatologic treatments include varied options. These are listed

below.4

Cleansing agents

Absorbent dressings (i.e., hydrocolloid patches or powder) and super-

absorbent powders


Anti-infective agents

Anti-inflammatory agents

Astringents (drying agents that precipitate protein, shrink and contract

the skin)

Emollients (skin hydrators and softeners)

Keratolytics (agents that soften, loosen, and facilitate exfoliation of the

squamous cells of the epidermis)

Vehicles of Topical Therapies

Topical therapies can be delivered in various vehicles, which include:

Powders

Liquids

Combinations of liquid and oil

The vehicle influences a therapy’s effectiveness and may cause adverse

effects (i.e., contact or irritant dermatitis). Generally, aqueous and alcohol-

based preparations are drying because the liquid evaporates are used in

acute inflammatory conditions.5 Powders are also drying. Oil-based

preparations are moisturizing and are preferred for chronic inflammation.

Vehicle selection is guided by location of application, cosmetic effects, and

convenience.6

Powders

Powders absorb moisture and decrease friction. Because they adhere poorly

to the skin, their use is mainly limited to cosmetic and hygienic purposes.

Generally, powders are used in the intertriginous areas and on the feet. The

adverse effects of powders include: caking (especially if used on weeping

skin), crusting, irritation, and granuloma formation.7 Furthermore, the user

may inhale powders. Most powders contain zinc oxide for its antiseptic and


covering properties, talc (primarily composed of magnesium silicate) for its

lubricating and drying properties, and a stearate for improved adherence to

the skin. Calamine is a popular skin-colored powder composed of 98% zinc

oxide and 1% ferric oxide and acts as an astringent to relieve pruritus. Other

drugs formulated as powders include some over-the-counter antifungals.8

Poultices

A poultice, also referred to as a cataplasm, is a wet solid mass of particles,

sometimes heated, that is applied to diseased skin. Historically, poultices

contained meal, herbs, plants, and seeds. The modern poultice often

consists of porous beads of dextranomer. Poultices are used as wound

cleansers and absorptive agents in exudative lesions such as decubiti and leg

ulcers.9

Ointments

Ointments are semisolid preparations that spread easily. They are

petrolatum-based vehicles, capable of providing occlusion, hydration, and

lubrication. Drug potency is often increased from an ointment vehicle

because of the ointment’s enhanced permeability. Ointment bases used in

dermatology can be classified into five categories: (1) hydrocarbon bases,

(2) absorption bases, (3) emulsions of water-in-oil, (4) emulsions of oil-in-

water, and (5) water-soluble bases.

Dermatologists commonly refer to the hydrocarbon bases and absorption

bases as ointments, and the water-in-oil or oil-in-water emulsion bases as

creams. In pharmaceutical terms, all of these preparations are ointments

and are specifically indicated for conditions affecting the glabrous skin

(palms and soles) and lichenified areas.10


Absorption Bases:

Absorption bases contain hydrophilic substances that allow for the

absorption of water-soluble drugs. The hydrophilic (polar) compounds

may include lanolin and its derivatives, cholesterol and its derivatives,

and the partial esters of polyhydric alcohols such as sorbitan

monostearate. These ointments are lubricating and hydrophilic, and

they can form emulsions. They function well as emollients and

protectants. They are greasy to apply but are easier to remove than

the hydrocarbon bases. They do not contain water. Examples include

anhydrous lanolin and hydrophilic petrolatum.11

Water-In-Oil Emulsions (Creams):

Emulsions are two-phase systems involving one or more immiscible

liquids dispersed in another, with the assistance of one or more

emulsifying agents. A water-in-oil emulsion, by definition, contains less

than 25% water, with oil being the dispersion medium. The two

phases may separate unless shaken. The emulsifier (or surfactant) is

soluble in both phases and surrounds the dispersed drops to prevent

their coalescence. Examples of surfactants used include sodium lauryl

sulfate, the quaternary ammonium compounds, Spans (sorbitan fatty

acid esters), and Tweens (polyoxyethylene sorbitan fatty acid esters).

Preservatives are frequently added to increase the emulsion’s shelf

life. Water-in-oil emulsions are less greasy, spread easily on the skin,

and provide a protective film of oil that remains on the skin as an

emollient, while the slow evaporation of the water phase provides a

cooling effect.7


Oil-In-Water Emulsions

An oil-in-water emulsion contains greater than 31% water. In fact, the

aqueous phase may comprise up to 80% of the formulation. This type

of formulation is the one most commonly chosen to deliver a

dermatologic drug. Clinically, oil-in-water emulsions spread very

easily, are water washable and less greasy, and are easily removed

from the skin and clothing. Invariably, they contain preservatives,

such as the parabens, to inhibit the growth of molds. Additionally, oil-

in-water emulsions contain a humectant (an agent that draws

moisture into the skin), such as glycerin, propylene glycol, or

polyethylene glycol (PEG), to prevent the cream from drying out. The

oil phase may contain either cetyl or stearyl alcohol (paraffin alcohols)

to impart a stability and velvety smooth feel upon application to the

skin. After application, the aqueous phase evaporates, leaving behind

both a small hydrating layer of oil and a concentrated deposit of the

drug.12

Water-Soluble Bases:

Water-soluble bases consist either primarily or completely of various

PEGs. Depending on their molecular weight, PEGs are either liquid

(PEG 400) or solid (PEG 4,000). These formulations are water soluble,

will not decompose, and will not support the growth of mold, and

therefore require no preservative additives. They are much less

occlusive than water-in-oil emulsions, nonstaining, greaseless, and

easily washed off of the skin. Without water, this ointment poorly

delivers its coformulated drug. Therefore, it will be useful in scenarios

where the practitioner desires a high surface concentration and low

percutaneous absorption of the drug. For example, topical antifungal


drugs and topical antibiotics (i.e., mupirocin) are formulated in this

type of base.

Gels are made from water-soluble bases by formulating water,

propylene glycol, and/or PEGs with a cellulose derivative or carbopol. A

gel consists of organic macromolecules uniformly distributed in a

lattice throughout the liquid. After application, the aqueous or alcoholic

component evaporates, and the drug is deposited in a concentrated

form. This provides a faster release of the drug independent of its

water solubility. Gels are popular because of their clarity and ease of

both application and removal. They are suitable for facial or hairy

areas because after application little residue is left behind.

Nevertheless, they lack any protective or emollient properties. If they

contain high concentrations of alcohol or propylene glycol, they tend to

be drying or cause stinging.

Gels require preservatives. Newer gel formulations may contain the

humectant glycerin, the emollient dimethicone, or the viscoelastic

polysaccharide hyaluronic acid, which can mitigate some of the

associated irritation. Nonaqueous gels, with bases such as glycerol,

may be used for poorly solubilized therapeutics such as 5-

aminolevulonic acid. Microspheres, or microsponges, are formulated in

an aqueous gel. Medication, in this case tretinoin, is combined into

porous beads 10–25 μm in diameter. The beads are made up of

methyl methacrylate and glycol dimethacrylate.13

Pastes

Pastes are simply the incorporation of high concentrations of powders (up to

50%) into an ointment such as a hydrocarbon base or a water-in-oil


emulsion. The powder must be insoluble in the ointment. Invariably, they

are “stiffer” than the original ointment. The powders commonly used are zinc

oxide, starch, calcium carbonate, and talc. Pastes function to localize the

effect of a drug that may be staining or irritating (i.e., anthralin). They also

function as impermeable barriers that serve as protectants or sunblock.

Pastes are less greasy than ointments, more drying, and less occlusive.14,15

Liquids

Liquids can be subdivided into solutions, suspensions, emulsions and foams.

These are described below.

Solutions:

A solution involves the dissolution of two or more substances into

homogenous clarity. The liquid vehicle may be aqueous,

hydroalcoholic, or nonaqueous (alcohol, oils, or propylene glycol). An

example of an aqueous solution is aluminum acetate or Burow

solution. A hydroalcoholic solution with a concentration of alcohol of

approximately 50% is called a tincture. A collodion is a nonaqueous

solution of pyroxylin in a mixture with ether and ethanol, and is

applied to the skin with a soft brush. Flexible collodions have added

castor oil and camphor and are used, for example, to deliver 10%

salicylic acid as a keratolytic agent.

Liniments are nonaqueous solutions of drugs in oil or alcoholic

solutions of soap. The base of oil or soap facilitates application to the

skin with rubbing or massage. Liniments can be used as

counterirritants, astringents, antipruritics, emollients, and

analgesics.16-18


Suspensions (Lotions)

A suspension, or lotion, is a two-phase system consisting of a finely

divided, insoluble drug dispersed into a liquid in a concentration of up

to 20%. Nonuniform dosing can result in the suspended particles

coalescing and separating out of a homogeneous mixture, therefore

shaking of the lotion before application may be required. Examples

include calamine lotion, steroid lotions, and emollients containing urea

or lactic acid. The applied lotion leaves the skin feeling cooler via

evaporation of the aqueous component.

Lotions are easier to apply and allow for uniform coating of the

affected area, and are often the favorite preparation in treating

children. Lotions are more drying than ointments, and preparations

with alcohol tend to sting eczematized or abraded skin. Additionally,

lotions are suitable for application to large surface areas due to their

ability to spread easily.19

Shake Lotions

Shake lotions are lotions to which a powder is added to increase the

surface area of evaporation. As a result of the increased evaporation,

the application of shake lotions effectively dries and cools wet and

weeping skin. Generally, shake lotions consist of zinc oxide, talc,

calamine, glycerol, alcohol, and water, to which specific drugs and

stabilizers may be added. Shake lotions tend to develop sediment, and

derive their name from the need to shake the preparation before each

use to obtain a homogeneous suspension. In addition, after water has

evaporated from the lotion, the powder component may clump

together and become abrasive. Therefore, patients should be


instructed to remove the residual particles before the reapplication of

shake lotions.20

Foams

Foams are triphasic liquids composed of oil, organic solvents and

water, which are kept under pressure in aluminum cans. Foams are

formulated with a hydrocarbon propellant, either butane or propane.

The foam lattice is formed when the valve is activated. Once in contact

with the skin, the lattice breaks down, the alcohol evaporates within

30 seconds, and leaves minimal residue on the skin. The alcohol

component of the foam is thought to act as a penetration enhancer,

momentarily altering the barrier properties of the stratum corneum

(outermost layer of the skin) and increasing drug delivery through the

intercellular route.

Previous studies have demonstrated that foam vehicles are highly

effective in delivering greater amount of active drug at an increased

rate when compared to other vehicles that traditionally depend upon

hydration of the intercellular spaces within the stratum corneum.

Foams have not been associated with an increase in adverse events

and compliance seems to be better with this formulation, especially for

localized conditions affecting the scalp.3,21

Aerosols

Topical aerosols may be used to deliver drugs formulated as solutions,

suspensions, emulsions, powders, and semisolids. Aerosols involve

formulating the drug in a solution within a pure propellant. Usually, the

propellant is a blend of nonpolar hydrocarbons. When applied to abraded or


eczematized skin, aerosols lack the irritation of other formulations, especially

when the quality of the skin makes direct application painful or difficult.

Furthermore, aerosols dispense a drug as a thin layer with minimal waste,

and the unused portion cannot be contaminated.

Aerosol foams, a relatively new vehicle for drug delivery, are commonly used

to deliver corticosteroids such as betamethasone valerate and clobetasol

propionate. The foam contains the drug within an emulsion formulated with

a foaming agent (a surfactant), a solvent system (such as water and

ethanol), and a propellant. On application, a foam lattice forms transiently

until both the heat of the skin and the heat of rubbing the foam onto the

skin break it down. Foams that are alcohol based leave very little residue

within seconds of their application. Furthermore, a given corticosteroid

formulated in a foam vehicle demonstrates comparable potency when

compared with the same corticosteroid in other vehicles. Although aerosols

allow for the ease of application (especially to hair-bearing areas) and high

patient satisfaction, they suffer from the disadvantages of being expensive

and potentially ecologically damaging.

Penetration Enhancers

A penetration enhancer is a compound that is able to promote drug

transport through the skin barrier.

Chemical Enhancers:

Skin hydration and interaction with the polar head group of the lipids

are mechanisms for increasing penetration. Water, alcohols (mainly

ethanol), sulphoxides (dimethylsulphoxide/DMSO),

decylmethylsulphoxide/DCMS, azones (laurocapram), and urea are

some of the most commonly used compounds. Urea is thought to act


as a penetration enhancer due to its keratolytic properties and by

increasing the water content in the stratum corneum. Other

substances that may also act as chemical enhancers include propylene

glycol, surfactants, fatty acids, and esters.

Vesicular systems are widely used in dermatologic and cosmetic fields

to enhance drug transport into the skin through the transcellular and

follicular pathways. Examples of vesicular systems include liposomes

(phospholipid-based vesicles), niosomes (nonionic surfactant vesicles),

proliposomes and proniosomes, which, respectively, are converted to

liposomes and niosomes upon hydration.5,22,23

Physical Enhancers:

Physical methods such as the application of a small electric current

(iontophoresis), ultrasound energy (phono- or sonophoresis) and the

use of microneedles increase cutaneous drug penetration.

Microdermoabrasion is the application of crystals (generally aluminum

oxide) on the skin and the collection of such crystals and skin debris

under vacuum suction. Microdermabrasion is a technique that

enhances drug permeation and facilitates drug absorption by altering

the architecture of the stratum corneum.24

Stabilizers

Stabilizers are nontherapeutic ingredients and include the preservatives,

antioxidants, and chelating agents. Preservatives protect the formulation

from microbial growth. The ideal preservative is effective at a low

concentration against a broad spectrum of organisms, nonsensitizing, odor

free, color free, stable, and inexpensive. Unfortunately, the ideal


preservative does not exist. The parabens are the most frequently added

preservatives, and are active against molds, fungi, and yeasts, but less

effective against bacteria. Alternative agents include the halogenated

phenols, benzoic acid, sodium benzoate, formaldehyde, the formaldehyde-

releasing agents, and previously, thimerosal. Most commonly used

preservatives may act as contact sensitizers.25

Antioxidants or preservatives prevent the drug or vehicle from degrading via

oxidation. Examples include butylated hydroxyanisole and butylated

hydroxytoluene, used in oils and fats. Ascorbic acid, sulfites, and sulfur-

containing amino acids are used in water-soluble phases. Chelating agents,

such as sodium EDTA and citric acid, work synergistically with antioxidants

by complexing heavy metals in aqueous phases.26

Thickening Agents

Thickening agents increase the viscosity of products or suspend ingredients

in a formulation. Examples include bees-wax and carbomers. In addition to

functioning as an ointment vehicle, petrolatum may be added to an emulsion

to increase its viscosity. As in this example, an ingredient may have a

therapeutic effect as well as acting as part of a vehicle.27

Categories and Indications of Topical Agents

Major categories of topical agents are listed below.

Cleansing

Moisturizing

Drying

Anti-inflammatory


Antimicrobial

Keratolytic

Astringent

Antipruritic

Cleansing agents

The principal cleansing agents are soaps, detergents, and solvents. Soap is

the most popular cleanser, but synthetic detergents are also used. Baby

shampoos are usually well tolerated around the eyes and for cleansing

wounds and abrasions; they are useful for removing crusts and scales in

psoriasis, eczema, and other forms of dermatitis. However, acutely irritated,

weeping, or oozing lesions are most comfortably cleansed with water or

isotonic saline.28

Water is the principal solvent for cleansing. Organic solvents (i.e., acetone,

petroleum products, propylene glycol) are very drying, can be irritating, and

cause irritant or, less commonly, allergic contact dermatitis. Removal of

hardened tar and dried paint from the skin may require a petrolatum-based

ointment or commercial waterless cleanser.8,9,22,29-34

The following table highlights the various types of topical compounds,

recommended usage and applications.

Moisturizing

agents

Moisturizers (emollients) restore water and oils to the skin and help

maintain skin hydration. They typically contain glycerin, mineral oil, or

petrolatum and are available as lotions, creams, ointments, and bath

oils. Stronger moisturizers contain urea 2%, lactic acid 5 to 12%, and

glycolic acid 10% (higher concentrations of glycolic acid are used as

keratinolytics, i.e., for ichthyosis). They are most effective when

applied to already moistened skin (i.e., after a bath or shower). Cold

creams are moisturizing over the counter (OTC) emulsions of fats

(i.e., beeswax) and water.


Drying agents

Excessive moisture in intertriginous areas (i.e., between the toes, and

in the intergluteal cleft, axillae, groin, and inframammary areas) can

cause irritation and maceration. Powders dry macerated skin and

reduce friction by absorbing moisture. However, some powders tend

to clump and can be irritating if they become moist.

Cornstarch and talc are most often used. Although talc is more

effective, talc may cause granulomas if inhaled and is no longer used

in baby powders. Cornstarch may promote fungal growth. Aluminum

chloride solutions are another type of drying agent (often useful in

hyperhidrosis).

Anti-

inflammatory

agents

Topical anti-inflammatory agents are either corticosteroids or

noncorticosteroids. Corticosteroids are the mainstay of treatment for

most noninfectious inflammatory dermatoses.

Lotions are useful on intertriginous areas and the face. Gels are useful

on the scalp and in management of contact dermatitis. Creams are

useful on the face and in intertriginous areas and for management of

inflammatory dermatoses. Ointments are useful for dry scaly areas

and when increased potency is required.

Corticosteroid-impregnated tape is useful to protect an area from

excoriation. It also increases corticosteroid absorption and therefore

potency. Topical corticosteroids range in potency from mild (class VII)

to superpotent (class I— Relative Potency of Selected Topical

Corticosteroids). Intrinsic differences in potency are attributable to

fluorination or chlorination (halogenation) of the compound.

Topical corticosteroids are generally applied 2 to 3 times daily, but

high-potency formulations may require application only once/day or

even less frequently. Most dermatoses are treated with mid-potency

to high-potency formulations; mild formulations are better for mild

inflammation and for use on the face or intertriginous areas, where

systemic absorption and local adverse effects are more likely.

All agents can cause local skin atrophy, striae, and acneiform

eruptions when used for > 1 mo. This effect is particularly problematic

on the thinner skin of the face or genitals. Corticosteroids also

promote fungal growth.

Contact dermatitis in reaction to preservatives and additives is also

common with prolonged use. Contact dermatitis to the corticosteroid

itself may also occur. Perioral dermatitis occurs with mid-potency or

high-potency formulations used on the face but is uncommon with

mild formulations. High-potency formulations may cause adrenal

suppression when used in children, over extensive skin surfaces, or

for long periods. Relative contraindications include conditions in which

infection plays an underlying role and acneiform disorders.

Noncorticosteroid anti-inflammatory agents include tar preparations.

Tar comes in the form of crude coal tar and is indicated for psoriasis.


Adverse effects include irritation, folliculitis, staining of clothes and

furniture, and photosensitization. Contraindications include infected

skin. Several herbal products are commonly used in commercial

products, although their effectiveness has not been well established.

Among the most popular are chamomile and calendula.

Antimicrobials

Topical antimicrobials include: Antibiotics

Antibiotics have few indications. Topical clindamycin and

erythromycin are used as primary or adjunctive treatment for

acne vulgaris in patients who do not warrant or tolerate oral

antibiotics. Topical metronidazole and occasionally topical

sulfacetamide, clindamycin or erythromycin, are used for acne

rosacea. Mupirocin has excellent gram-positive (mainly

Staphylococcus aureus and streptococci) coverage and can be

used to treat impetigo when deep tissues are not affected.

OTC antibiotics such as bacitracin and polymyxin are often

used in postoperative care of a skin biopsy site and to prevent

infection in scrapes, minor burns, and excoriations. Topical

neomycin causes contact dermatitis more frequently than other

antibiotics. The use of topical antibiotics and washing with

antiseptic soaps in healing wounds may, however, actually slow

healing.

Antifungals:

Antifungals are used to treat candidiasis, a wide variety of

dermatophytoses, and other fungal infections.

Insecticides:

Insecticides (i.e., permethrin, malathion) are used to treat lice

infestation and scabies.

Nonspecific antiseptic agents:

Nonspecific antiseptic agents include iodine solutions (i.e.,

povidone iodine, clioquinol), gentian violet, silver preparations

(i.e., silver nitrate, silver sulfadiazine), and zinc pyrithione.

Iodine is indicated for presurgical skin preparation. Gentian

violet is used when a chemically and physically stable

antiseptic/antimicrobial is needed and must be very

inexpensive.

Silver preparations are effective in treating burns and ulcers

and have strong antimicrobial properties; several wound

dressings are impregnated with silver. Zinc pyrithione is an

antifungal and a common ingredient in shampoos used to treat

dandruff due to psoriasis or seborrheic dermatitis. Healing

wounds should generally not be treated with topical antiseptics

other than silver because they are irritating and tend to kill

fragile granulation tissue.


Keratolytics

Keratolytics soften and facilitate exfoliation of epidermal cells.

Examples include 3 to 6% salicylic acid and urea. Salicylic acid is used

to treat psoriasis, seborrheic dermatitis, acne, and warts. Adverse

effects are burning and, if large areas are covered, systemic toxicity.

It should rarely be used in children and infants.

Urea is used to treat plantar keratodermas and ichthyosis. Adverse

effects are irritation and intractable burning. It should not be applied

to large surface areas.

Astringents

Astringents are drying agents that precipitate protein and shrink and

contract the skin. The most commonly used astringents are aluminum

acetate (Burow solution) and aluminum sulfate plus Ca acetate

(Domeboro solution). Usually applied with dressings or as soaks,

astringents are used to treat infectious eczema, exudative skin

lesions, and weeping pressure ulcers.

Witch hazel is a popular OTC astringent.

Antipruritics

Doxepin is a topical antihistamine that is effective in treating itching of

atopic dermatitis, lichen simplex chronicus dermatitis, and nummular

dermatitis. Topical benzocaine and diphenhydramine (present in

certain OTC lotions) are sensitizing and not recommended. Other

antipruritics include camphor 0.5 to 3%, menthol 0.1 to 0.2%,

pramoxine hydrochloride, and eutectic mixture of local anesthetics

(EMLA), which contain equal parts lidocaine and prilocaine in an oil-in-

water vehicle.

Topical antipruritics are preferred over systemic drugs (i.e., oral

antihistamines) when smaller surface areas of skin are affected and

pruritus is not intractable. Calamine lotion is soothing but not

specifically antipruritic.

Factors Affecting Absorption

Several kinds of medications have systemic effect when applied

transdermally. Rate of medication absorption depends on drug form, size of

molecules (smaller molecules are more rapidly absorbed), and medication

base (oil-based or more readily absorbed water-based vehicles). Such

medications as hormones, antianginals, antihypertensives, analgesics, and

antihistamines may be specifically applied transdermally for prolonged

release for systemic therapy. General goals of therapy are to remove causes

of skin disorders, find measures to restore and maintain normal skin


function, and relieve symptoms such as itching, dryness, pain, or

inflammation.35

Many forms of dermatologic preparations - such as liquids, ointments, gels,

beads, pastes, plasters, creams, powders, foams, and sprays - are available

to treat skin disorders. The selected form depends on the desired

therapeutic effect and the ability of the person's skin to absorb medication.

Skin keratin, when moisturized, provides a waterproof barrier for the body;

therefore, skin must be hydrated for absorption of water-based drugs.

Some drugs are placed in dressings to trap perspiration and prevent water

loss and to assist with hydration and absorption. Water-soluble drugs are

more readily absorbed and excreted, whereas fat-soluble drugs in a lipid

base have slower excretion rates. In some body areas, such as the eyelids or

behind the ears, the thinness of skin allows rapid absorption of medication,

whereas areas such as the palms of the hands and soles of the feet are

thick, making them almost impenetrable by medications. Some products

contain lanolin to smooth skin and apply moisture in a lipid-soluble base.

Other products, in alcohol bases, dry skin.

Product use dictates the medication base needed, its method and site of

application, and ability to be absorbed. Just as with medications taken by

other routes, the patient's medical record should be checked for allergies to

medications to prevent skin irritation or other allergic reactions. Skin should

be clean and dry for optimal absorption. If medication is for a specific site,

such as a topical anti-infectant for an infected wound, it should be applied to

the specific site without spreading onto surrounding tissues. If patches are

used for systemic medications, sites should be rotated to avoid skin irritation


and prevent decreased absorption occurring because of skin sensitization to

medication.36-38

Primary Factors Affecting Absorption

This section covers the primary factors affecting skin absorption of

dermatology topical products.

Stratum Corneum:

The stratum corneum is the rate-limiting barrier to percutaneous drug

delivery. This cornified layer is composed of ceramides, free fatty acids, and

cholesterol in a 1:1:1 molar ratio. By weight, the stratum corneum consists

of 50% ceramides (acylceramides being the most abundant), 35%

cholesterol, and 15% free fatty acids. The stratum corneum thickness and,

thus, drug penetration will vary depending on body site.

There are two main routes for permeation through the stratum corneum: 1)

the transepidermal, and 2) the transappendageal pathways. The

transappendageal, or shunt route, involves the flow of molecules through

the eccrine glands and hair follicles via the associated sebaceous glands. In

the transepidermal route, molecules pass between the corneocytes via the

intercellular micropathway, or through the cytoplasm of dead keratinocytes

and intercellular lipids, defined as the transcellular micropathway. The

intercellular pathway is considered the most important route for cutaneous

drug delivery.

An important consideration in topical therapy is that diseased skin may have

an altered (increased, decreased, or absent) stratum corneum, thus

changing the body sites’ barrier function. Abraded or eczematized skin


presents less of a barrier. Solvents, surfactants, and alcohols can denature

the cornified layer and increase penetration; as a result, topical medications

with these components may enhance absorption. Importantly, simple

hydration of the stratum corneum enhances the absorption of topically

applied steroids by four to five times.2,4,21

Occlusion:

Occlusion via closed, airtight dressings or greasy ointment bases increases

the hydration and temperature of the stratum corneum, limits rub-off/wash-

off of the drug and, consequently, enhances drug penetration. Occlusion

techniques range from application under an airtight dressing, such as vinyl

gloves, plastic wrap, and hydrocolloid dressings to occlusion with cotton

gloves or socks at night for treatment of hands and feet, to application of a

medication already impregnated into an airtight dressing, as seen in

flurandrenolide tape. To derive the greatest benefit from occlusion, the

patient should hydrate the skin by immersion in water for approximately 5

minutes before the application of a cream or ointment. Clinically, this may

correspond to application immediately after bathing and before drying

completely.

With many drugs, occlusion increases drug delivery by 10 – 100 times the

amount of drug delivered when not occluded. This approach can lead to

more rapid onset times and increased efficacy when compared with topical

application alone. On the other hand, occlusion may also lead to a more

rapid appearance of the drug’s adverse effects, such as the ability of topical

corticosteroids to induce local skin atrophy or suppression of the

hypothalamus-pituitary–adrenal (HPA) axis. Occlusion may promote

infection, folliculitis, or miliaria. In the case of topical anesthetics such as

lidocaine and prilocaine, occlusion hastens absorption into both the skin and


the bloodstream, which has led in rare cases to cardiac complications from

lidocaine toxicity or methemoglobinemia from prilocaine toxicity.26,28,36,39

Frequency of Application:

The frequency of drug application likely has little effect on increasing a

topical drug’s overall efficacy. One daily application is enough for most

topical glucocorticoids, for example, but the nonspecific emollient or

protective effect of creams and ointments are likely enhanced by more

frequent applications. Regardless, increasing the contact time for a topical

drug augments its total absorption.29

Quantity of Application:

The quantity of the drug applied likely has a negligible effect on drug

absorption. Obviously enough of the drug must be dispensed and spread to

cover the affected areas. Furthermore, the quantity of drug applied might

affect patient adherence to the prescribed regimen. For example, too much

applied drug might negatively alter the subjective experience of having a

medication on the skin, i.e., the drug may feel “wrong” (greasy, caked,

chalky, etc.) or is cosmetically unattractive (shiny, white color). Regardless,

the amount prescribed must be adequate to treat the affected body surface

area for the necessary length of time. In this regard, patient education is

critical to prevent wasteful overuse or ineffective underuse of the

medication.

For topical medications like sunscreens that are used over large areas, under

application is a problem for most patients. However, for smaller areas,

patients may apply a large amount of an ointment, for example, leading to

complaints of greasiness or rubbing off on clothing, which can be minimized

by using an appropriate amount.2


Adherence:

Topical medication adherence is a critical although often overlooked aspect

of medication efficacy. Generally, adherence to a treatment regimen is

associated with female gender, employment, being married, and low

prescription costs. Lower adherence is seen for patients with extensive

disease and, paradoxically, disease on the face. One 8-week survey using

electronic monitoring showed that adherence to treatment for a twice-daily

topical prescription decreased from 84% the first week to 51% during the

eighth week, with topical nonadherence being especially notable on

weekends. Furthermore, adherence is negatively affected by depression,

which is common in people with chronic skin conditions and found in up to

20% of patients with psoriasis.

Tachyphylaxis:

Defined as the decrease in drug response when used over a prolonged

period of time, tachyphylaxis is commonly observed during corticosteroid

topical therapy. It is now thought that adherence may be a contributing

factor, rather than loss of corticosteroid receptor function.

Increase in adherence may be achieved by asking patients to use it only on

weekends (weekend therapy) or specific days of the week (pulse therapy).

Rebound Effect:

Worsening of preexisting dermatoses can occur in patients who have been

using topical potent corticosteroids for prolonged regimens. Either tapering

down the corticosteroid strength to moderate- or low-potency corticosteroids

or increasing the duration of time between applications of the topical drug

might prevent the rebound effect.9,13,40


Miscellaneous Factors:

Vigorous rubbing or massaging of the drug into the skin not only increases

the surface area of skin covered, but also increases blood supply to the area

locally, augmenting systemic absorption. It may cause a local exfoliative

effect that will also enhance penetration. The presence of hair follicles on a

particular body site also enhances drug delivery, with the scalp and beard

areas presenting less of a barrier when compared with the relatively hairless

body sites.

Although having a thinner stratum corneum, the skin of older individuals is

poorly hydrated, with fewer hair follicles and, therefore, may impede drug

delivery. Reducing the particle size of the active ingredient increases its

surface area–volume ratio, allowing for a greater solubility of the drug in its

vehicle. This forms the basis for the increased absorption of certain

micronized drugs.23,24,41

Inactive Components in Topical Formulations

The vehicle is the inactive part of a topical preparation that brings a drug

into contact with the skin. The vehicle of a topical formulation often has

beneficial nonspecific effects by possessing cooling, protective, emollient,

occlusive, or astringent properties. Rational topical therapy matches an

appropriate vehicle that contains an effective concentration of the drug. The

vehicle functions optimally when it is stable both chemically and physically

and does not inactivate the drug. The vehicle also should be nonirritating,

nonallergenic, cosmetically acceptable, and easy to use. Additionally, the

vehicle must release the drug into the pharmacologically important

compartment of the skin.


Finally, the patient must accept using the vehicle or else compliance will be

poor. For example, although ointments are often pharmacodynamically more

effective than creams, patients generally prefer creams to ointments, and

thus, it is no surprise that more prescriptions are written for cream-based

formulations.33,36,42,43

The following is a list of the most commonly used ingredients in topical

preparations. Many of these compounds may serve more than one function

in a particular formulation.7

Emulsifying Agents

o Cholesterol

o Disodium monooleamidosulfosuccinate

o Emulsifying Wax

o Polyoxyl 40 stearate

o Polysorbates

o Sodium laureth sulfate

o Sodium lauryl sulfate

Auxiliary emulsifying agents or emulsion stabilizers

o Carbomer

o Catearyl alcohol

o Cetyl alcohol

o Glyceryl monostearate

o Lanolin and lanolin derivatives

o Polyethylene glycol

o Stearyl alcohol

Stabilizers

o Benzyl alcohol


o Butylated hydroxyanisole

o Butylated hydroxytoluene

o Chlorocresol

o Citric Acid

o Edetate disodium

o Glycerin

o Parabens

o Propyl gallate

o Propylene glycol

o Sodium bisulfite

o Sorbic acid/potassium sorbate

Solvents

o Alcohol

o Diisopropyl adipate

o Glycerin

o 1,2,6 - Hexanetriol

o Isopropyl myristate

o Propylene carbonate

o Propylene glycol

o Water

Thickening Agents

o Beeswax

o Carbomer

o Petrolatum

o Polyethylene

o Xanthum gum


Emollients

o Acprylic/capric triglycerides

o Cetyl alcohol

o Glycerin

o Isopropyl myristate

o Isopropyl palmitate

o Lanolin and lanolin derivatives

o Mineral oil

o Petrolatum

o Squalene

o Stearic acid

o Stearyl alcohol

Humectants

o Glycerin

o Propylene glycol

o Sorbitol solution

Risks Associated with Topical Agents

Local Effects

Either the vehicle or its active ingredients may cause local toxicity to the

applied site. Local adverse effects are usually minor and reversible. Major

cutaneous side effects include irritation, allergenicity, atrophy,

comedogenicity, formation of telangiectases, pruritus, stinging, and pain.

The mechanism of toxicity may be as simple as the desiccation of the

stratum corneum (for example, the removal of sebum and oils by the

preparation’s emulsifiers), or involve a more complex effect on either the


cells of the epidermis or dermis and the structures these cells comprise (i.e.,

epidermis, adnexae). Local damage may occur either directly at, or within

close proximity to, the treated site. In addition, irritation and damage may

appear even after a drug has been discontinued. Often the therapeutic

effects of the active ingredient mask or immediately treat the toxic effects of

the formulation so that acutely toxic effects are transient.28,44

Irritant Contact Dermatitis:

Irritation is driven less by drug penetration and more by drug concentration.

Thus, lowering the concentration of an irritating drug may lower the risk of

side effects. However, a change in formulation may reduce the preparation’s

efficacy. Nevertheless, often using a less concentrated preparation over a

greater period of time is as therapeutically efficacious while minimizing

adverse effects; for example, the use of benzoyl peroxide 2% to 5%

preparations in contrast to 10% preparations. In some instances, though,

skin irritancy might be central to drug efficacy. For example, although not

conclusively shown, the power of immunomodulating agents such as

imiquimod might rely on an increased innate (inflammatory or irritant)

immune response.

Subjective or Sensory Irritant Contact Dermatitis:

Patients may detect burning or stinging sensations without any signs of

cutaneous irritation after applying a topical medication. Several compounds

may induce sensory irritant contact dermatitis in predisposed individuals,

such as tacrolimus, sorbic acid, propylene glycol, benzoyl peroxide hydroxy

acids, mequinol, ethanol, lactic acid, azelaic acid, benzoic acid, and tretinoin.

Allergic Contact Dermatitis:


In contrast to local irritation, contact allergy development depends on local

penetration. Allergy, of course, is driven by antigen recognition and

presentation and, thus, percutaneous absorption of the drug must be at a

level that guarantees interaction with the immune effector cells of the skin.

Therefore, the contact allergenicity of a drug relates most significantly to

percutaneous absorption. In some instances, cutaneous allergy may be

therapeutic, for example, the treatment of patients with cutaneous T-cell

lymphoma with topical nitrogen mustard. The shift in malignant T cells from

T helper (Th) 2 to Th1-type cytokine expression is believed to lead to

apoptosis of the malignant T cells and tumor regression.

Malignancies:

Rarely, topical therapy may result in neoplasia. For example, the risk of

secondary malignancies, such as keratoacanthomas, basal and squamous

cell carcinomas, lentigo maligna and primary melanoma have been reported

with the long-term use of nitrogen mustard.

Other Effects:

The application of topical corticosteroids to the periorbital skin has been

reported both to induce cataracts and increase in intraocular pressure.24,26,31

Systemic Effects

One should be aware of the potential systemic toxicities of topical drugs.

Although generally safer than the other routes of administration, topical

application can result in systemic toxicities ranging from end-organ toxicity

(central nervous system, cardiac, renal, etc.), teratogenicity, and

carcinogenicity to drug interactions. These outcomes may relate to the drug

itself, its metabolites, or even a component of the vehicle.


The kinetics of topically applied drugs differ significantly from those

administered by other routes. One important consideration is the lack of

hepatic first-pass metabolism of a topical drug. This is especially relevant to

drugs such as salicylic acid that are relatively innocuous when given

enterally, but may manifest central nervous system toxicity when applied

topically. Additionally, acting as a reservoir, the stratum corneum may store

large amounts of a topical drug, and a subsequently long diffusion period of

many days may ensue, delivering a steady supply of drug to the systemic

circulation.45-47

Percutaneous toxicity directly relates to percutaneous absorption. Therefore,

factors that modulate absorption also influence toxicity. These include the

following: the concentration of the drug, its vehicle, the use of occlusion, the

body site and area treated, frequency of use, the duration of therapy, and

the nature of the diseased skin. For example, 6% salicylic acid in Eucerin

used for 11 days in the treatment of psoriasis has been associated with

epistaxis and deafness, while the same concentration of salicylic acid in

hydrophilic cream under occlusion for 4 days for the treatment of dermatitis

(involving the same amount of body surface area) may result in

hallucination. Similar to their effect on systemically administered drugs,

renal and hepatic diseases, by influencing drug clearance, also contribute to

an increased potential for drug toxicity.5

Young children have a greater surface area – volume ratio, and thus are at

greater risk of percutaneous toxicity than adults. This phenomenon

necessitates alternative drugs, formulations, and dosing schedules for

children with widespread cutaneous disease. Patients with acute fares of

cutaneous illness (for example, psoriasis or atopic dermatitis) may require

the treatment of a larger body surface area in a relatively abbreviated period


of time. These patients may also increase their dose and frequency of

application during such fares.

Coupled with the likely increased percutaneous absorption of the diseased

skin, these scenarios exponentially increase the possibility of systemic

toxicity, and patient education is vital to prevent adverse outcomes. To

reduce the risk of toxicity from topical drugs and to increase treatment

efficacy, many practitioners will rationally advocate systemic approaches

(i.e., methotrexate, cyclosporine, injectable or infusible biologics, or

ultraviolet radiotherapy) to patients whose disease involves an extensive

body surface area.48,49

Type I Hypersensitivity Reactions:

In rare instances, anaphylactic shock can be precipitated by topical drug

application. For example, when applied to diseased or abraded skin,

bacitracin ointment can induce an immediate-type (type I) hypersensitivity

reaction in susceptible individuals. Such reactions might be represented by a

local and then subsequently generalized pruritus leading to cardiopulmonary

arrest. Nonimmunologic acute toxicity results from substances such as

pesticides and chemical warfare agents that rapidly diffuse through the skin

and reach target organs.

Malignancies:

Systemic calcineurin inhibitors have been associated with increased risk of

lymphoma and nonmelanoma skin cancer. But the topical use of such drugs

does not appear to be related to cancer. In fact, the risk for lymphoma with

the use of topical calcineurin inhibitors was assessed in animal studies that

demonstrated an increased risk only when blood levels were 30 times higher

than those measured after topical application in human subjects.


Numerous studies have demonstrated the efficacy and safety of topical

calcineurin inhibitors. More than 50 cases of lymphoma have been reported,

although the topical calcineurin inhibitor use may be coincidental.

Nevertheless, there is a clear need for additional follow-up information to

establish the long-term safety profile of this class of drugs. Two long-term

trials currently being conducted might help address these concerns.

Endocrine System:

Topical corticosteroids can rarely cause hypothalamic–pituitary–adrenal axis

suppression, growth retardation, hyperglycemia, iatrogenic Cushing

syndrome and femoral head osteonecrosis. Factors that enhance drug

absorption are directly related to an increase in these side effects; therefore,

carefully monitoring must be ensured when prescribing usage in large

surfaces areas, prolonged use of potent corticosteroids, usage under

occlusion, high potency corticosteroids, or use for the pediatric age group

(due to their increased surface to body mass ratio).

Transdermal drug delivery, in contrast to topical drug delivery, uses topical

application of therapeutic drug as a delivery system for systemic therapy.

The most commonly used patches are for nitroglycerin and fentanyl.

Advantages of this approach include controlled release, a steady blood-level

profile with zero-order kinetics, lack of a plasma peak, and, in some cases,

improved patient compliance. These patches remain on the skin for 12 hours

to 1 week. A patch consists of a plastic backing, a reservoir of medication,

either a rate-controlling membrane or a polymer matrix system for

controlled diffusion, followed by an adhesive facing the skin. The most

common adhesives used are acrylates, silicones, and polyisobutylenes.

These patches have been tested and are approved for use on the thighs,


buttocks, lower abdomen, upper arms, and chest; application to other sites

can lead to either subtherapeutic or supratherapeutic blood levels.

Adverse effects of patches include local irritation and allergic contact

dermatitis to either an adhesive or to the drug itself and may necessitate

discontinuation. Topical therapies are a mainstay of treatment for the

dermatologist. An understanding of the interactions between a drug’s

concentration, penetration, availability, and treatment of diseased skin

allows providers to maximize both efficacy and tolerability of topical therapy.

Also, an understanding of local and systemic toxicities allows selection of

appropriate, safe therapy for patients and minimizes unwanted effects.

Appropriate selection of topical agents and patient education on proper use

can optimize therapeutic outcomes.2,3,20,26,39,50

Specific Types of Topical Agents

Topical Antibiotics

Topical antibiotics play an important role in the management of many

common dermatologic conditions. They are prescribed most often by

dermatologists for the management of mild-to-moderate acne vulgaris or as

adjunctive treatment with oral agents. For localized superficial infections,

such as impetigo, the use of a topical agent (i.e., mupirocin or retapamulin)

may eliminate the need for oral antibiotics and the accompanying problems

of compliance, gastrointestinal side effects, and potential drug interactions.

Topical antibiotics are still frequently prescribed as prophylactic agents after

minor surgery or cosmetic procedures (chemical peel or laser resurfacing) to

reduce the risk of postoperative wound infection and to speed wound

healing. The use of topical antibiotics for prophylaxis after such minor

procedures has been proven to be unnecessary and incurs risk of inducing


allergy. Petrolatum is recommended for use after clean surgical

procedures.51

Agents Used In the Topical Treatment of Acne and Rosacea

The efficacy of topical antibiotics for the treatment of acne vulgaris and

rosacea may be due to their direct antibiotic effect, but many of the topical

antibiotics exhibit anti-inflammatory properties by suppressing neutrophil

chemotactic factor or by other mechanisms. There are concerns about the

use of topical antibiotics in the treatment of acne vulgaris because of the

increasing levels of antibiotic resistance. Combining the antimicrobial

benzoyl peroxide with antibiotics reduces the development of antibiotic

resistance.45 The following table outlines topical antibiotics with anti-

inflammatory properties 28,52-57

Erythromycin Erythromycin belongs to the group of macrolide antibiotics and is active

against both Gram-positive cocci and Gram-negative bacilli. It is used

principally as a topical agent in the treatment of acne. Erythromycin

binds to the bacterial 50S ribosome and blocks translocation of the

peptidyl-transfer RNA (tRNA) molecule from the acceptor to the donor

site, interfering with the formation of the polypeptide chain and

inhibiting protein synthesis. In addition to its antibacterial properties,

erythromycin has anti-inflammatory activity.

Erythromycin is available as a 1.5% to 2.0% solution, gel, pledgets,

and ointment as a single agent. It is also available in combination with

benzoyl peroxide.

Clindamycin Clindamycin is a semisynthetic lincosamide antibiotic that is derived

from lincomycin. The mechanism of action is very similar to that of

erythromycin, with binding to the 50S ribosome and suppression of

bacterial protein synthesis. Clindamycin is used topically as a 1% gel,

solution, suspension (lotion), and foam primarily for the treatment of

acne. It is also available as a combination with benzoyl peroxide, which

may slow the development of antibiotic resistance to clindamycin.

Pseudomembranous colitis rarely has been reported to occur with the

topical use of clindamycin.

Metronidazole Metronidazole, a topical nitroimidazole, is currently available as a

0.75% gel, cream, or lotion and as a 1% cream or gel for the topical

treatment of rosacea.


In the lower strength, it is applied twice daily, and in the higher

strength, it is used once daily. Orally, metronidazole has broad-

spectrum activity against many protozoal organisms and anaerobes.

Azeliac Acid Azelaic acid is a dicarboxylic acid found in food (whole-grain cereals

and animal products). There is a normal human plasma level (20–80

ng/mL); topical application does not significantly alter this level. The

mechanism of action is thought to be normalization of the

keratinization process (decreased thickness of the stratum corneum,

decreased number and size of keratohyaline granules, and decreased

amount of filaggrin).

There are reports of in-vitro activity against Propionibacterium acnes

and Staphylococcus epidermidis, which may be due to protein

synthesis inhibition. In aerobic microorganisms, there is inhibition of

oxidoreductive enzymes (such as tyrosinase, mitochondrial enzymes of

the respiratory chain, 5α-reductase, and DNA polymerases).

In anaerobic bacteria, there is disruption of glycolysis. Azelaic acid is

used principally in the treatment of acne vulgaris and rosacea,

although there are some advocates for its use in the treatment of

hyperpigmentation (such as melasma for which it was initially

developed). However, the US Food and Drug Administration has not

approved the drug for this indication. Azelaic acid is available as a 15%

gel or 20% cream preparation.

Sulfonamides Sulfacetamide is a topical sulfonamide used in the treatment of rosacea

and acne. The antibacterial mechanism of action for most sulfonamides

is competition with para-aminobenzoic acid (PABA) during the

synthesis of folic acid. The mechanism of action for topical treatment of

rosacea is not understood.

Sulfacetamide is available as a 10% lotion and in combination with 5%

sulfur in a gel, cream, suspension, cleanser, cloths, and mask.

Dapsone Topical 5% dapsone gel is approved by the FDA for the topical

treatment of acne. The mechanism of action of dapsone in acne

vulgaris is not known at this time; however, it is possible that

inhabitation of neutrophils activity may be important. If benzoyl

peroxide is applied after topical dapsone, temporary orange/yellow

discoloration of skin and facial hair has been noted.

Corticosteroids

Topical corticosteroids are used to relieve inflammation and pruritus of

contact dermatitis, insect bites, minor burns, seborrheic dermatitis,

psoriasis, and eczema. These medications contain a drying agent or


conversely an emollient and are usually found in creams, ointments, lotions,

and gels to facilitate absorption at the site of action. Absorption is high in

areas of thin skin, but penetration is poor with thick skin. These preparations

vary widely in strength, with those available over the counter (OTC) being of

low potency.

Systemic toxicity may be a side effect with long-term therapy using high-

potency topical preparations. Site of application influences the medication

form choice. Gels and lotions are used in hairy areas. Creams rub easily into

tissue if needed for weepy, wet tissue lesions. Lipid-based ointments are

more occlusive and moisturizing and are best for application on dry or scaly

areas.58

Corticosteroids have specific and nonspecific effects that are related to

different mechanisms of action, including anti-inflammatory,

immunosuppressive, antiproliferative, and vasoconstrictive effects. Most of

their actions are mediated by an intracellular receptor called the

glucocorticoid receptor. The glucocorticoid receptor α-isoform is located in

the cytosol, binds glucocorticoids, and translocates to a region of the nuclear

DNA known as the corticosteroid responsive element, where it is then able to

stimulate or inhibit transcription of the adjacent genes, thus regulating the

inflammatory process. The glucocorticoid receptor β-isoform does not bind

glucocorticoids, but is able to bind the antiglucocorticoid/antiprogestin

compound RU-486 to regulate gene expression. The glucocorticoid receptor

β can attenuate the ligand-mediated transactivation of hormone-sensitive

genes by the α-isoform and may be an important marker of steroid

insensitivity.58-59


Anti-Inflammatory Effects:

Corticosteroids are thought to exert their potent anti-inflammatory effects by

inhibiting the release of phospholipase A2, an enzyme responsible for the

formation of prostaglandins, leukotrienes, and other derivatives of the

arachidonic acid pathway. Corticosteroids also inhibit transcription factors,

such as activator protein 1 and nuclear factor κβ, which are involved in the

activation of proinflammatory genes. Genes known to be upregulated by

corticosteroids and that play a role in the resolution of inflammation include

lipocortin and p11/calpactin-binding proteins, both involved in the release of

arachidonic acid. Lipocortin I inhibits phospholipase A2, reducing the release

of arachidonic acid from phospholipids. Corticosteroids also decrease the

release of interleukin-1α (IL-1α), an important proinflammatory cytokine,

from keratinocytes. Other proposed mechanisms for the anti-inflammatory

effects of corticosteroids include inhibition of phagocytosis and stabilization

of lysosomal membranes of phagocytizing cells.58,60

Immunosuppressive Effects:

The effectiveness of corticosteroids is, in part, also due to their

immunosuppressive properties. Corticosteroids suppress the production and

effects of humoral factors involved in the inflammatory response, inhibit

leukocyte migration to sites of inflammation, and interfere with the function

of endothelial cells, granulocytes, mast cells, and fibroblasts. Several studies

have shown that corticosteroids can cause mast cell depletion in the skin.

Experiments have also shown that topical corticosteroids cause local

inhibition of chemotaxis of neutrophils in vitro, and decrease the number of

Ia+ Langerhans cells in vivo.

Corticosteroids reduce eosinophilia in patients with asthma. They also reduce

T-cell proliferation and induce T-cell apoptosis, in part from inhibition of the


T-cell growth factor IL-2. In addition, several cytokines are directly affected

by corticosteroids, including IL-1, tumor necrosis factor-α, granulocyte-

macrophage colony-stimulating factor, and IL-8. These effects may also be a

result of the steroid action on antigen presenting cells.11,61

Antiproliferative Effects:

The antiproliferative effect of topical corticosteroids is mediated by inhibition

of DNA synthesis and mitosis, partly explaining the therapeutic action of

these drugs in scaling dermatoses. They are known to reduce the

keratinocyte size and proliferation. Fibroblast activity and collagen formation

are also inhibited by topical corticosteroids.62

Vasoconstriction:

The mechanism by which corticosteroids induce vasoconstriction is not yet

completely clear. It is considered related to inhibition of natural vasodilators

such as histamine, bradykinins, and prostaglandins. Topical steroids cause

capillaries in the superficial dermis to constrict, thus reducing erythema. The

ability of a given corticosteroid agent to cause vasoconstriction usually

correlates with its anti-inflammatory potency and, thus, vasoconstriction

assays are often used to predict the clinical activity of an agent. These

assays, in combination with double blind clinical trials, have been used to

separate the topical corticosteroids into seven classes based on potency.

Class 1 includes the most potent, while class 7 contains the least potent.

Corticosteroids have a basic skeletal structure comprising 17 carbon atoms

arranged in three six-membered rings and one five-membered ring.36,60

Modifications of cortisol, by addition or alteration of functional groups at

certain positions, have led to compounds with variable anti-inflammatory

potency, glucocorticosteroid versus mineralocorticoid activity, and adverse


effects. Before choosing a topical glucocorticoid preparation, one must

consider the patient-related and drug-related factors that can affect its

systemic absorption. The age of the patient, the extent and location of the

body surface area to be treated and the presence or absence of skin

inflammation, greatly affect the activity of the topical agent.23,24

Penetration of the glucocorticoid varies according to the skin site, which, in

turn, is related to the thickness of the stratum corneum and the vascular

supply to the area. For example, penetration of topical steroids through the

eyelids and scrotum is four times greater than for the forehead and 36 times

greater than for the palms and soles. Inflamed, moist, and denuded skin

also shows increased penetration.

Areas of the body where the skin is inherently thin not only allow for

increased penetration of the drug but also are more susceptible to develop

side effects than other areas where the skin is thick. Potent topical steroids

(classes 1 and 2) should rarely, if ever, be used in the areas with the highest

level of penetration, such as the eyelids. The concentration of the

therapeutic agent used, the duration of the application, the use of occlusive

dressings, the elected vehicle, and the intrinsic characteristics of the chosen

molecule, can also affect the absorption and the degree of adverse effects.21

The target site for topical corticosteroids is the viable epidermis or dermis,

and clinical response to a formulation is directly proportional to the

concentration of corticosteroid achieved at the target site. A comparison

study of skin concentrations after topical versus oral corticosteroid treatment

found that most topical corticosteroids have the potential to achieve greater

effective drug levels in the superficial layers of the skin than those achieved

with standard doses of oral prednisone. Therefore, the apparently greater


efficacy of oral corticosteroid therapy may be due in part to poor patient

compliance with topical therapy.28

Topical corticosteroids are compounded in several formulations and with

varying strengths. Recent research has emphasized the importance of

treatment adherence in the management of skin conditions. As such, newer

formulations including spray, foam, lotion, hydrogel, and shampoo

formulations have been developed to improve patient convenience and

acceptance, without sacrificing the efficacy, safety and tolerability of the

traditional ointment and cream formulations. A recent systematic review of

the literature found that while there are few direct comparison studies

between clobetasol propionate, a class 1 steroid, in different vehicles, the

efficacy rates for more recent formulations is roughly comparable to that of

clobetasol ointment in the treatment of psoriasis. The most common adverse

effect was mild and transient stinging or burning at the lesion site, which

may be due to the alcohol content found in these formulations. None of the

clinical trials directly compared these formulations with one another.63,64

Increasing hydration of the stratum corneum can enhance absorption of

topical corticosteroids by four to five times. Absorption is also enhanced by

ten times with occlusion. A retrospective study of wet dressings used with

topical corticosteroids (hydrocortisone 1% cream to the face and folds and

triamcinolone 0.1% cream from the neck down) for adults with recalcitrant

pruritic dermatoses of different etiologies, alleviated the pruritus in 98% of

the patients. The enhanced corticosteroid penetration is only one of the

numerous benefits of the wet dressings.64

Topical corticosteroids are recommended for their anti-inflammatory activity

in inflammatory skin diseases, but they can also be used for their antimitotic


effects and their capacity to decrease the synthesis of connective tissue

molecules. Certain variables must be considered when treating skin

disorders with topical glucocorticoids. For example, the responsiveness of

diseases to topical glucocorticoids varies. In this setting, diseases can be

divided into the three categories: (1) highly responsive, (2) moderately

responsive, and (3) least responsive.65

Topical glucocorticoids are highly effective, and few side effects are observed

when a low-potency preparation is used for brief periods of time without

occlusion in children. However, children and, in particular, infants, are at an

increased risk of absorbing topical corticosteroids for several reasons. They

have a higher ratio of skin surface area to body weight and application to a

given area results in a greater potentially systemic dose of steroid. Infants

may also be less able to metabolize potent glucocorticoids rapidly.

Premature infants are especially at risk because their skin is thinner and the

penetration rate of topically applied drugs is greatly increased. Application of

topical steroids to the diaper area results in occlusion of the steroid by the

diaper, and increased penetration occurs. Excess absorption of topical

glucocorticoids can suppress endogenous cortisol production. Consequently,

subsequent cessation of topical steroid therapy after an extended treatment

period can, albeit rarely, result in an Addisonian crisis. Deaths from

Addisonian crisis have been reported with the use of topical steroids, and the

risk of this occurring is greater in children.61,66

Chronic suppression of cortisol production can also lead to growth

retardation. A morning plasma cortisol level can be performed to screen for

adrenal suppression, although adrenocorticotropic (ACTH) stimulation testing


with cosyntropin is more accurate. If suppression is present, the child should

be slowly weaned from the steroids to prevent these complications.

Corticosteroids have been used with success for atopic dermatitis for several

decades. Placebo-controlled trials have found them effective in 75% or more

of patients with atopic dermatitis when compared with fewer than 30% of

placebo-treated patients. They are important for managing acute changes.

As with other skin conditions, selecting the appropriate strength according to

the body site, the extent of involvement and the intensity of change is

essential for treatment success.63,67

Education of the patients and caregivers is critical to improve adherence to

the prescribed medication and optimize compliance. Results from large-scale

surveys show that patients or caregivers overestimate the actual risks of

topical corticosteroids leading to treatment noncompliance. Adequate time

should be spent transmitting the important role of intermittent topical

corticosteroid therapy, and the beneficial risk-benefit ratio with their

appropriate use.68

Hemangiomas of infancy show a good or partial response to treatment with

ultrapotent topical glucocorticoids in 74% of infants. The majority reported

accelerated cessation of growth. Small, superficial hemangiomas,

particularly at sites prone to ulceration, disfigurement or both, and small

periocular lesions that have not yet caused significant visual impairment are

the best candidates for therapy. Corticosteroids act in hemangiomas to

decrease proliferation but the mechanism of this action is unknown.

Intralesional corticosteroid injection of hemangiomas before and after

treatment, have revealed an increase in mast cells, reduced transcription in

several cytokines and enhanced transcription of cytochrome b gene.36


Elderly patients similarly can have thin skin, which allows for increased

penetration of topical glucocorticoids. They are also more likely to have

preexisting skin atrophy secondary to aging and may be diaper dependent,

so the same precautions used in the treatment of infants should be used

when treating elderly patients.69

Uses in Pregnancy:

Appropriate human studies using topical glucocorticoids in pregnancy have

never been undertaken. Studies in animals, however, show that topical

steroids are systemically absorbed and may cause fetal abnormalities,

especially when used in excessive amounts, under occlusive dressings, for

prolonged periods of time, or when the more potent agents are used. The

U.S. Food and Drug Administration (FDA) rates most topical steroids as

category C drugs, which implies that caution must be exercised when used

in pregnancy. A recent, systematic review of the safety of topical

corticosteroids in pregnancy performed by Chi et al., found that the current

data is inconclusive and limited and unable to detect an association between

topical corticosteroids and congenital abnormalities, preterm delivery, mode

of delivery or stillbirth.70

The current evidence shows no statistically significant effects for pregnant

women who use topical corticosteroids as compared with unexposed women.

However, in a small cohort study of participants from a single maternity

center, there appears to be an association of highly potent corticosteroids

with low birth weight. Most of the previous studies only assessed the risk for

congenital abnormality or orofacial cleft. Further cohort studies with

comprehensive outcome measures (including fetal growth, preterm birth,

and birth death), consideration of corticosteroid potency, dosage and

indications, and a large sample size are required in order to detect a small


risk. It is currently unknown whether topical glucocorticoids are excreted in

breast milk; however, they should be used with caution in breastfeeding

mothers and should never be used on the breasts before breastfeeding.71-73

Dosing Regimen:

The frequency of topical application of corticosteroids was developed in an

empirical manner, with most textbooks and physicians recommending twice-

daily use. For superpotent corticosteroids, once-daily application is

considered as beneficial as twice-daily application. Likewise, there is at best

a slight difference with once versus twice daily application of potent or

moderately potent corticosteroids. These observations suggest that once-

daily application of topical corticosteroids may be as effective as twice daily,

while decreasing the risks of side effects, tachyphylaxis, and cost of therapy,

and improving patient compliance.

Tachyphylaxis has been demonstrated in experimental conditions by

diminished vasoconstriction, rebound of DNA synthesis, and recovery of

histamine wheals after application of topical steroids in patients with a

history of long-term topical steroid usage. As a working rule in adults, no

more than 45 g/week of potent or 100 g/week of weak or moderately potent

topical corticosteroid should be applied (without occlusion) if systemic

absorption is to be avoided.58,60,74

Monitoring Therapy:

Application of corticosteroids to large surface areas, occlusion, higher

concentrations, or more potent derivatives directly increases the risk of

hypothalamic–pituitary–axis suppression. If the latter is suspected,

laboratory analyses that include a complete blood cell count, a chemistry

panel, and a baseline morning cortisol level should be performed. In a


patient with confirmed HPA suppression, gradual reduction of potency and

amount of topical steroid, and possibly the simultaneous institution of oral

steroid supplementation, are needed.63

Risks and Precautions:

Local as well as systemic side effects have been documented with the use of

topical corticosteroids. Under normal conditions, up to 99 % of the applied

topical corticosteroid is cleared from the skin, and only 1 % is

therapeutically active. Cutaneous adverse effects can result from the small

percentage of percutaneously absorbed corticosteroid or may also result

from its transient presence onto the skin. Continued use of topical

corticosteroids may also lead to tachyphylaxis. Considerations for prescribing

topical corticosteroids to prevent side effects should be followed.31,64

Complications:

Local adverse effects of topical corticosteroid use are more prevalent than

systemic reactions. They are largely due to the antiproliferative effects of

these agents.

Atrophic Changes:

Skin atrophy is the most prominent cutaneous adverse effect, and

involves both the epidermis and dermis. Dermal atrophy develops from

the direct antiproliferative effects of topical corticosteroids on

fibroblasts, with inhibition of collagen and mucopolysaccharide

synthesis, resulting in loss of dermal support. Decreased synthesis of

types I and III collagens after topical glucocorticoid use has been

shown in numerous studies. Reduction of glycosaminoglycan

production has also been described. Levels of hyaluronan, the major


glycosaminoglycan in the skin, are also rapidly decreased after short-

term glucocorticoid treatment, because of decreased hyaluronan

synthesis.

Fragmentation and thinning of elastic fibers develop on the upper

layers, whereas deeper fibers form a compact and dense network. As a

result of these atrophic changes, there is vascular dilatation,

telangiectasias, purpura, easy bruising, stellate pseudoscars (purpuric,

irregularly shaped, and hypopigmented atrophic scars), and ulceration.

Although atrophy is, to some extent, reversible, formation of striae,

visible linear scars that form in areas of dermal damage presumably

during mechanical stress, are permanent.

Acneiform Reactions:

The development or exacerbation of dermatoses of the face, including

steroid rosacea, acne, and perioral dermatitis, is a well-known side

effect of topical corticosteroids. Although steroids initially lead to the

suppression of inflammatory papules and pustules, patients become

addicted because they notice that the lesions change when treatment

is withdrawn. This frequently leads to the continued use of greater

potency topical corticosteroids. For these reasons, steroid use should

be discouraged in the treatment of rosacea and perioral and periocular

dermatitis.

Prolonged corticosteroid treatment can also result in “steroid acne,”

which is characterized by crops of dense, inflamed pustules in the

same developmental stage. These lesions occur on the face, chest, and

back. Patients with psoriasis are also susceptible to a papulopustular


change after withdrawal of high-potency, topical corticosteroid therapy

to an extensive surface area for a prolonged period of time.

Hypertrichosis:

Hypertrichosis occurs rarely in women and children who apply potent

corticosteroids to the face. The mechanism is still unknown.

Pigmentary Changes:

Decreased pigmentation is a common side effect of topical steroid use.

The pigment generally returns after discontinuation of therapy.

Development of Infections:

Topical corticosteroids are responsible for exacerbating and/or

masking cutaneous infectious diseases. The incidence of skin infection

during corticosteroid therapy varies but is probably between 16% and

43%. Tinea versicolor, disseminated Alternaria infection, and

dermatophytosis, including tinea incognito (masked dermatophyte

infection), can develop.

Granuloma gluteale infantum, characterized by reddish–purplish

granulomatous lesions on the diaper area, is a well-known

complication of diaper dermatitis that is being treated with

corticosteroids. Candida albicans is commonly recovered in these

patients. Topical corticosteroids have also an effect on prolongation or

worsening of herpes simplex, molluscum contagiosum, and scabies

infection.


Allergic Reactions:

Allergic contact dermatitis from steroids should be suspected when its

use worsens the dermatitis, does not lead to improvement or changes

the clinical pattern of disease. It occurs more commonly in patients

with an impaired barrier function, such as patients with stasis

dermatitis, leg ulcers and atopic dermatitis. The prevalence of topical

corticosteroid sensitization ranges between 0.2% and 6.0%, and

increases with prolonged exposure and selection of certain drugs.

In a 6-year retrospective study, 127 of 1,188 patients (10.7%) patch

tested with topical corticosteroids showed a positive reaction to at

least one agent, with 56 patients reacting to multiple topical

corticosteroids. Topical corticosteroids were recognized as the

American Contact Dermatitis Society’s 2014 allergen of the year based

on their prevalence. A classification has been created to determine

cross-reactivity among the various available preparations.

This classification has four groups on the basis of structure and cross-

reactivity patterns. Each class is represented by an agent. Class A is

represented by the hydrocortisone type, class B by the acetonide

steroids, class C by the betamethasone type and class D, subdivided

into two groups, includes D1 represented by betamethasone

dipropionate and D2 by methylprednisolone aceponate. Patch-test

reactions to class A steroids are most common, whereas patch-test

reactions to class C steroids are extremely rare.

When an allergy to a topical corticosteroid is highly suspected and

patch testing is not available, the clinician should prescribe a class C

steroid with a vehicle that contains no allergens. Desoximethasone


0.25% ointment and 0.05% gel are the only two products that meet

these criteria. The vehicle or the preservative can also be responsible

for the allergy to the corticosteroid preparation. A systematic review of

ingredients in corticosteroid vehicles was recently published. The

authors found seven vehicle ingredients that are commonly used in

topical corticosteroid preparations and are well-known allergens: (1)

propylene glycol, (2) sorbitan sesquioleate, (3) formaldehyde-releasing

preservatives (imidazolidinyl urea and diazolidinyl urea), (4) parabens,

(5) methylchloroisothiazolinone/methylisothiazolinone, (6) lanolin, and

(7) fragrance. Of 166 topical corticosteroids, 128 (including all creams)

had at least one of these vehicle components. More generic products

were free of allergens than were the branded products. Solutions and

ointments were the least allergenic vehicles. The most commonly

present potential allergens were propylene glycol and sorbitan

sesquioleate.36,46,67,75-79

Relative Potency of Topical Corticosteroids80

Class* Drug

I Betamethasone dipropionate 0.05% ointment

Clobetasol propionate 0.05% cream or ointment

Diflorasone diacetate 0.05% ointment

Halobetasol propionate 0.05% cream or ointment

II Amcinonide 0.1% ointment

Betamethasone dipropionate 0.05% cream

Betamethasone dipropionate 0.05% ointment

Desoximetasone 0.25% cream, 0.05% gel, 0.25% ointment

Diflorasone diacetate 0.05% ointment

Fluocinonide 0.05% cream, gel, ointment, or solution

Halcinonide 0.1% cream


Class* Drug

Mometasone furoate 0.1% ointment

III Amcinonide 0.1% cream or lotion

Betamethasone dipropionate 0.05% cream

Betamethasone dipropionate 0.05% lotion

Betamethasone valerate 0.1% ointment

Desoximetasone 0.05% cream

Diflorasone diacetate 0.05% cream

Fluocinonide cream 0.05%

Fluticasone propionate 0.005% ointment

Halcinonide 0.1% ointment or solution

Triamcinolone acetonide 0.1% ointment

IV Fluocinolone acetonide 0.025% ointment

Flurandrenolide 0.05% ointment

Mometasone furoate 0.1% cream or lotion

Triamcinolone acetonide 0.1% cream or ointment

V Betamethasone valerate 0.1% cream

Desonide 0.05% ointment

Fluocinolone acetonide 0.025% cream

Flurandrenolide 0.05% cream

Fluticasone propionate 0.05% cream

Hydrocortisone butyrate 0.1% cream, ointment, or solution

Hydrocortisone valerate 0.2% cream or ointment

Triamcinolone acetonide 0.1% lotion or 0.025% ointment

VI Alclometasone dipropionate 0.05% cream or ointment

Betamethasone valerate 0.1% lotion

Desonide 0.05% cream

Flumethasone pivalate 0.03% cream

Fluocinolone acetonide 0.01% cream or solution


Class* Drug

Triamcinolone acetonide 0.1% cream

Triamcinolone acetonide 0.025% cream or lotion

VII Hydrocortisone 1% or 2.5% cream, 1% or 2.5% lotion, 1% or 2.5%

ointment

Hydrocortisone acetate (1% or 2.5% cream, 1% or 2.5% lotion, 1% or

2.5% ointment) and pramoxine hydrochloride 1%

*Class I is the most potent, and class VII is the least potent. Potency depends on

many factors, including the drug’s characteristics and concentration and the base

in which it is used.

Therapy of Superficial Bacterial Infections and Burns

Localized impetigo, superficial dirty abrasions, and secondarily infected

chronic dermatoses are commonly treated with topical antibiotics. However,

widespread impetigo, infection of the lower extremities, or disease occurring

in immunocompromised individuals should be treated with systemic

antibiotics to reduce the risk of serious complications. Topical antibiotics are

still at times used following minor surgical procedures. The result of a large

study comparing bacitracin and petrolatum in more than 1,200 minor

surgical procedures demonstrated that bacitracin did not statistically

decrease the already low rate of infection. Several patients were, however,

shown to be allergic to bacitracin. Petrolatum proved to be cheaper, of equal

efficacy and to have fewer side effects than bacitracin. When clean wounds

are made during minor surgery, there is no need to use antibacterial

ointment to aid in healing or prevent infection. Because burns produce a

fertile ground for life-threatening secondary infection, prophylactic topical

therapy is often used.29 The table below lists topical antibiotics,

recommended uses and administration.20,29,53,81-83


Mupirocin Mupirocin, which was formerly known as pseudomonic acid A, is a

topical antibiotic agent derived from Pseudomonas fuorescens. The

drug reversibly binds to isoleucyl-tRNA synthetase and inhibits

bacterial protein synthesis.

The activity of mupirocin is limited to Gram-positive bacteria,

especially staphylococci and most streptococci. Its activity is

enhanced in an acid pH environment (5.5), which is the normal pH

of the skin. Mupirocin is somewhat temperature-sensitive, and thus

loses efficacy if exposed to high temperatures.

Mupirocin ointment 2% is applied three times daily and is

principally indicated for the treatment of localized impetigo caused

by S. aureus and Streptococcus pyogenes. One study in the

Tennessee Veterans’ Affairs Hospital demonstrated that prolonged

use of mupirocin ointment to control methicillin-resistant S. aureus

(MRSA) carriage, especially in bedridden patients with decubitus

ulcers, led to significant resistance.

Furthermore, Japanese researchers found that low serum

concentrations of mupirocin are achieved after intranasal

application and postulated that this might explain the selection of

mupirocin-resistant strains of S. aureus. A small pilot study using

intranasal application of a combination antibiotic ointment

containing bacitracin, polymyxin B, and gramicidin successfully

decolonized 80% (9 out of 11) of MRSA-positive patients who

remained clear after a mean follow-up of 2 months. All cases of

mupirocin-sensitive MRSA were eradicated, whereas only three of

five cases of mupirocin-resistant were eliminated.

New formulations that involve the use of the calcium salt of

mupirocin (the calcium salt aids in chemical stability in the

intranasal preparation) are available for intranasal use as a 2%

ointment and a 2% topical cream.

Retapamulin Retapamulin is approved for topical treatment of impetigo in

patients older than 9 months of age. It is a semisynthetic

pleuromotilin antibiotic derived from fermentation in Clitopilus

paseckerianus with activity against staphylococci. The antibacterial

mechanism of action is inhibition of protein synthesis via 50S

bacterial ribosomes at protein L3, near the peptidyl tranferase

center. Retapamulin binding inhibits peptidyl tranferase and partial inhibition of binding of initiator tRNA to P-site of ribosome. Allergic

contact dermatitis to the active ingredient has been reported.

Bacitracin Bacitracin is a topical polypeptide antibiotic originally isolated from

the Tracy-I strain of Bacillus subtilis. Bacitracin is a cyclic

polypeptide with multiple components (A, B, and C). Bacitracin A is

the major component of commercial products and is often used as

the zinc salt. Bacitracin interferes with bacterial cell wall synthesis

by binding to and inhibiting the dephosphorylation of a membrane-

bound lipid pyrophosphate.


It is active against Gram-positive cocci such as staphylococci and

streptococci. Most Gram-negative organisms and yeast are resistant

to the drug. It is available as bacitracin ointment and as zinc

bacitracin, with 400 to 500 units per gram.

Topical bacitracin is effective for the treatment of superficial

bacterial infections of the skin such as impetigo, furunculosis, and

pyodermas. It is often combined with polymyxin B and neomycin as

a triple antibiotic ointment applied several times daily for the

treatment of secondarily infected eczematous dermatitis such as

atopic dermatitis, nummular dermatitis, or stasis dermatitis.

Unfortunately, the topical application of bacitracin carries with it the

risk of allergic contact sensitization and, rarely, anaphylactic shock.

Polymyxin B Polymyxin B is a topical antibiotic derived from a spore-forming soil

aerobe B. polymyxa. Polymyxin B is a mixture of polymyxin B1 and

B2, which are both cyclic polypeptides. They function as cationic

detergents that interact strongly with bacterial cell wall membrane

phospholipids, thus disrupting the integrity of the cell membrane.

Polymyxin B is active against a wide range of Gram-negative

organisms, including P. aeruginosa, Enterobacter, and Escherichia

coli. Polymyxin B is available in ointment form (5,000 to 10,000

units per gram) in combination with bacitracin or as triple antibiotic

ointment with bacitracin and neomycin. It should be applied one to

three times a day.

Topical

Aminoglycosides

(Neomycin and

Gentamicin)

The aminoglycosides are an important group of antibiotics used

both topically and systemically for the treatment of infections

caused by Gram-negative bacilli. Aminoglycosides exert their

bactericidal effects by binding to the 30S ribosomal subunit and

interfering with protein synthesis. Neomycin sulfate, the

aminoglycoside most often used topically, is a fermentation product

of Streptomyces firadiae.

Commercial neomycin is a mixture of neomycin B and C, whereas

framycetin, used in Canada and some European countries, is pure

neomycin B.9 Neomycin sulfate has activity against aerobic Gram-

negative bacteria and is used most commonly for prophylaxis

against infection in superficial abrasions, cuts, and burns. It is

available in ointment form (3.5 mg/g) and is also packaged in

combination with other antibiotics such as bacitracin, polymyxin,

and gramicidin.

Other agents, such as lidocaine, pramoxine, or hydrocortisone, also

are available in combination with neomycin. Many dermatologists

do not recommend neomycin because it is responsible for a large

number of cases of allergic contact dermatitis. The prevalence of

contact dermatitis is high, with 6% to 8% of patients undergoing

patch testing being positive. Neomycin sulfate (20%) in petrolatum

is used to assess for contact allergy. Gentamicin sulfate is derived

as a fermentation product from Micromonospora purpurea. It is

available as a topical 0.1% cream or ointment.


Gentamicin sulfate is used by some dermatologic surgeons when

operating on the ear, especially in diabetic or other

immunocompromised patients, to provide prophylaxis against

malignant otitis externa due to P. aeruginosa. The ophthalmic

formulation is useful in caring for operative wounds in the

periorbital area.

Sulfonamides

(Silver

Sulfadiazine and

Mafenide

Acetate)

The sulfonamides are structurally similar to PABA and compete with

it during the synthesis of folic acid. Sulfonamides are used to treat

acne vulgaris, acne rosacea, and burns. Silver sulfadiazine is

thought to release silver slowly and exerts its effect on the bacterial

cell walls and membranes. The mechanism of action of mafenide is

not the typical sulfonamide mechanism of action because PABA

does not antagonize its performance.

Mafenide acetate, if used over large areas of skin, has the potential

to cause metabolic acidosis, and it can cause intense pain on topical

administration. Both agents are broad-spectrum antibacterials

useful in the treatment of burns. Candida superinfection may be a

problem with mafenide cream.

Nitrofurazone Nitrofurazone (Furacin) is a nitrofuran derivative used for the

treatment of burns. The mechanism of action involves the inhibition

of bacterial enzymes involved in the aerobic and anaerobic

degradation of glucose and pyruvate. Nitrofurazone is available as a

0.2% cream, solution, or soluble dressing, and its spectrum of

activity includes staphylococci, streptococci, E. coli, Clostridium

perfiringens, and Proteus sp.

Miscellaneous Agents

Gramicidin Gramicidin is a topical antibiotic derived from B. brevis. The

gramicidins are linear peptides that form stationary ion channels in

susceptible bacteria. The antibiotic activity of gramicidin is

restricted to Gram-positive bacteria.

Clioquinol Clioquinol (also known as iodochlorhydroxyquin) is a broad-

spectrum antibacterial/antifungal topical that is currently indicated

for the treatment of inflammatory skin disorders and tinea pedis

and has been used for minor bacterial infections. It is a synthetic

hydroxy-quinoline whose mechanism of action is unknown.

The disadvantages of clioquinol include discoloration of clothing,

skin, hair, and nails and the potential to cause irritation. Clioquinol

may interfere with thyroid function determination when taken orally

and possibly topically if used extensively. The iodine moiety

interferes with tests that rely on iodine uptake (this effect can last

for up to 3 months after application). However, clioquinol does not

interfere with testing for T3 or T4.


Topical Retinoids

In topical preparations, retinoids are widely used as prescription drugs as

well as cosmeceuticals. In some of these products, retinoids are naturally

occurring compounds while others are synthetic molecules. Until recently,

clinical use of topical retinoids has been limited to all-trans-retinoic acid,

which is approved in the U.S. for the treatment of acne, photo-aged skin,

and melasma. Topical adapalene and tazarotene have also received approval

for acne; tazarotene has received approval for psoriasis and photo-aging.

More recently, bexarotene was approved for management of cutaneous T-

cell lymphoma and alitretinoin was approved for patients with Kaposi

sarcoma. It is widely accepted that topical retinoids are extremely effective

for acne therapy, especially for comedonal (mild acne) lesions.84

Of the different classes of antiacne medications, retinoids are thought to be

the best, if not the only, agents to normalize the abnormal follicular

epithelial differentiation or desquamation important in the pathogenesis of

acne lesions. Therefore, the use of retinoids can also provide protection

against the development of new lesions. This prophylactic property is the

basis for including topical retinoid in almost all antiacne regimens. A

potential for aggravating inflammation exists in treating inflammatory acne

(i.e., papules and pustules) with topical retinoids, but when properly

administered, this type of acne also responds well to retinoids.85

Fine wrinkles and dyspigmentation are two features of photo-aged skin that

are improved by topical tretinoin or tazarotene. Several weeks of treatment

are required before clinical improvement is appreciated. For the effacement

of fine wrinkles by topical tretinoin, partial restoration of markedly reduced

levels of collagen in sun-exposed skin toward those seen in sun-protected

skin appears to be responsible. Tretinoin’s ability to improve photo-aging is


specific and does not result from the irritation or retinoid dermatitis

frequently produced by this compound. Topical adapalene is not approved

for the treatment of photo-aging; however, a recent study indicates that it

also holds promise in ameliorating the clinical features of photo-damage.17,86

Many other skin disorders have been reported to improve by topical

retinoids, but most of these have not been rigorously studied; thus, their

therapeutic claims should be interpreted with caution. Molluscum

contagiosum, warts, and various forms of ichthyosis may be improved by

topical retinoids to a variable degree. In psoriasis, especially, irritation of

treated skin has limited the use. Topical tazarotene, which is approved for

psoriasis, does not appear to have fully overcome the irritation problem;

thus, it is typically used in combination with topical steroids.87

With such a wide variety of skin conditions treatable by topical retinoids,

their use has included all age groups, perhaps with the exception of

neonates. The use of topical retinoids in pregnancy is an emotional issue.

Because none of the dermatologic conditions seen in pregnancy that may

respond to topical retinoids (i.e., acne, melasma, stretch marks) is life-

threatening to the mother or the fetus, it seems prudent to delay the

treatment until after delivery. In a study that demonstrated that early,

inflammatory stretch marks were improved by topical tretinoin, all

pregnancy-related stretch marks were treated postpartum. Therefore, even

in this pregnancy-associated condition, the therapeutic benefit could be

achieved by instituting the treatment after delivery.88

Dosing Regimen:

For decades, tretinoin was the only topical retinoid available for clinical use

sold under the trade name Retin-A. Now, tretinoin is also available in other


formulations. Adapalene is also available in varying formulations and, more

recently, combination medications have been introduced. For acne and

psoriasis, topical tazarotene is available and for photo-aging treatment,

tretinoin and tazarotene are approved for use.

Tretinoin 0.05%/hydroquinone 4%/fuocinolone 0.1% is a topical

combination approved for the treatment of melisma (a common condition of

grey-brown patches on the face).17 Different formulations allow some

flexibility in terms of tailoring the therapy to an individual’s skin dryness or

oiliness. Finally, more recently approved topical retinoids include bexarotene

and alitretinoin, sold in gel formulations.89

Regardless of the retinoid preparation or the patient’s age, the most

important element in topical therapy is patient/guardian education. It must

be clearly explained to each patient that, as part of the treatment, local skin

irritation, characterized by redness and peeling, can be expected. The

concept that clinical improvement correlates with the degree of irritation has

been erased through a large, controlled clinical study in which 0.025% and

0.1% tretinoin were shown to be equally efficacious, but the former was

significantly less irritating than the latter.90 Therefore, unlike most

medications for which the dosing schedule may be set as once or twice daily,

administration of a topical retinoid should be titrated depending on the skin

reaction. For some individuals, it may be applied only twice a week, for

others four times a week, and this can be increased, as tolerated, to a once-

daily regimen. This method of individualizing topical therapy minimizes

unwanted acute retinoid dermatitis.91

Under the nonprescription category, there are countless “natural retinoid”

preparations with various claims (mostly anti-aging) being sold throughout


the world. Most of these contain retinyl esters, especially retinyl palmitate,

retinaldehyde, or retinol. Whether any of these products can deliver retinoid

activity to human skin is subject to question. Percutaneous absorption

(especially for retinyl esters), adequate concentrations, and stable

formulations (especially for retinol) are some of the important unknowns for

this group of products.10 Based on human in-vivo work, all-trans-retinol and

all-trans retinaldehyde hold the most promise of these natural retinoids in

being biologically active, provided the stability of the compound can be

maintained with a proper formulation.

When the sun-protected skin of individuals older than 80 years of age was

treated for 7 days with 1% retinol, fibroblast growth and dermal collagen

were increased significantly. Concomitantly, retinol markedly reduced the

levels of matrix-degrading metalloproteinases that are elevated in aged skin.

These findings suggest that retinol may reverse and partially prevent skin

atrophy that accompanies intrinsic aging. A recent clinical study has

confirmed that topical retinol improves the fine wrinkles associated with

atrophic, naturally aged skin of the elderly.92

Risks and Precautions or Adverse Effects:

By far the most common adverse effect associated with topical retinoid use

is local skin irritation characterized by erythema, peeling, dryness, tightness,

and burning sensation. This predictable skin response is temporary, but

troubling, for many patients. It tends to peak within the first month of

treatment and diminishes thereafter. It responds to a temporary reduction in

the frequency or amount of retinoid application and to liberal use of

emollients. Retinoid activation of the receptors is followed by subsequent

induction of HB-EGF and AR in human skin in vivo.93


The importance of this signaling pathway in the hyperplastic response of the

epidermis to topical retinoids was recently demonstrated when

pharmacologic antagonists of EGF receptor tyrosine kinase activity blocked

retinoid-induced epidermal thickening in human skin organ culture and in

vivo. This observation suggests that it may be possible to reduce the

clinically undesirable effects of retinoids on epidermal keratinocytes.

However, the erythema response following topical retinoic acid may not be

retinoid-receptor mediated because all-trans-retinol, which induces

epidermal hyperplasia and CRABP-II mRNA-like retinoic acid (two indicators

of receptor activation), is minimally associated with clinical erythema.20

For bexarotene and alitretinoin, local irritation is also the most common side

effect. With alitretinoin, the local erythema can increase to edema and

vesiculation with continued use. However, most reactions are mild-to-

moderate with only 7% of patients requiring treatment withdrawal in clinical

trials. Finally, the central hypothyroidism seen with systemic bexarotene is

not observed in the gel formulation. Systemic retinoid exposure has been

well documented and established as a cause of embryonic death and

congenital malformation and, understandably, there is concern about

potential teratogenicity from long-term topical retinoid use.32

Systemic absorption of retinoids from topical application is negligible, and

the levels of endogenous retinoic acid in the blood are not increased by twice

daily application of 0.025% tretinoin to more than 40% of body area over 1

month. Furthermore, controlled topical administration of tretinoin at doses

used for acne therapy (2 g of 0.025% gel applied daily to the face, neck, and

upper part of the chest for 14 days) has less influence on plasma levels of

endogenous retinoids than diurnal and nutritional factors. Indeed, a large,

population-based study demonstrated no excess risk of birth defects in


offspring born to mothers who were exposed to topical tretinoin during

pregnancy. Therefore, no evidence exists for teratogenicity of topical

tretinoin in humans.17,94

“Sun sensitivity” is a frequently discussed subject with topical retinoid use

and requires clarification. When formally tested in humans, topical tretinoin

does not lower the minimal erythema dose of ultraviolet B (UVB) light.

Because its presence in human skin does not increase the likelihood of

sunburn reaction, tretinoin is not a phototoxic agent. The patients, who

complain of such sun sensitivity, describe an uncomfortable skin sensation

that is felt within minutes of being in the sun rather than hours later. This

timeline is not consistent with a typical sunburn reaction, which takes a few

hours to be noticed. Furthermore, this sensation often is reported as

accentuated in warmer temperatures, which suggests participation of

infrared irradiation (heat). Related to sun sensitivity is the issue of

photocarcinogenesis. In an animal model of photocarcinogenesis, topical

tretinoin has caused skin cancer. However, when human skin was grafted

onto mice with severe combined immunodeficiency disease, gross

inadequacy of the commonly used rodent model of photocarcinogenesis was

demonstrated. Specifically, the traditional rodent models significantly

overestimate the human carcinogenic potential of tested agents.86,87

Topical retinoids appear to have a protective effect against UV-induced

premalignant and malignant lesions. In those predisposed by nevoid basal

cell carcinoma syndrome or xeroderma pigmentosum to the development of

nonmelanoma skin cancer, systemic retinoids have provided effective

protection. In this regard, topical tretinoin’s ability to prevent UV induction

of c-Jun is relevant; c-Jun is a proto-oncoprotein that is minimally detectable

in normal human skin in vivo. Its partner c-Fos; however, is constitutively


expressed. Ultraviolet irradiation to human skin does not affect the level of

c-Fos expression, but it markedly induces c-Jun protein, which can then

heterodimerize with c-Fos, forming a complete active AP-1 transcription

factor.95,96

The critical importance of AP-1 in mediating carcinogenic transformation of

papillomas has been demonstrated. In human squamous cell carcinomas, c-

Jun expression is elevated, and systemic retinoids prevent carcinomas of the

head and neck. Mechanisms involved in this chemopreventive effect of the

retinoid likely include c-Jun suppression. These clinically observed

anticarcinogenic activities of retinoids are also supported by in vitro data,

demonstrating that tretinoin treatment of human skin upregulates the

antigen-presenting activity of Langerhans cells without concomitant increase

in autoreactivity. Such a retinoid effect would improve cutaneous immune

responsiveness to tumor antigens. Therefore, topical retinoic acid is not a

carcinogen in humans.97

Drug Interaction and Compatibilities:

Retinoids, in general, are photo-labile and therefore can be photo-

inactivated. Based on this chemistry, it is recommended to apply the agents

in the evening rather than before the start of the day. Because the major

avenue of tretinoin inactivation is through CYP26, drugs that modulate the

activity of this enzyme can potentially cause drug interactions. Ketoconazole

and liarozole are effective inhibitors of CYP26 and, therefore, are RAMBAs.

Concurrent use of these azoles and topical tretinoin can increase the amount

and prolong the half-life of tretinoin locally in the skin, thereby aggravating

local side effect. Other than retinoids, no other compounds have been shown

to induce CYP26. The use of vitamin D3 and its analogs has increased in

dermatology, and, in particular, for psoriasis. Vitamin D effects in human


skin are largely mediated via its nuclear receptor VDR. Like RAR, VDR

functions in human skin mainly as a heterodimer with RXR (VDR-RXR). In

contrast with retinoid signaling via RAR-RXR, in which the presence of RXR-

ligand confers no additional effect, RXR-ligand provides a synergistic effect

with VDR-ligand in vitamin D signaling. Therefore, topical retinoids that

possess or, through metabolic conversion, acquire RXR selectivity can

positively influence vitamin D pharmacology in human skin.88,90,92,98

Antifungals

Superficial fungal infections, including dermatophytoses, candidiasis, and

pityriasis versicolor, are most often restricted to the epidermis. In treating

these infections, the clinician must select between topical or systemic

management. Factors guiding management include, but are not limited to,

the 1) extent and severity of the infection, 2) site of involvement, 3) any

comorbid conditions or potential drug interactions, 3) anticipated efficacy of

treatment, cost and access to medication, and 4) ease of use.8

Patients with limited fungal infections confined to glabrous skin are usually

best treated with topical agents. Conversely, those with extensive or

recalcitrant disease, or with involvement of terminal hair or nails, may be

better suited for systemic management. In some cases, either treatment

option may be reasonably chosen.99

Treatment with topical antifungal therapy enjoys several advantages over

systemic management, including: fewer side effects, fewer drug interactions,

localization of treatment, and generally lower cost.7 Numerous topical

antifungal medications are available. For the most part, specific antifungal

agents have replaced nonspecific topical treatments, such as keratolytics

(salicylic acid) or antiseptics (gentian violet or Castellani paint), which were


once the first choice for management. The ideal topical antifungal is

efficacious, inexpensive, well tolerated, and has low resistance within

targeted fungi.

Despite widespread availability, few topical antifungal agents have been

directly compared with one another in clinical trials. Studies sponsored by

the manufacturer often compare just the active agent to the vehicle.

Extrapolation between studies is further complicated due to differences in

study design, duration of therapy, site of infection, selection methodology,

or treatment endpoint. Most topical antifungals belong to one of three

classes: (1) imidazoles, (2) allylamines and benzylamines, and (3)

polyenes.100,101

Imidazoles

Imidazoles represent a broad class of antifungal medications. Certain of

these, such as clotrimazole, have been around for decades, while others,

such as sertaconazole, have only become available recently. Imidazoles

impede synthesis of a component of the fungal cell wall through inhibition of

lanosterol 14α-demethylase, a cytochrome P450-dependent enzyme, which

converts lanosterol to ergosterol. Depletion of ergosterol results in

membrane instability and hyperpermeability; changes incompatible with

growth and survival of the fungus. Imidazoles are considered fungistatic in

practical application, with the possible exception of sertaconazole when used

to treat some Candida species. While all imidazoles possess the same

mechanism of action, in-vitro studies demonstrate that not all

dermatophytes are uniformly susceptible to an imidazole at an equivalent

concentration, and this may explain some treatment failures.102,103


Topical imidazoles possess anti-inflammatory activity via inhibition of

neutrophil chemotaxis, calmodulin activity, synthesis of leukotrienes and

prostaglandins, and histamine release from mast cells. Some agents, such

as ketoconazole, yield anti-inflammatory effects equivalent to 1%

hydrocortisone. Topical imidazoles also demonstrate limited antibacterial

properties, particularly with respect to gram-positive organisms. All

marketed imidazoles demonstrate excellent penetration of the stratum

corneum with strong keratinophilic behavior. Sulconazole may be detected in

the stratum corneum up to 96 hours after application. Similarly,

sertaconazole, the newest of all marketed imidazoles, has a half-life within

the stratum corneum of more than 60 hours.

Because of this high affinity for keratin, systemic absorption of imidazoles is

low, with urinary excretion usually in the range of 0.3%–1.0% of the applied

dose. Even when applied to inflamed skin, absorption of imidazoles does not

usually exceed 4% of the applied dose. Again, sulconazole is unique in that

percutaneous absorption in the range of 8%–11% of the applied dose

exceeds that of all other imidazoles.104-106

Due to inherent antibacterial activity, some topical imidazoles have

demonstrated modest efficacy in treating erythrasma, impetigo, and

ecthyma. Because there are more potent antibacterial agents, this is not a

preferred indication for imidazole use. Cure rates for superficial fungal

infection treated with imidazoles are variable and often depend upon study

design. For example, topical miconazole has demonstrated a 63%–100%

cure rate, depending upon the study quoted. A thorough review of the

literature provides no compelling evidence that significant differences in cure

or relapse exist among the various topical imidazoles; however, other

considerations may dictate selection of a particular imidazole.99,103,105


Topical imidazoles are available as a cream or lotion. Although lotions are

better suited for use over large areas or upon hair-bearing skin, limited

studies suggest a cream may be marginally more effective. In studies

performed by the manufacturer, oxiconazole cream yielded a clinical and

mycologic cure in 52% of tinea pedis cases while the lotion yielded the same

cure in just 41% of cases. Additionally, the potential for irritancy must be

considered. In one study of topical clotrimazole for treatment of tinea cruris,

erosive reactions developed in 4 of 27 patients while sulconazole did not

cause any erosions in the same population.102

Topical imidazoles are available in a multitude of forms. Econazole,

ketoconazole, and oxiconazole are approved for once-daily dosing but twice-

daily dosing is recommended for the remainder. Although twice-daily dosing

is recommended for sulconazole, a study comparing once-daily to twice-daily

dosing in tinea corporis and tinea cruris reported an identical rate of cure.

This might have been predicted based upon the 60-hour half-life within the

stratum corneum. Application of all topical antifungals, including imidazoles,

should include normal skin for a radius of 2 cm beyond the affected area.

Duration of treatment with imidazoles has varied. In general, tinea corporis

and tinea cruris require treatment for approximately 2 weeks, whereas tinea

pedis may require treatment for up to 4 weeks. Treatment should be

continued for at least 1 week after all symptoms have abated.103,104,107,108

Risks associated with the use of topical imidazoles include those inherent to

all topical medications, and consist chiefly of irritant and allergic reactions.

Additionally, clotrimazole is marketed in combination with the topical

glucocorticoid, betamethasone dipropionate. It was initially assumed that the

addition of the steroid would more rapidly relieve inflammation, scaling, and

pruritus. Early studies demonstrated the combination was indeed more


effective than clotrimazole alone in alleviating symptoms. However,

betamethasone dipropionate is a potent topical steroid, and striae and other

cutaneous side effects from the steroid component may occur. Longer-term

studies also reported a higher relapse rate (36%) with the combination

product. This combination product may comprise 50% or more of antifungal

prescriptions by primary care providers, compared to less than 7% among

dermatologists. It is likely that overuse by nonspecialists occurs because of

the mistaken assumption either that the steroid agent is mild, or that the

combination will be a better choice when the differential diagnosis is

unresolved. The U.S. Food and Drug Administration has twice revised the

product warnings for clotrimazole-betamethasone dipropionate, discouraging

use on thin skin, for prolonged periods, or when the diagnosis is in

doubt.20,103,105

Use of topical imidazoles is associated with few complications. Because of

low systemic absorption, drug reactions with topical imidazoles are rare.

However, in a single study, increased serum tacrolimus levels were observed

in renal transplant recipients who used clotrimazole troches for

mucocutaneous candidiasis. For this reason, use of nystatin may be

preferred when treating thrush in transplant patients using tacrolimus.

Concerns of resistance must also be considered. Resistance of Candida

albicans to clotrimazole has been described in human immunodeficiency

virus-positive patients with mucocutaneous candidiasis. There has also been

documentation of low levels of in-vitro resistance of various Candida species

to other topical imidazoles. Often, this resistance is associated with

resistance to oral fluconazole.20,50


Allylamines and Benzylamines

Allylamines and benzylamines are closely related compounds. Currently, two

topical allylamines and single topical benzylamine are marketed in the

United States. Allylamines and benzylamines impede synthesis of ergosterol

through inhibition of squalene epoxidase, an enzyme that converts squalene

to squalene oxide. Depletion of ergosterol results in membrane instability

and hyperpermeability. Allylamines and benzylamines are considered

fungicidal because the accumulation of intracellular squalene leads directly

to cell death. The clinical significance of this cidal action is unclear. Unlike

imidazoles, the activity of allylamines and benzylamines is independent of

the cytochrome P450 enzyme system. When compared to naftifine,

terbinafine demonstrates a 10- to 100-fold increased potency in vitro,

although this does not appear to be relevant in clinical use.109,110

Like imidazoles, allylamines, and benzylamines demonstrate anti-

inflammatory activity. Naftifine inhibits adhesion of polymorphonuclear cells

to endothelium, interrupts chemotaxis, and inhibits the 5-lipoxygenase

proinflammatory pathway. It is assumed that terbinafine and butenafine

yield anti-inflammatory effects through similar mechanisms. Allylamines and

benzylamines also demonstrate limited antibacterial properties. A recent

study showed lowered minimum inhibitory concentrations for both bacteria

and fungi when terbinafine was used in combination with benzoyl

peroxide.111

Allylamines and benzylamines are highly lipid soluble and efficiently

penetrate the stratum corneum, where they may persist for extended

durations. Butenafine has been detected within the stratum corneum at

minimum inhibitory concentration for at least 72 hours after application, and

terbinafine may persist at a similar level for up to 7 days after application.


Systemic absorption of these agents is quite low, with typical urinary

excretion in the range of 3%–5% of the applied dose. Despite antibacterial

properties, terbinafine has proven inferior to mupirocin for treatment of

impetigo, and a traditional antibacterial agent should be used. Similarly,

although allylamines and benzylamines do demonstrate activity against fungi

involved in systemic infection, such as Sporothrix schenckii, Blastomyces

dermatitidis, and Histoplasmosis capsulatum, topical therapy is

inappropriate.110,112,113

Limited evidence suggests that topical allylamines or benzylamines may be

preferred over topical imidazoles for certain dermatophyte infections. Some

trials for tinea pedis indicate that 1 week of topical terbinafine is as effective

as 4 weeks of topical imidazoles, with cure resulting in 53%–95% of cases.

Use of this abbreviated treatment with terbinafine has been confirmed in

trials using the active agent versus vehicle alone. In some instances,

resolution of tinea pedis using terbinafine has occurred with as few as three

doses. Generic terbinafine 1% cream is more expensive than an equivalent

amount of clotrimazole 1%, but considering the frequency of application, the

amount of medication required, the likelihood of patient compliance and

ease of use, and the rapidity of results, some experts recommend topical

terbinafine over topical imidazoles for tinea pedis.107,114,115

Topical allylamines and benzylamines are available in a number of forms.

Each agent has a slightly different dosing regimen based upon the

formulation and the location and severity of infection. Risks associated with

use of topical allylamines and benzylamines are those inherent to all topical

medications. A recent case report highlighted a possible interaction between

topical terbinafine and acenocoumarol, and speculated this might be due to

high protein binding of terbinafine, with displacement of the anticoagulant,


but this is likely exceptional; complications arising from use of topical

allylamines or benzylamines are few.109,110,116

Polyenes

Polyenes were among the first agents discovered to possess specific

antifungal properties. The two major topical polyene antifungals are nystatin

and amphotericin B. Only topical nystatin is actively marketed in the United

States. Like all polyenes, nystatin binds irreversibly to membrane sterols

present in susceptible species of Candida. The polyene molecules

demonstrate a higher affinity for fungal sterols, including ergosterol, than for

human sterols, yielding imperfect selective toxicity. This irreversible binding

alters membrane permeability, causing leakage of essential intracellular

components and fungal death. In low concentrations, nystatin is fungistatic,

but, at high concentrations, it may be fungicidal.106,117

Nystatin is insoluble in water and is not absorbed from intact skin, the

gastrointestinal tract, or the vagina. Topical nystatin is used to treat

mucocutaneous candidiasis caused by C. albicans, and other susceptible

species such as C. parapsilosis, C. krusei, and C. tropicalis. Repeated studies

have demonstrated that topical imidazoles are more effective than nystatin

in treating vulvovaginal candidiasis, and use of nystatin for this indication

has diminished in recent years. Nystatin is not effective against

dermatophytes or Pityrosporum; and, hence, it is not indicated for treatment

of tinea or pityriasis versicolor.106,118

Nystatin is available as a powder, cream, ointment, suspension, and pastille.

To treat oral candidiasis (thrush), the suspension or pastille is used four to

five times daily, usually for 2 weeks. To treat cutaneous infection, the

powder, cream, and ointment are used twice daily for approximately two


weeks. Risks associated with use of topical nystatin are those inherent to all

topical medications. A significant number of cases of allergic contact

dermatitis attributed to nystatin alone have been reported. These reactions

have been reported with topical and oral use. Anaphylaxis has been

described with use of nystatin-containing vaginal suppositories but the

reaction was attributed to ingredients other than nystatin.119,120

A combination agent consisting of nystatin and triamcinolone acetonide is

widely marketed. The addition of triamcinolone may provide additional

benefit over nystatin alone during the first few days of treatment when

inflammation is maximal. After this initial period, the manufacturer

recommends a transition to nystatin alone or to other topical antifungal

agents. Although triamcinolone acetonide is only a midpotency agent,

cutaneous sequelae, including striae, skin atrophy, and steroid-induced

acne, has been reported. Because candidiasis often involves thin and fragile

skin, such as that of the intertriginous areas, the risk of damage is likely

potentiated. Finally, many of the combined formulations contained, or may

still contain, ethylenediamine, a sensitizer that may cause allergic contact

dermatitis. As with clotrimazole-betamethasone dipropionate, the

combination agent of nystatintriamcinolone acetonide is more often

prescribed by nondermatologists.107,121,122

Complications with topical polyenes are few. Nystatin resistance may be

encountered in some Candida. This resistance may either be seen in wild

strains (primary type) or it may be induced during therapy (secondary type).

Although C. albicans maintains a low rate of spontaneous resistance to

nystatin, particularly in comparison to resistance to imidazoles, other

species, such as C. tropicalis, C. guilliermondi, C. krusei, and C. stellatoides,

rapidly acquire resistance upon exposure to nystatin.117


Other Agents

Some topical antifungals, such as ciclopirox olamine, tolnaftate, and

undecylenic acid, do not fit well into the major classes and are instead

discussed separately.1,2,8,82,99,106,114,121,123-125

Ciclopirox

Olamine

Ciclopirox olamine is a hydroxypyridone antifungal agent with a unique

structure and mode of action. Unlike most other topical antifungals,

ciclopiroxolamine does not interfere with sterol synthesis. Instead, it

interrupts active membrane transport of essential cellular precursors,

particularly trivalent cations. Ultimately, this disrupts cellular function,

leading to demise of the fungus. If concentrations of the drug are high

enough, the membrane integrity of the fungus may actually be impaired.

Ciclopirox olamine also has inherent anti-inflammatory activity exerted

through inhibition of prostaglandin and leukotriene synthesis within

polymorphonuclear cells. Broad-spectrum antibacterial properties have

also been attributed to ciclopirox olamine. In one study, topical

ciclopirox olamine had broader coverage against Gram-positive and

Gram-negative organisms than did topical imidazoles or topical

allylamines.

When applied to the skin, ciclopirox olamine remains in high

concentration within the epidermis and upper dermis. Ciclopiroxolamine

penetrates keratin easily, with cadaveric skin demonstrating

concentrations in the epidermis that were 10–15 times the minimum

inhibitory concentration for a sensitive species. This ability to penetrate

keratin recommends use for onychomycosis, as the drug is also capable

of penetrating the nail plate material. Studies of drug metabolism have

demonstrated that, with typical use, approximately 10% of the

administered dose is excreted in the urine.

Ciclopirox olamine is indicated for the treatment of dermatophytoses and

onychomycosis, candidiasis, pityriasis versicolor, seborrheic dermatitis,

and even cutaneous infections with unusual saprophytes. In tinea pedis,

a mycologic cure rate of up to 85% has been observed, and in

seborrheic dermatitis, a significantly larger percentage of users had

>75% improvement with 2 weeks of use than those using the shampoo

vehicle alone. Although treatment with ciclopirox olamine for tinea pedis

and seborrheic dermatitis has yielded results on par with other

modalities, use in onychomycosis has met with more modest success.

Often, an assessment of efficacy depends upon whether a mycologic

cure (culture-negative) or clinical cure (a disease-free nail) defines

success. Although a disease-free nail is often the patient’s true goal,

ciclopiroxolamine achieved such a response in just 5.5%–8.5% of those

treated with a standard 48-week course. Two recent trials demonstrated

increased efficacy when using oral terbinafine in combination with topical

ciclopirox olamine, as opposed to oral terbinafine alone.


Debate regarding the use of ciclopiroxolamine as an independent or

adjunct treatment for onychomycosis is ongoing. Ciclopiroxolamine is

available in a wide range of forms. Cutaneous candidiasis,

dermatophytoses, and pityriasis versicolor should be treated twice daily

for 2 weeks to 1 month, but treatment for tinea pedis should continue 1

month or longer. When using ciclopirox shampoo for seborrheic

dermatitis, treatment may continue twice weekly for an indefinite

duration. Improvement is generally noted in 2–4 weeks. Finally, in

treating onychomycosis, the nail lacquer is applied daily to the nail and

hyponychium for 48 weeks and excess medication is removed weekly

with alcohol. Risks associated with use of topical ciclopirox olamine are

those inherent to all topical medicaments. Allergic contact dermatitis has

been reported only rarely, and ciclopirox olamine is considered a weak

sensitizer. In patients with an allergic reaction to ciclopirox, imidazoles

may be used with relative safety because of a markedly different

chemical structure. Serious complications with topical ciclopirox olamine

are few.

Tolnaftate Tolnaftate is a thiocarbamate first developed in the 1960s but now

contained only in over-the-counter anti-fungal remedies. The precise

mechanism of action for tolnaftate is unknown. It is thought to impair

ergosterol synthesis via inhibition of squalene epoxidase but in a

different manner than that of allylamines and benzylamines. Tolnaftate

may be fungistatic or fungicidal, depending upon the concentration. No

antibacterial properties have been attributed to tolnaftate. Little data

exists regarding the pharmacokinetics of tolnaftate.

Like other topical antifungals, systemic absorption is assumed to be

negligible from a clinical standpoint. Tolnaftate is indicated for the

treatment of dermatophytosis and pityriasis versicolor. Early studies

demonstrated a cure rate for tinea pedis as high as 73 percent to 93

percent, but later studies demonstrated lower efficacy, essentially

equivalent to undecylenic acid. Although direct comparisons are lacking,

topical tolnaftate is widely considered less effective than topical

imidazoles, allylamines, and benzylamines. Tolnaftate is ineffective for

candidiasis.

Tolnaftate is available in a variety of formulations. Twice-daily use for at

least 2 to 4 weeks, and up to 6 weeks on hyperkeratotic skin, is

recommended. To diminish the incidence of recurrence, others simply

recommend treatment be continued 2 weeks beyond apparent

resolution. Risks associated with use of topical tolnaftate are those

inherent to all topical medicaments. Allergic contact dermatitis has been

reported on occasion. Serious complications with use of topical tolnaftate

are few.

Undecylenic

Acid

Despite more than 60 years of use, the mechanism of action for

undecylenic acid is largely unknown. It appears that the organic acid

interacts with components in the fungal cell wall. In C. albicans, the

inhibition of germ tube formation has been recently identified, and a

similar effect has been noted in conidia formation in Trichophyton

rubrum.


Undecylenic acid is available as a zinc, calcium, or copper salt. As tissue

pH rises, this salt fails to dissociate, and the antifungal properties of the

medication diminish. The acid is practically insoluble in water, but is

miscible in ethanol, water, or ether. With topical use, systemic

absorption is negligible. The zinc contained in the zinc undecylenate

form, the most common in clinical use, provides some astringent action

that may aid in reducing rawness and irritation. Topical undecylenic acid

is used for the treatment of dermatophytosis and candidiasis.

Although early studies indicated a cure rate in excess of 80 percent,

subsequent studies demonstrated cure rates of 53 percent or less.

Undecylenic acid and its salts are widely considered less effective than

miconazole, clotrimazole, or tolnaftate in the treatment of tinea pedis. A

trial of topical undecylenic acid for herpes labialis demonstrated a

decreased incidence and duration of viral shedding, with a decrease in

pain and tenderness. The antiviral effect was of short duration and most

pronounced when acid was applied during the prodrome.

Other long chain alcohols enjoy specific approval for abbreviation of

herpes labialis and appear more effective. Undecylenic acid and its salts

are available as a powder, aerosol, cream, and solution. Standard dosing

for children and adults is twice-daily for 4 weeks of use. Risks associated

with use of topical undecylenic acid are those inherent to all topical

medicaments. Allergic contact dermatitis has been recently reported,

and a protocol for patch testing exists if such an allergy is suspected.

Topical forms of undecylenic acid may yield an unpleasant “fishy smell”

that discourages use. Complications with topical undecylenic acid are

few. Because undecylenic acid is widely accepted to be less effective

than imidazoles, clinical monitoring for treatment failure is indicated.

Cosmetic Dermatology

Cosmetic dermatology is often referred to as desire dermatology and

supports individuals to achieve the appearance they want. While

dermatology is often a combination of medical and desire treatment, there is

more of an evolving marketplace influence and overlapping of dermatology

specialties that come together in the field of cosmetic dermatology. This

section considers the integrated medical and surgical practices of

conventional dermatology and the key practices involved in a rapidly

evolving model of cosmetic practice.


Botulinum Toxin (Botox) Injections

Botulinum toxin (Botox), an exotoxin

produced by the bacteria Clostridium

botulinum, occurs naturally in

nature. The use of C. botulinum A

exotoxin, commonly known as

botulinum toxin type A (Botox-A),

has emerged over the last decade as

one of the most popular methods of

combating cutaneous signs of aging,

particularly the dynamic wrinkles of

the face. The therapeutic application

of this potent neurotoxin has carved

a comfortable niche in the cosmetic

realm of dermatology practice for

practical reasons. Results appear within several days of administration, the

procedure itself is short in duration and relatively uncomplicated, and side

effects are minimal.126

Although medicinal use of Botox by physicians is widespread, professional

opinions vary as to the best ways to administer the treatment. For instance,

the ideal dilution of the toxin, the number of units to inject, and the

longevity of prepared and refrigerated Botox remain debated issues. The

methods described in this section are those used most frequently by the

primary author. The novice injector should try the various methods espoused

by experienced specialists to determine which yields the best results in his or

her own practice.127


Mechanisms of Action

Acetylcholine (ACh) is the neurotransmitter associated with induction of

muscle movement. Botox achieves chemical denervation of striated muscles

by cleaving one or more of the proteins required for the release of ACh. The

target protein depends on the serotype of toxin used. The result is

temporary flaccid paralysis of the injected muscles, which persists

approximately 3 to 5 months. As new neuromuscular junctions form, muscle

function returns. There are seven Botox serotypes (A–G). Serotype A is the

most potent and was the first to be made available in the United States for

medical use. Botox Cosmetic™ (Allergan Inc., Irvine, CA) and Dysport™

(Ipsen Products, Maidenhead, Berkshire, UK) are both formed from serotype

A, which functions by cleaving the SNAP-25 protein, a component of the

SNARE (Soluble N-ethylmaleamide-sensitive factor Attachment protein

Receptor) complex. The presence of an intact SNARE complex, composed of

synaptobrevin, SNAP-25, and syntaxin, is necessary for vesicles containing

ACh to fuse with the cell membrane and to release ACh into the

neuromuscular junction. Botox-B, now available in the United States as

Myobloc™ (known as Neurobloc in Europe), cleaves synaptobrevin, thus

preventing the release of Ach.127,128

Clinical Uses of Botox

Dynamic Wrinkles:

Botox can be injected into specific muscles to induce temporary paralysis

resulting in an inability to move and wrinkle the skin overlying the treated

muscle. Botox is only beneficial for dynamic wrinkles, also known as

“wrinkles in motion.” It is not as effective for static wrinkles, although

prolonged use of Botox may help prevent wrinkles in motion from becoming

wrinkles at rest. Botox can be combined with dermal fillers and resurfacing


techniques to optimize patient satisfaction. The upper part of the face

contains distinct muscle groups that can be selectively paralyzed by a

knowledgeable injector. In the lower part of the face, the muscle groups are

less distinct and thus more difficult to inject accurately. The paralytic effects

of Botox appear approximately 3 to 7 days after injection. However, the

effects may increase for up to 2 weeks.129,130

To use Botox, 2.5 cc of preservative-free saline diluent is added to the 100-U

vial. This yields 4 U per 0.1 cc. To use Reloxin/Dysport, 2.5 mL of 0.9%

preservative-free saline diluent is added to the 500-U vial. This provides 20

U per 0.1 mL. To use Myobloc, 1.2 cc of saline diluent is added to the 2500-

U vial. This yields 200 U per 0.1 cc, which is injected with a 1-cc syringe and

a 30-gauge needle.131

Glabellar Region:

To treat the glabellar region (skin

between the eyebrows and above

the nose), 0.1 cc (4 U of Botox or

200 U Myobloc) is injected into each

corrugator muscle along with 0.1 cc

into the procerus muscle. Glabellar

injections are currently the only

injections approved by the FDA for

cosmetic use. The glabellar

indication is also the only one under

consideration by the FDA for

Reloxin. In men or patients with

stronger musculature, two sites

superior to the corrugator muscle


may need to be injected. Doses of 20 U in the glabella work for most men

while retaining a natural look; one study showed that 40 to 60 U in the

glabellar area was more effective in males.

The injector should avoid the periosteum as this can induce post-injection

headache. After injecting the procerus muscle, massage the area laterally

across the bridge of the nose to ensure that the toxin enters the depressor

supercilii portion of the corrugator muscle, which will subtly lift the patient’s

medial brow, resulting in a more youthful appearance. Proper treatment of

the glabellar area or “brow furrow” prevents the patient from frowning,

leading to a more relaxed, less angry look. In addition, relaxation of these

muscles for long periods of time may prevent or reduce wrinkle formation in

the brow area.132,133

Forehead Region:

Botox-A is clinically used more broadly than its FDA indication of glabellar

treatment. Expanded use is permissible for licensed providers and is referred

to as “off label” use. To treat wrinkles of the forehead, 0.1 cc (4 U Botox,

200 U Myobloc) is injected across the forehead.

Injection of the forehead is an art as well as a science as it can dramatically

affect eyebrow shape. Therefore, prior to injecting the forehead, the provider

should consider whether she or he wants to enhance the arch of the eyebrow

to create a more horizontal eyebrow shape. Generally, women prefer a more

arched brow because it imparts a more feminine look, while men prefer a

more horizontal brow. The forehead should be injected about every two

square centimeters where movement of the muscles is seen on eyebrow

elevation.


It is important not to inject all patients in the same way. Forehead injections

should be tailored or customized to the patient’s forehead size and shape. In

addition, one must take into consideration the placement of the eyebrow

over the superior orbital rim. Low brows will become even lower after

injections of Botox to the forehead; therefore, forehead injections should be

avoided in some patients. Alternately, injections can be performed in the

higher regions of the forehead in patients with low brows.

The major pitfalls with forehead injections are the following: (1) unwanted

eyebrow shape (2) brow ptosis, (3) missed areas and (4) drooping eyelids.

It is important not to over-inject the forehead area as this may lead to brow

ptosis. Additionally, one must take care to avoid the area 1 cm above the

eyebrows to reduce the chances of brow ptosis. The provider should warn

the patient with low forehead wrinkles within this 1-cm area that these

wrinkles cannot be treated with Botox, and will remain after

treatment.131,134,135

Care must be taken to avoid forehead injections in individuals with low-set

brows and/or excessive eyelid skin. In older patients and patients with

excess eyelid skin, overtreatment of the forehead area may result in

drooping eyelids. Hooding of the upper eyelids by the descending eyebrow

tissue results in a neural reflex that increases the activity of the frontalis

muscle in an effort to keep the vision clear of the descending tissue that

would otherwise obstruct vision or interfere with eyelid function. In this

population the upward pulling of the frontalis muscle is needed to raise the

baggy upper eye skin. These patients are better treated with blepharoplasty

first, then with Botox. The ideal patient for Botox treatment in the forehead

is a young patient (20s–40s) with no excess upper eyelid skin.126,136,137


Crow’s Feet:

To treat crow’s feet with Botox, 0.1 cc is injected 1 cm lateral to the lateral

canthus. Then 0.05 cc is injected 1 cm above the first injection and 0.1 cc 1

cm below. If wrinkles progress medially, one can inject 0.05 cc

approximately 1 cm apart along the orbital rim to the midpupillary line.

When using Dysport, fewer injection sites may be required because of

increased diffusion. Injecting medial to the midpupillary line does not correct

medial wrinkles and can lead to an ectropion; therefore, this area should be

avoided. Most patients do not notice these wrinkles prior to Botox injections

and sometimes mistakenly believe that Botox “caused” these previously

unobserved wrinkles. When used properly, Botox can temporarily erase the

lateral crow’s feet lines.138

Brow Lift and the Microdroplet Technique:

Botox has been used to elevate the eyebrow position by treating between

the eyebrows as well as the lateral eyebrow with relatively few injection

sites, and with relatively large quantities of Botox (1.5–2.5 U Botox-A). This

technique is limited by the possibility of inducing the undesired side effect of

upper eyelid ptosis caused by the unwanted diffusion of Botox into the

levator palpebrae superioris muscle, which is responsible for eyelid

elevation.139

The position and appearance of the eyebrows is determined at rest and

dynamically by the opposing action of several groups of muscles that act on

the eyebrow. The frontalis muscle primarily performs eyebrow elevation.

Brow elevation is opposed by the septal and orbital portions of the

orbicularis oculi muscle; including, the depressor supercilii component of the

orbicularis oculi muscle, and the procerus muscle. The medial position of the


eyebrow is also influenced by the activity of the corrugator supercilii muscle.

Additionally, the shape of the brows is affected by the activities of the

eyebrow elevators and the eyebrow depressor muscles where they

interdigitate along the eyebrow to create facial expression.134,140

With age there is a gradual fall in the position of the eyebrows, which is

known as brow ptosis, resulting in smaller appearing eyes that is not

aesthetically desirable. Botox can also be used to elevate the brows,

resulting in a more youthful appearance. This is referred to as a chemical

brow lift. The technique of lifting the brow includes injection of the glabellar

area as described above. After injecting the procerus muscle with 0.1 cc of

Botox the nasal bridge should be massaged in order to ensure that the toxin

enters the depressor supercilii portion of the corrugator muscle. This can be

used to try and correct an asymmetry of the medial brow. Injecting 0.05 cc

of Botox into the lateral brow depressor muscles can raise the lateral aspect

of the eyebrow.131,141

Treatment of the lateral depressors of the brow results in an average brow

elevation of 4.83 mm when measured from the lateral canthus. Injections of

Botox into the glabellar area and lateral brow have also been shown to yield

brow elevations of 1 to 3 mm when measured from the eyebrow to the

midpupillary point. However, the lateral brow lift with Botox provides

inconsistent results and leads to lateral brow lowering in some patients. (The

procerus injection consistently raises the brows). Therefore, it is preferred to

use a dermal filler injected into the lateral brow to achieve a brow lift.142

A novel technique that has been recently introduced is intended to

temporarily elevate the eyebrows without provoking any undesirable side

effects. This “microdroplet technique” uses small quantities of Botox


dissolved in micro droplets of injectable saline carrier to treat the septal and

orbital orbicularis muscles on each side of the patient’s face. The provider

treats the frontalis at and below the brow by injecting very small volumes of

fluid in multiple locations. These micro droplets have volumes of 10 to 50 L

of injectable saline containing as small as 0.001 to 1 U Botox. Treatment is

based on 100 U Botox and 3 mL of injectable saline, which equals

approximately 0.33 U of Botox per 10 L.143,144

A typical treatment involves a total of approximately 100 micro droplets

placed in double or triple rows just above, in, and below the brow, stopping

around the level of the lowest brow cilia. The microdroplet injections are

placed superficially approximately 1 mm into the skin to trap the Botox at

the interface between the orbicularis oculi and the skin. For crow’s feet, the

needle is inserted before the midline of the lateral palpebral raphe. The

glabellar area is also treated. The combination of these treatments produces

a uniform brow-lift effect.145

Bunny Lines:

The upper nasalis muscle across the bony dorsum of the nose causes

fanning wrinkles (“bunny lines’’) at the radix of the nose and can lead to

medial wrinkling around the eyes. Two to four units of Botox can be injected

into the nasalis muscle to reduce or eliminate these lines.

Many physicians inject into the wrinkles rather than into the nasalis muscle

resulting in an incomplete correction. The correct injection points are in the

belly of the muscle, inferior to the angular vein. If the injection is too low,

the levator labii superioris will be relaxed, which leads to an unwanted upper

lip ptosis.137


Treating Nasal Tip Ptosis/Nasal Tip Lift:

Botox has been used for lifting the nasal tip. More than one technique exists

but there is no consensus on an optimal method. The main muscles that

influence the nasal tip are the nasalis, the depressor septi nasi, the levator

labii superioris, and the alaeque nasi muscle.

Atamoros in 2003 described the injection of 4 U of Botox into each of the

alar portions of the nasalis and 4 U into the depressor septi. Dayan and

Kempiners later described the injection of 5 U of Botox into each depressor

septi nasi and 3 U into each levator labii superioris. Ghavami et al.

demonstrated similar results as Dayan and Kempiners with only 1 to 2 U

injected to each of the depressor septi nasi and further stressed that proper

studies excluding confounding variables, such as concomitant rhinoplasty or

chemodenervation of synergistic muscles, are required before Botox

injection alone can be recommended as a treatment for dynamic nasal tip

ptosis. It is recommended to use 2 to 3 U injected at the base of the

columella. This procedure is most effective for those with a short- or normal-

sized upper lip. Those with a long length between the top of the columella

and the top of the lip, that is, long upper lip, do not receive good results

from this procedure. Those with a long upper lip will benefit from a dermal

filler to raise the nasal tip.134,140,145

Cosmetic Use of Botulinum Toxin Type A in the Lower Face:

Cosmetic treatments with Botox-A have focused mainly on the upper face,

particularly the glabellar, forehead, and periocular areas. With the huge

increase in the number of cosmetic Botox injections delivered each year and

its clinical effectiveness, a variety of off-label interventions using Botox-A for

the lower face have emerged. However, this area has an increased incidence


of side effects and should only be treated by experienced Botox users. As

such, Botox-A is now more widely used in lower face and neck rejuvenation,

in treating the chin and corners of the mouth as well as in recontouring of

the jawline.

Yet another area where Botox-A has shown promise cosmetically is in the

treatment of facial and chest wall flushing. The response of the lower facial

muscles to Botox-A is greater than upper facial muscles. Moreover, it has

been established that the lower facial muscles will have a longer-lasting

response to Botox-A than upper facial musculature. The dose for the lower

muscles therefore needs to be adjusted to the muscle size and patient

gender to be approximately half or one-third the dose injected in the upper

facial muscles.142,146,147

Upper Gum Show:

The levator labii superioris alaeque nasi muscle retracts the upper lip. In

some individuals, this muscle is overactive and pulls the lip back excessively,

allowing visualization of the upper gums and upper incisors. Injecting 1 - 2 U

into the levator labii superioris alaeque nasi muscle on each side of the bony

nasal prominence will slightly drop the lip, preventing the upper gum show.

This procedure works better in young patients because it causes vertical

elongation of the lip. This can be used in combination with fillers such as

CosmoPlast in the vermilion border to prevent the elongated lip.148

Melomental Folds:

The melomental folds are also called marionette lines. They extend from the

downturned corner of the mouth to the lateral chin. The depressor anguli


oris pulls down the corner of the mouth in opposition to the zygomaticus

major and minor contributing to these folds.

Dermal fillers often correct marionette lines; however, some physicians

prefer to combine dermal fillers with Botox injections. Botox can be injected

into the depressor anguli oris to weaken it, allowing the zygomaticus to

elevate the corners of the mouth and return them to a horizontal position.

For reducing the melomental folds, a dose of 2 - 4 U should be injected at

the depressor anguli oris immediately above the angle of the mandible and 1

cm lateral to the lateral oral commissure. Care must be taken not to use too

high of a dose as this can lead to drooping of the lateral lower lip, flaccid

cheeks, an incompetent mouth, or an asymmetric smile.129,139

Perioral Lines:

Many factors are implicated in the formation of perioral lines. Smoking,

photo-aging, loss of subcutaneous tissue in the lower face, and the purse

string-like action of the orbicularis oris muscles are the most important

causes. Botox-A injection is usually reserved for deep perioral lines

worsened with muscular pursing of the lips. The dosage is dependent on the

depth of lines but generally 1 U of Botox-A injected into each site with a

total of 2 U per half of the upper lips. The middle upper lip should be avoided

in patients wanting to retain their cupid bow.

It is critical to measure the placement on the upper lips first so that the

sides are treated in exactly the same spot to preserve symmetry. The best

results occur when Botox is combined with laser resurfacing or lip fillers to

enhance the vermillion border and smooth the surface of the skin.145,149


Mentalis Muscle and Chin Puckering:

Relaxing the hyperkinetic muscle fibers of the chin and the mentalis muscle

with Botox-A can reduce and eliminate chin puckering. A single dose of 4 to

6 U of Botox-A placed in the exact center of the point of the chin is effective.

An overdose in this area can result in the inability to approximate the lower

lips tightly against the teeth, ultimately leading to involuntary dribbling from

the lip when drinking or drooling from the corners of the mouth.150,151

Neck Lines and Platysma:

Brandt and Bellman were the first to report using Botox to treat aging of the

neck. Platysmal bands and neck vertical lines represent an accurate gauge of

chronological age specifically for those people with exaggerated outdoor sun

exposure. Separation of the platysma anteriorly occurs with aging, resulting

in banding or “turkey neck.” Vertical platysmal bands may be successfully

treated with Botox-A. The extended or marked platysmal bands are grasped

between the thumb and index fingers and the needle is vertically inserted

into the muscle band. The dose is usually 2 to 4 U spaced 4 cm apart with an

overall cumulative dose of 8 to 12 U per band and a total maximum in the

neck of 25 to 30 U.

Because of the nature of the muscle and the site of injection, complications

such as dysphagia and dysphonia can be encountered. Patients should be

warned about the possibility of such untoward effects.129, 152

Nefertiti Lift:

The platysma muscle pulls downward with age, leading to jowl formation and

frequent rhytides. Jawline redefinition with neurotoxin has not been widely

exposed in the literature and there exists a discrepancy in the exact dosing


and techniques to best define this area. A technique described recently by

Levy was named the “Nefertiti Lift” (after the perfect jawline of the ancient

queen). This technique releases the downward tension of the depressor

effect of the aging platysma and releases the skin to the elevator muscles

for lifting action. The “mini-lift” technique requires an injection of 2 to 3 U of

Botox-A along and under each mandible and to the upper part of the

posterior platysmal band for a total of 15 to 20 U per side.153

Chest:

The upper area of the chest is a site of predilection for photodamage.

Textural, pigmented, and photodamage changes are frequently seen in the

V- shaped area of the chest. Both photodamage and muscular sagging of the

upper chest cause static and dynamic wrinkles. Anatomically, the platysma

is known to originate at the second rib; however, it can still present as far

down as the fourth rib after which it traverses the pectoralis major and

inserts in the mandible.

To date there is no consensus or indication for upper chest injection of

Botox-A; however, there are various ways to inject Botox in the upper chest.

The techniques used are the curved, the “V,” and the triangular approaches,

during which Botox is injected over a curved, V-shaped area, or a triangular

area with “5 to 10” sites identified within, each targeted with 2 to 8 U of

Botox.145,154

Other Uses of Botulinum Toxin:

Hyperhidrosis -

Hyperhidrosis is a troublesome problem leading to awkward social

situations for those affected. Unfortunately, topical and oral


medications, iontophoresis, and surgery have not proven efficacious in

the majority of patients. Sympathetic nerves that use ACh as the

neurotransmitter innervate the eccrine glands. Therefore, Botox is

effective in temporarily reducing or abolishing sweat production. Botox

is the only medication that is approved by the FDA for axillary

hyperhidrosis.

Botox for hyperhidrosis is diluted with 5.0 cc of preservative-free

saline, yielding 2 U per 0.1 cc. Reloxin/Dysport can also be diluted with

5.0 cc of preservative-free saline, providing 10 U per 0.1 cc. To use

Myobloc, 5000-U vial has 2.1 cc of saline diluent added. This yields

200 U per 0.1 cc. Using a 1-cc tuberculin syringe with a 30-gauge

needle, 0.05 cc is subcutaneously injected with an approximate depth

of 3 mm with care to avoid intramuscular injections. The palm or sole,

including the webs of the hands and feet, should be injected every

square centimeter.

When treating the axilla, patients should be asked which areas bother

them to determine how far beyond the hair bearing area to inject. A

starch-iodine test may be performed prior to injections to ascertain

which areas need to be injected. The iodine solution is applied to the

affected area and then covered with starch. The areas that produce

sweat will turn black, indicating which areas to inject. Although this

test is messy, it is a useful technique for evaluating the efficacy of the

injections and for determining which areas to inject.

It is recommended to inject the tips of the fingers and toes as well to

avoid compensatory sweating in these areas. It is usually necessary to

inject 100 U Botox or 5000 U Myobloc per palm or sole and 50 U Botox


or 2500 U Myobloc per axilla. The effects last approximately 4 months

although there are reports in the literature of longer lasting

results.155-157

Inguinal Hyperhidrosis -

Inguinal hyperhidrosis (IH) is a focal and primary form of

hyperhidrosis in which the individual has intense sweating in the

inguinal region. Appearing in adolescence, usually not later than the

age of 25, the condition continues into adulthood. Inguinal

hyperhidrosis is characterized by chronic, intense sweating in the

inguinal region, a situation that is potentially embarrassing for the

patient. It is a condition that symmetrically affects the groin region,

including the suprapubic area, the shallow depression that lies

immediately below the fold of the groin (corresponding to the femoral

triangle), the medial surfaces of the upper inner thighs, and the

genital area. It may also include the lower part of the gluteus

maximus, gluteal fold, and natal cleft.150,158

No study to date has described the ideal doses of Botox for the

treatment of IH. The threshold doses of Botox-A for the treatment of

hyperhidrosis depend on the severity of the condition. Two or three

units of Botox-A per square centimeter can be used to treat the

hyperhidrotic area in the inguinal region. The only side effects reported

are those related to the injections, such as rare small hematomas and

temporary edema.157

Other Neuroglandular Disorders -

The effects of Botox-A at the neuroglandular junction have not been

explored as extensively as those occurring at the neuromuscular


junction. Clinical studies examining the effect of intracutaneous Botox

for focal hyperhidrosis found complete abolition of sweating in the

injected area within 3 to 7 days. No adverse effects were reported,

and in a 5-month follow-up there were no clinical recurrences of the

hyperhidrosis.

Gustatory sweating is another area of neuroglandular dysfunction in

which Botox-A has proven effective. Gustatory sweating (or Frey’s

syndrome) is a disabling disorder in which the cheek skin sweats

profusely during eating. The syndrome may occur after parotidectomy,

and is likely due to the misdirection of regenerating parasympathetic

fibers that innervate the sweat glands of the face. Intracutaneous

Botox-A has been reported to significantly decrease or prevent

sweating for more than 6 months, with no clinical evidence of facial

weakness in any patients. Botox-A injected into the submandibular

glands has been reported to significantly decrease salivation resulting

from stimulation of the lingual nerves. The decreased salivation was

temporary, and did not appear to be directly toxic to the acinar cells of

the gland. Canine studies have also shown that vasomotor rhinorrhea,

a parasympathetically controlled phenomenon, responds favorably to

topical Botox-A.133,150,159

While the duration of action of Botox-A at the neuromuscular junction

appears to be approximately 3 months, a longer-lasting effect may

occur at the glandular level. Botox-A has produced anhydrosis for

more than 12 months in patients with gustatory sweating. The reason

for the difference in duration of action is uncertain; hypotheses include

a higher rate of resynthesis of SNAP-25 (the protein cleaved by Botox)

in neuromuscular synapses, and a higher area of axonal sprouting and


consecutive reinnervation of muscle fibers as compared to that in

glandular tissue.140

Botulinum Toxin in Persistent Facial Flushing -

Facial flushing is not an uncommon problem in fair-skinned individuals

of Celtic and northern European descent. A vasomotor phenomenon

that results in increased erythema, persistent facial flushing can be

accompanied by facial telangiectasias and gustatory sweating. Facial

flushing is categorized as either autonomic neural-mediated (wet) or

direct vasodilator-mediated (dry). The method by which Botox-A works

to affect vasodilation is unknown, and the results regarding its efficacy

for this indication are inconclusive.

One theory is that Botox might work through reduction of local

subclinical inflammation, which contributes to persistent erythema.

Moreover, the anti-inflammatory role of Botox-A in blocking substance

P, vanilloid receptor 1 (TRPV-1), and calcitonin gene-related peptide

(CGRP) is important in decreasing the subclinical inflammation that

might present as erythema. Only Yuraitis et al. have described an

improvement related to facial flushing in limited case reports.

Alexandroff as well as Kranendonk et al. failed to show an effective

response to Botox-A for facial flushing in three published cases.

Further studies are required to better assess the safety and efficacy of

this procedure.135,145

Botulinum Toxins and Acne Vulgaris -

Acne, which most commonly occurs during adolescence, is influenced

by several factors. The pathology centers on the pilosebaceous follicle

(comprising the sebaceous gland), the follicle (pore), and vellus hair.


Factors that promote the formation of comedones (whiteheads or

blackheads) include the following: (1) increased sebum production; (2)

inflammation of the dermis and follicles by inflammatory mediators;

(3) hyperkeratinization and obstruction of the upper region of the

follicle; and, (4) colonization of the follicle by the bacterium

Propionibacterium acnes.131

Adolescence is marked by an

increase in levels of circulating

androgens, particularly

dehydroepiandrosterone sulfate

(DHEAS). The increased androgen

levels are thought to cause

sebaceous glands to enlarge and

increase sebum production. While

most acne patients have normal

hormone levels, increased sebum

production plays an important

role in acne.

A correlation exists between the rate of sebum production and the

severity of acne. In addition, acne patients typically produce sebum

that is deficient in linoleic acid, which is a potential cause of abnormal

keratinization and follicular obstruction. Increased sebum levels can

also irritate keratinocytes, causing the release of interleukin-1, which

in turn can cause follicular hyperkeratinization. The final common

pathway in each of these acne-causing routes, which are not mutually

exclusive, is follicular obstruction.


Botox may inhibit the cascade of events leading to acne. This is likely

achieved through parasympathetic effects, inhibiting sweat gland

activity, and sebaceous gland secretion as well as stimulating

keratinocyte locomotion. Associated anti-inflammatory and

antiandrogenic effects may also contribute.127,132

It is thought that Botox-A toxin inhibits the formation of acne through

at least three different pathways. First, Botox inhibits sebum

production by sebaceous glands through cholinergic inhibition and

sebocyte differentiation. Botox injections results in a lowered sebum

potential across the ducts and skin, which inhibits cholinergic

secretions normally attributed to increased sebum production.

Moreover, decreased sebocyte promoter differentiation and lower

sebum levels may clinically improve acne by decreasing the growth of

P. acnes. Thus, the ability to decrease sebum production decreases P.

acnes growth and acne development. Additionally, Botox inhibits sweat

production by sweat glands. Decreased perspiration may clinically

improve acne by reducing the growth of P. acnes.133,160

Follicular occlusion by keratinocytes is the final common pathway in

each of the various routes leading to acne. Keratinocyte migration is

inhibited by the high-dose stimulation of nicotinic ACh receptors. By

inhibiting the release of ACh, Botox may indirectly increase the

migration of keratinocytes, thus reducing follicular occlusion. The

androgen surge during puberty is a known instigator of acne, and

studies have shown that androgens increase the number of ACh

receptors. Interestingly, androgen receptors are found on

pilosebaceous duct keratinocytes, which are important in follicular

occlusion. It is postulated that during puberty androgens increase the


number of ACh receptors on the pilosebaceous keratinocytes, leading

to further inhibition of keratinocyte locomotion through increased ACh

stimulation. By inhibiting the release of ACh, Botox decreases the

number of ACh receptors on the pilosebaceous keratinocytes, thereby

increasing keratinocyte locomotion through decreased ACh

stimulation.161,162

Finally, results from recent research have shown that holocrine gland

secretions are controlled by various neuropeptides, with substance P

playing a significant role. Botox-A blocks substance P, TRPV-1, and

CGRP, which are important mediators in inflammation, and therefore

helps decrease the inflammatory aspect of acne development.163

Botulinum Toxin and Chemical Liposuction:

Obesity is a medical problem with obvious cosmetic implications.

Liposuction, gastric volume reduction, laparoscopic banding, lipase

inhibitors, and mesotherapy are all methods employed in the

treatment of obesity. Fat distribution and its physiology are partly

known to be under the control of the autonomic nervous system.

Multiple research studies have revealed that lipoatrophy and

degradation of adipocytes was noticed after denervation. There is

disagreement regarding whether or not nervous system innervation

plays a role in fat accumulation. Bilbao et al. showed that vagotomy

reduced fat accumulation in rats and postulated that vagotonia plays a

role in the development of obesity. On the other hand, Jones et al.

showed that muscle action-related sympathetic activity is associated

with advancing age and increased abdominal adiposity. This disparity

was linked to a high sympathetic to parasympathetic ratio.139 Following


observations of coincidental lipoatrophy after Botox injections, it has

been:

“postulated that Botox injected in subcutaneous fat might

achieve fat loss for cosmesis. Lim et al., suggested a scheme by

which subcutaneous fat denervation and hence focal lipoatrophy

could be achieved. They recommended a maximum injectable

total dose of 200 U for the intended area of fat reduction with an

even distribution of each injection. Further research in this area

is required to establish a better risk–benefit ratio of this potential

Botox use and to provide a guided consensus for its optimal

use.”164

Botulinum and Hair Growth Control -

Focal hair loss following Botox-A treatment for blepharoplasm and

oromandibular dystonia has been reported, but remains controversial.

Several theories have been suggested to explain this observation,

specifically the fact that hair follicles contain cholinergic receptors,

which are essential signaling elements for nerve transmission that

send growth signals to hair follicles. When inhibited by Botox, those

receptors may lead to hair loss. Hair loss has also been described in

conditions related to peripheral nerve dysfunction such as diabetic

peripheral neuropathy, myxoma of the nerve sheath, and after

occipital nerve block with corticosteroid.

Botox could have the same effect through chemodenervation. Some

studies have actually reported regrowth of hair rather than loss after

Botox was administered for alopecia areata, extending the debate over

whether Botox actually causes hair regrowth or loss.129,131


Botox-A and Cosmetic Surgery -

Botox-A can be used before or after the surgical manipulation to either

enhance or sustain benefits. If injected in the pre-operative period, the

toxin may allow improved tissue manipulation and reduced incisional

tension leading to improved healing. Prior to endoscopic brow lift or a

face-lift using endoscopy, Botox-A injections help in raising the

position of the brow and can reduce the amount of surgical

manipulations necessary. Finally, when used after surgery, Botox-A

weakens the musculature, prolonging the anticipated effect.165

Combined Therapies

The superiority of Botox-A when used with other cosmetic procedures has

been documented in a number of studies. When administered one week prior

to the treatment with filling agents, Botox-A prevents the distortion of the

fillers and prolongs the effects of augmentation by reducing the muscular

activity associated with rhytide formation. Botox-A therapy works

synergistically with resurfacing techniques to provide an optimal

improvement of dynamic rhytides and in some cases enhance overall skin

tone and texture. One study indicated that CO2 ablative laser resurfacing

combined with Botox-A provided a stronger and longer-lasting effect.164,166

Within many cosmetic practices, Botox-A is now a part of the standard

resurfacing protocol. The synergistic effects of Botox-A and other

rejuvenation procedures can extend to intense pulsed light protocols. In one

study, the combined effect of intense pulsed light and Botox-A produced a

more pronounced global aesthetic improvement in reducing crow’s feet,

telangiectasia, pore size, and lentigines, as well as ameliorating facial skin

texture as compared with the use of intense pulsed light alone.130


Risks and Complications

Resistance to Botulinum Toxin:

This section addresses the development of antibodies during Botox therapy.

Botulinum neurotoxins may be immunogenic, and antibodies may inactivate

the molecule. The Botox molecule is composed of a light chain and a heavy

chain. The toxin is embedded in a protein complex that protects the toxin’s

binding site until the desired pH is reached and the toxin is released.

Antibodies to this critical binding site on the heavy chain of the Botox

molecule will prevent binding of the toxin to its receptor, thereby crippling

the actions of the toxin. “Neutralizing antibodies” have been reported in

patients treated with high doses of Botox for neurologic disorders such as

cerebral palsy. It is important to understand that there are many types of

antibodies that can interact with Botox; however, the only antibodies that

can affect the efficacy of the toxin are neutralizing antibodies.

Antibodies may develop to Botox that are inconsequential to the patient, yet

the antibodies that are capable of neutralizing the toxin are a concern as

they have the potential to decrease the efficacy of the toxin. By definition,

antibodies that neutralize Botox-A would not neutralize Botox-B and vice

versa. Patients who develop antibodies to Botox-A can still enjoy the benefits

of Botox-B. For this reason, it is recommended that practitioners have

several different Botox serotypes available on the market.

The incidence of antibody-mediated resistance to Botox, as determined by

the mouse lethality assay, is reported between 3% and 9.5% and is

accepted generally to be approximately 5%. The only apparent symptom of

the development of antibodies is lack of response to further injections. The

use of other serotypes (F or B) may benefit those who have developed


antibody resistance. There are two types of therapy resistance to Botox,

primary and secondary. A patient who does not respond to the first injection

of Botox-A is referred to as a “primary nonresponder,” but reasons for

nonresponse can include inappropriate site of injection, poor technique,

and/or insufficient dose.

Immunogenicity should be suspected in a patient who no longer responds to

Botox-A (“secondary nonresponder”) following a successful course of earlier

injections. Antibody formation could be targeted against the neurotoxin

component of Botox or against its nontoxic protein component. The

recommended approach is to inject 20 U Botox into the hypothenar or

forehead muscles. If the patient responds to Botox, then transient weakness

will develop in the muscle 1 to 2 weeks after injection. An alternative is to

take blood for an antibody assay that is rarely used. In secondary

nonresponders, the problem can be further overcome by using a different

Botox serotype, for example, Botox-B if resistance develops to Botox-A.

Risk factors for the development of antibodies include higher doses, shorter

intervals between injections, booster doses, and young age.

Recommendations to help prevent development of antibodies include the

following: (1) use of the smallest possible dose to achieve relief, (2) an

interval between injections of at least 1 month (the preferred interval is 3

months), and (3) “touch-up injection” avoidance.

Many researchers have postulated that the risk of antibody formation is due

in part to the quantity of protein or the “protein load” of the toxin, the type

of protein present in the toxin, and to other factors. Manufacturers of Botox

have attempted to minimize each of these factors in order to create a less

immunogenic product. For example, the original Botox that was used until


December 1997 contained a higher level of protein than the Botox currently

in use; therefore, it should lead to a lower incidence of antibody formation.

Merz Pharmaceuticals, the manufacturer of the new Botox product Xeomin,

claims that its product contains a negligible amount of bacterial proteins

(0.6 ng) with lower immune response. In spite of the concerns regarding

immunogenicity, there are no known or published reports of antibody

production in patients treated with doses of any of the available Botox

products for cosmetic indications, which may be explained by the lower

doses used in comparison with neurologic and cervical dystonia indications

where reports of resistance are centered.

Side Effects:

Complications from the use of Botox injections occur infrequently and are

transient and reversible. Bruising at the injection site(s) is one of the most

common adverse events and avoiding aspirin, NSAIDs, green tea, vitamin E,

and other anticoagulants for 10 days prior to treatment can lessen the

incidence. Anecdotal reports reveal that application of ice packs to the area

prior to injection reduces the pain of the procedure and the incidence of

bruising. Some studies have shown an association with flu-like symptoms

(Botox and Myobloc) and dry mouth (Myobloc) after injection of these

products in larger doses used for neurologic indications.

The most serious side effects of Botox treatment in the upper face are ptosis

and, very rarely, diplopia or ectropion. Proper placement of the toxin with

good injection technique will drastically reduce the incidence of these

temporary side effects. In fact, many experts anecdotally state that

physicians just learning to perform Botox injections in the upper face have

approximately a 4% incidence of inducing ptosis, which, with practice, falls

to 0.5% incidence. Adverse effects from injection into the platysma can


include bruising, drooling, down-turning of the corner of the mouth,

weakness in the neck muscles, and dysphagia. Lip ptosis or mouth

asymmetry may result from injections in this area. Treatment of the palms

and soles for hyperhidrosis can induce temporary muscle weakness. One

should exercise caution when treating patients that require a strong grip

(i.e., tennis players) and manual dexterity (i.e., piano players) and these

patients should be aware of the risks of treatment of the palms.

The use of Botox has been reported, in one patient, to unmask underlying

myasthenia gravis; therefore, its use is contraindicated in patients with

myasthenia gravis, systemic lupus, and other autoimmune disorders

associated with a preexisting neuromuscular condition. Dysport is the only

brand of Botox that contains lactose. Its use has been blamed for a fixed

drug eruption in one patient. Care should be taken to label all syringes

containing Botox to avoid inadvertent administration of the

toxin.48,147,151,167,162,168-174

The injection of the C. botulinum A exotoxin is a safe; fast, and

nontraumatic approach to correcting wrinkles, raising eyebrows, and

improving hyperhidrosis. A significant number of physicians worldwide

perform this procedure for cosmetic purposes. There are many new forms

and brands of Botox entering the market. It is certain that much more

research will be seen that examines this interesting agent in the near future.

Pain Control

With the expanding use of botulinum toxins in cosmetic practice, pain

alleviation remains an important aspect of the injection. Pain sensation is

dependent on many factors, most importantly the concentration of the

neuropeptides (substance P) at the site of injection, the tissue density


(higher tissue density implies more pain), and the density of the nociceptor

distribution at the site of injection. Other factors include the volume injected,

the bore of the needle used, the layer of skin within which the toxin is

injected, the rate of the fluid injection, and, of course, the provider’s level of

experience.171

Differences in pain perception among patients treated with the commercially

available toxin preparations have not been studied extensively; however,

results from the only comparative study of three available preparations of

the toxin showed that the pain induced by Neurobloc (Botox-B) was found to

be significantly higher than that induced by Botox and Dysport (Botox-A),

between which no significant difference was found. The study concluded that

the different chemical properties and pharmaceutical adjuvants in toxins A

and B likely affect the pain sensation and speculated that the pH difference

of Neurobloc (pH 5.6) and Botox/Dysport (pH 6.8) influences pain

perception.129

Pain sensation during toxin injections is usually fleeting, and simple

measures can improve patient comfort. For facial wrinkles, anesthesia is not

necessary unless the patient prefers it. The 30-gauge needles that are used

to inject the medication are the same size as acupuncture needles and cause

minimal pain in a calm patient. Allowing the Botox to come to room

temperature may decrease the level of pain otherwise felt by the patient.

When the provider approaches the patient in a calm and reassuring manner,

not allowing the patient to see the needles prior to and during the injections,

the patient’s anxiety is significantly reduced as is the perception of pain.

Topical anesthetic creams such as EMLATM or LMXTM can be applied prior to

injection to decrease the sensation of pain. Botox should not be mixed with

local anesthetics because they can alter the pH of the preparation and cause


the toxin to lose potency. Ice packs can be applied prior to injections, which

may decrease the pain and encourage vasoconstriction, resulting in less

bruising.131

For hyperhidrosis, pain control is a necessity, especially for the palms and

soles. Although some physicians perform nerve blocks, many recommend

the following method: at least 1 hour prior to treating for hyperhidrosis, the

topical anesthetic ElaMax™ or EMLA (eutectic mixture of local anesthetic) is

applied to the area to be treated. Next, these areas are occluded with plastic

bags or gloves when treating hands and feet or with tape when treating

axillae.

Many attempts have been made to decrease the pain associated with the

use of Botox for palmar hyperhidrosis. These have included topical

anesthetics, intravenous regional anesthesia, nerve blocks, ice, Frigiderm

spray, and others. The use of nitrous oxide (“laughing gas”) requires office

training and can induce an anxiolytic rather than a pain-diminishing effect.

Ongoing trials to assess the effects of different anesthetics for an optimal

injection with minimal pain are needed to establish the full potential of the

different approaches of pain reduction with Botox injections.155

Dermal Fillers

The dermal filler market is rapidly growing worldwide. According to the

American Academy of Aesthetic Plastic Surgeons, 1,448,716 people received

hyaluronic acid (HA) injections by plastic surgeons in 2007. The actual

number is likely much higher when factoring in procedures performed by

dermatologists and other aesthetically oriented physicians and physician

extenders. Although collagen products (Zyplast and Zyderm) were the first


dermal fillers to become widely available, collagen fillers have largely been

replaced by HA fillers.175

The ultimate goal of dermal fillers is to smooth out wrinkles and folds, even

out scars, volumize furrows and sunken valleys, contour unevenness and

laxity, and sculpt skin into a 360-degree, rejuvenated look. Over the last

quarter century, several kinds of products suitable for soft tissue

augmentation have become available, with intense industry research yielding

more and more filler options with increasing regularity. Different regulatory

mechanisms usually leave the U.S. a few months or years behind other

developed countries in making the latest products available to patients.176

In the U.S., dermal fillers are regulated as medical devices. In order to

obtain FDA approval, the company applying for approval for a dermal filler

must satisfy the intense safety and efficacy criteria including

nonteratogenicity, nonmigration, noncarcinogenesis, biocompatibility, and

optimal purity, as well as reproducible and durable efficacy in correcting skin

defects. Unfortunately, some physicians and physician extenders choose to

use dermal filling substances that have not yet received FDA approval for

any indication. This is not advisable for several reasons including the fact

that it is illegal and that the safety of these products has not been

established. With the multitude of safe, efficacious, and durable fillers on the

market, there is no need or justifiable reason to use unapproved dermal

fillers in the U.S.177

Patient Evaluation and Consultation

When embarking on soft tissue augmentation, proper preparations are

essential. An initial consultation should include distant and close evaluation

of the patient’s facial structure and discussion of the cosmetic treatment


options. The patient’s history is taken to assess contraindications including

allergy to filler components, herpes facialis, pregnancy/lactation, keloid

predisposition, and autoimmune diseases. In addition, use of medications

that inhibit clotting such as aspirin and ibuprofen should be examined. The

ideal cosmetic outcome is achieved through a combination of various

cosmetic procedures in order to attain an even tone, smooth texture, and

adequate facial volume and shape.

The discussion of the sequence and description of each proposed procedure,

alternatives, risks and benefits, financial cost, and recovery period prepares

the patient for realistic expectations and informed decision-making. After the

treatment procedures are selected and informed consent is signed and

witnessed, the patient should undergo pretreatment photography for the

purpose of documentation; posttreatment photography is scheduled

immediately after and on the follow-up visits. For novice patients, it is better

to start the soft tissue intervention with the temporary and predictable fillers

(i.e., collagen and hyaluronic acid), and then gradually advance with more

lasting fillers (i.e., Sculptra and Radiesse) based on their comfort level and

desire.178-180

The best approach to minimizing the side effects of soft tissue augmentation

is, first, to prevent them. To reduce bruising, patients should avoid

anticoagulant medications or supplements (i.e., aspirin, vitamin E, etc.) for

10 days prior and several days after the procedure. The utility of Arnica

montana oral tablets or topical gel or post-procedure oral bromelain

supplements to decrease ecchymoses is anecdotal but these are often used

in the primary author’s practice. The pain associated with injection can be

diminished with topical (i.e., lidocaine cream, ice), regional (i.e., infraorbital,


dental nerve block), or intraprocedural anesthesia (i.e., fillers that contain

lidocaine).181-183

Patients prone to regional herpes outbreaks should obtain antiviral

prophylaxis with systemic medications (i.e., valcyclovir 1 g twice daily for 3

days, starting a day before the procedure). The procedure should be

conducted in a clean, safe, well-lit, and soothing environment that is

prepared to address any potential complications. Vasovagal responses are

not uncommon; therefore, orange juice should be available in the event that

the patient feels dizzy or faint. Topical steroids may be needed in case of a

contact allergy to lidocaine cream. Most importantly, nitropaste should be

immediately available in case a purple duskiness is seen on injection,

warning of a possible arterial occlusion. Some physicians suggest keeping

hyaluronidase on hand in case an arterial occlusion occurs with hyaluronic

acid.178,184

Types of Dermal Fillers

Dermal fillers can be classified based on various criteria: depth of

implantation (superficial upper and mid-dermis, deep dermis, and

subcutaneous levels); longevity of correction (temporary, semi-permanent,

and permanent); allergenicity (whether pre-procedure allergic testing is

required); composition of the agent (xenografts, allografts, or autologous,

semi/fully synthetic); and stimulatory behavior (capacity to drive physiologic

processes of endogenous tissue proliferation) versus replacement fillers

(space-replacing effect). The FDA requires safety and efficacy studies of the

available fillers; however, studies looking at the durability of the filler are not

required and, therefore, subject to disagreement and frequent citing of

anecdotal evidence. The lasting effect of the filler is dependent on the

composition, amount used, depth injected, and carrier of the agent. The


discussion of fillers to follow will proceed by dividing them according to

composition: collagen fillers will be discussed first, followed by hyaluronic

acid (HA) fillers, and then other agents.185

Temporary Fillers (Collagen and Hyaluronic Acid)

Injectable fillers such as collagen and hyaluronic acid are biodegradable and

last from 4 to 9 months. These fillers commonly serve an important role as

the initial step for new patients interested in soft tissue augmentation.

Because of their transient effect, the potential patient dissatisfaction and

side effects are also short-lived. Therefore, temporary fillers should always

be the first line of therapy, saving the longer-lasting fillers for future patient

visits.

Collagen

The major structural component of the dermis, collagen is the most

abundant protein in the human organism as well as, in particular, the skin.

Collagen confers strength and support to the skin. It is also one of the

strongest natural proteins, imparting durability and resilience to the skin,

and comprising 70% of dry skin mass. Collagen is actually a meshwork of

scaffolding-like structures composed of a complex family of over 18 types,

11 of which are found in the dermis. Type I collagen (80%–85%) and type

III collagen (10%–15%) are the primary collagen constituents in the dermal

matrix of adult human skin. Dermal fibroblasts produce a precursor form of

collagen, procollagens, which in turn produce both collagen types I and III,

each of which is composed of three collagen chains.

Skin fragility and wrinkles result from the loss of collagen, which occurs with

aging as well as solar exposure and other insults. UV light, free radicals, and


other factors cause the body to produce collagenase, an enzyme that breaks

down collagen. The injection of various forms of collagen into the skin helps

it regain a youthful appearance, but such results are temporary. The range

of collagen products has increased in recent years as manufacturers have

worked to extend the duration of product effects.186,187 The table below lists

the types of collagen products and describes the properties, method of

administration and action of each.178,183,184,188-190

Bovine Collagen With a record of safety and efficacy spanning over two decades,

bovine collagen was the traditional dermal filler agent used to

ameliorate undesirable signs of cutaneous facial aging. In 1977,

Zyderm I was introduced as the first injectable bovine collagen

implant; it was approved by the FDA in 1981 for fine lines and

shallow acne scars. Zyderm II and Zyplast were introduced and

approved, respectively, in 1983 for moderate lines and deeper

acne scars and 1985 for deep dermal folds and lines.

Although these products were the standard for years to which

newer implants were compared, because of better safety

profiles, human-derived collagen and HA products have become

more widely used. Zyderm I is 96% type I collagen and 4%

type III collagen derived from the bovine skin of U.S. enclosed

cattle herds.

Zyderm I and II differ only by collagen concentration. Zyderm I

contains 35 mg/cc, while Zyderm II contains 65 mg/cc. The

difference in concentration is significant insofar as it renders

Zyderm II thicker and stiffer than Zyderm I. Like Zyderm I,

Zyplast contains 35 mg/cc of collagen, but this collagen is cross-

linked with glutaraldehyde, which makes it last longer via

resistance to degradation. Consequently, Zyplast is more

viscous and less immunogenic than Zyderm. Zyderm and

Zyplast are white substances prepackaged in 0.5-, 1-, and 2-mL

syringes and injected with a 30-gauge, 0.5-inch needle. The product should be stored in the refrigerator ideally at 4 C.

While Zyderm I is properly injected into superficial dermis at

20- to 30-degree angles with the expectation of temporary skin

blanching, Zyderm II can be injected slightly deeper at 35- to

45-degree angles with less anticipated blanching and minimal

overcorrection. Since Zyderm is diluted with phosphate-buffered

sterile saline, which is rapidly reabsorbed in skin, to achieve the

optimal effect, overcorrecting implantation is necessary. Zyplast

is implanted into even deeper dermis at 45- to 90-degree angles

with minimal delayed blanching and without overcorrection.


Bovine-derived collagen dermal filling agents effectively reduce

wrinkles and scars. Zyplast is appropriate for shaping the

vermilion border of the lips and treating moderate and deep

wrinkles, such as nasolabial folds and atrophic scars. Zyderm I

is well suited for treating superficial rhytides (i.e., horizontal

forehead wrinkles, crow’s feet, fine perioral wrinkles, and scars)

or for use over Zyplast in deeper wrinkles. The higher

concentration of collagen in Zyderm II renders this product

more appropriate for acne scar revision, but Zyplast lasts longer

because it is cross-linked. Collagenase ultimately succeeds in

degrading these products, returning the skin to its appearance

prior to injection. Zyplast is the most commonly used bovine

collagen product and lasts approximately 4 months, just slightly

longer than Zyderm I and II.

Bovine collagen can be safely reinjected 3 to 4 times per year if

needed. Zyderm and Zyplast are the least expensive dermal

fillers on the market and typically engender less bruising than

products that contain HA.

All the bovine collagen products contain 0.3% lidocaine to

reduce the pain associated with the procedure. Two skin tests, 6

and 2 weeks before the scheduled treatment, are required

before the use of bovine collagen agents to reduce the risk of

inducing hypersensitive or allergic reactions.

A positive skin response can occur as early as 6 hours after the

test, but are more likely to emerge 48 hours or 4 weeks after

the test. A positive skin test disqualifies a patient for treatment

with bovine collagen. Approximately 3% of the general

population is thought to be sensitive to bovine collagen.

Although a patient is unlikely to react to bovine collagen

implants after two negative skin tests, the risk is never

completely eliminated.

The risk of hypersensitive reaction is 1.3% to 6.2% after one

negative test and 0.5% after two negative tests. Patients should

be advised that should such a reaction occur, it can be expected

to spontaneously resolve within 4 to 24 months.

Allergic reactions also arise, albeit rarely, following multiple

treatments. Topical, intralesional, or a brief course of systemic

corticosteroids can be effective to treat these reactions. Oral

cyclosporine and topical tacrolimus have also reportedly been

used for the successful treatment of recalcitrant hypersensitive

reactions to bovine collagen. Patients with lidocaine

hypersensitivity are contraindicated for obtaining these

injections because the fillers contain lidocaine.

Nonhypersensitive reactions to bovine collagen fillers can also

infrequently occur (i.e., abscesses, bacterial infections, beading,

cyst and granuloma formation, ecchymoses, and local necrosis).


Several previously discussed preventative steps can be taken to

reduce the likelihood of such outcomes. Because of its viscosity,

Zyplast should not be injected into the glabellar region, as there

have been reports of local necrosis and retinal artery occlusion

leading to visual loss. However, Zyderm I or II can be injected

into the glabellar area very slowly and with extreme caution.

Vascular occlusion or compression manifests as prominent

immediate blanching and pain.

Warm compresses, topical nitroglycerin, and meticulous wound

care are necessary treatments. Prior to 1990, beads and cysts

were reported at the injection site in 0.04% of patients treated

with Zyderm or Zyplast, most likely caused by injections that

were too superficial. Injections should be made only into the

dermis to avoid such reactions.

Abscesses should be treated with incision and drainage and a

combination of antibiotics and corticosteroids to reduce

secondary scarring. More than a decade ago, there was some

speculation that autoimmune diseases, namely, polymyositis

and dermatomyositis, might be induced by the injection of

bovine collagen, but studies have demonstrated that antibodies

to bovine collagen do not cross-react with human collagen.

Therefore, the FDA has agreed that it is unlikely that bovine

collagen causes connective tissue disease in humans. A study by

Hanke et al. showed that the incident rate of polymyositis or

dermatomyositis in patients receiving bovine collagen was not

higher than the control-matched population.

Despite the studies cited above, experts recommend avoiding

the use of bovine collagen containing fillers in patients with a

history of autoimmune disease. Another major downside to

using bovine collagen is the minimal durability of about 3 to 4

months.

Bioengineered

Human Collagen

Over the last 10 years, several companies, motivated by the

drawbacks of bovine-derived collagen, have developed human-

derived soft tissue fillers. Unlike earlier cadaver-derived collagen

(i.e., Cymetra) and, more recently, autologous collagen (i.e.,

Isolagen), bioengineered human collagen is pregenerated to

ensure ease of accessibility.

The manufacturing process begins with the harvesting of dermal

fibroblasts from bioengineered human skin and placement into a

three-dimensional mesh. The fibroblasts are then cultured in a

bioreactor that simulates the conditions of the human body.

Then, the fibroblasts synthesize collagen and extracellular

matrix proteins. The derived collagen is purified to enhance

safety. Human- bioengineered collagen implants include

CosmoDerm I, CosmoDerm II, and CosmoPlast (Allergan

Corporation, Irvine, CA), which contain human collagen types I

and III, and were approved by the FDA in March 2003.


CosmoDerm I is composed of 35 mg/cc human-bioengineered

collagen distributed in a phosphate-based saline solution and

0.3% lidocaine. CosmoDerm II contains twice the collagen

concentration of CosmoDerm I. CosmoPlast contains the same

ingredients as CosmoDerm I, but is cross-linked by

glutaraldehyde, yielding a product more resistant to

degradation, thus lasting longer, and more appropriate for use

in treating deeper furrows. While

CosmoDerm is indicated for superficial wrinkles and shallow

scars, CosmoPlast, which exhibits a stiff consistency (even more

so than products containing HA), is well suited to treating the

vermilion border of the lips, as well as raising the corners of the

mouth. In addition, it is a good choice to correct deformities of

the bridge of the nose or to raise the nasal tip.

CosmoPlast is typically used in combination, usually with an HA

agent, to treat medium and deep wrinkles, with the collagen

product injected first to create a volume-filling base and the HA

filler injected more superficially into the same location. Similar

to bovine collagens, CosmoDerm and CosmoPlast are white

substances prepackaged in 1-mL syringes and injected via 30-

gauge 0.5-inch needles.

Although some anecdotal reports indicate better rheology of

human collagen fillers, their technique of injection, cosmetic

outcome, and durability are comparable to bovine collagen

fillers. Furthermore, like bovine collagen, CosmoDerm and

CosmoPlast must be kept refrigerated when stored. For human-

derived collagen devices, on average, one syringe is used for

patients in their twenties, two syringes for patients in their

thirties, three syringes for patients in their forties, and as

needed for older patients to correct age-related lines and folds.

Given the absence of allergy risk associated with these agents,

no skin testing is required. This allows for patients to be treated

in their initial visit to the physician. The cosmetic effects of

CosmoDerm and CosmoPlast are immediate, lasting about 3

months for the former and about 4 months for the latter, and

are typically associated with less bruising than the effects of

procedures using agents containing HA.

Also similar to the bovine-derived fillers, CosmoDerm and

CosmoPlast contain lidocaine to mitigate the pain of injection

and lower the risk of edema and ecchymoses by inhibiting the

activation of eosinophils.

CosmoPlast can create the beautiful “Snow White line” and

“Cupid’s bow” shape of the lip borders as well as upturn the tip

of the nose to create a poised appearance. Although HA fillers

are favored because they last longer and are softer,

CosmoDerm I can be used to plump the body of the lip.


CosmoDerm I can be layered over CosmoPlast for the purpose

of ideal contouring of deep lines, such as nasolabial folds and

marionette lines. In addition, to treat medium and deep

wrinkles, HA fillers can be superimposed on top of CosmoPlast

or injected in the same plane as CosmoPlast.

Although fillers should be used rarely and with great caution in

the glabellarrhytides because of the potential risk of tissue

necrosis, CosmoDerm I can be used with great care in this

region. At the time of publication of this text, there were no HA

fillers geared for superficial placement, although Prevelle,

Juvéderm, and Restylane may have superficial fillers soon.

Therefore, CosmoDerm I, although it lasts only about 3 months,

is the filler of choice for periorbital wrinkles and smoker’s lines

above the top lip. CosmoDerm II is most often used for acne

scars. Bioengineered human-derived collagen is expensive to

produce, rendering these agents somewhat costly.

Further, the cosmetic effects from these products do not last, on

average, any longer than the bovine-derived products. The

duration is thought to be around 4 months. However, these

products are associated with less bruising, erythema, and pain

than other filling agents and, consequently, remain desirable

options for those who cannot afford to have downtime.

Excluding the reduction in immunogenic potential, human

collagen fillers have similar side effect profiles to bovine

collagen fillers. Likewise, patients with lidocaine allergies should

avoid these agents.

Cadaveric Collagen

Approved by the FDA in 2000 for soft tissue augmentation,

Cymetra® (LifeCell Corp., Palo Alto, CA) is a micronized

collagen derived from processed human cadaver skin. A similar

product, Fascian (Fascia Biosystems, Beverly Hills, CA), is

obtained from cadaver fascia, and has a heavier consistency.

Cymetra is packaged as a 330-mg white powder in a 5-cc

syringe, stored at room temperature and reconstituted with 1

mL of 1% lidocaine to create a thick paste.

Tunneling and threading injection methods are accomplished

through a 26-gauge syringe into a subcutaneous plane, avoiding

overcorrection. This acellular and purified filler negates a

potential sensitivity reaction and pretesting is, therefore,

unnecessary. The cadaver collagen has somewhat longer

durability versus other collagen products, lasting from 3 to 9

months, although durability is controversial.

Cymetra is indicated for use in deep rhytides (i.e., nasolabial

folds), depressed scars, and volumizing of the lips.

Reconstitution with lidocaine yields reduction in intraprocedural

pain. Based on the composition of the product, Cymetra is

contraindicated in patients with gentamicin allergies.


The product is very viscous, which makes it difficult to operate,

generating more local tissue discomfort and trauma as well as

leading to longer recovery time for patients. Fascian is an even

thicker and stiffer product, which translates to more side effects

and difficulty in administration. The implantation of cadaver

products into superficial and mobile wrinkles can induce

migration and, therefore, is discouraged. The major issues with

employing these agents are the cumbersome preparations and

deficit of adequate clinical trials demonstrating their long-term

efficacy and safety.

Hyaluronic Acid

In the last few years, hyaluronic acid filler substances have become the new

gold standard, far outpacing in usage the other soft tissue augmentation

agents. Hyaluronic acid, or hyaluronan, is a nonsulfated glycosaminoglycan

(GAG) that occurs naturally in the skin and other tissues (specifically,

connective, epithelial, and neural tissues) as space-occupiers of the

extracellular matrix. It is also ubiquitous across animal species, which makes

HA nonimmunogenic. This polysaccharide has the capacity to bind water up

to 1000 times its mass. The biologic behavior of HA is predictable; it creates

lubrication and volume with an aqueous and pliable framework that

suspends and adheres to collagen, elastin, and cells.178

With age, the concentration of HA in skin decreases, translating to more lax,

sallow, and dull skin. The viscoelastic qualities of HA serve to plump up the

skin, yielding a more youthful appearance. Naturally occurring, unmodified,

or uncross-linked HA has a half-life of about 24 hours. For this reason, HA is

cross-linked when formulated into a dermal filler product. Higher

concentrations and moderate cross-linking of the HA in a product impart

greater longevity. There exists a certain threshold where beyond that value

additional cross-linking can cause biocompatibility issues. In effect, cross-

linking has to be in the right balance to maintain duration and


biocompatibility of the HA filler. Hyaluronic acid is readily metabolized by the

liver and yields by-products, water, and carbon dioxide. In the skin, HA is

broken down by hyaluronidase, mechanical degradation caused by facial

movement, and by free radicals. Supplementation with oral antioxidants

theoretically will increase the duration of HA fillers, but this has not been

proven.191-193

There are two main categories of HA fillers: animal derived (i.e., Hylaform)

and bacteria derived (i.e., Restylane, Captique, Juvéderm, etc.). Medicis, the

company that sells Restylane, trademarked the name “nonanimal derived

synthetic hyaluronic acid (NASHA)” to show that their products, Restylane

and Perlane, are not animal based. Because of the expense of animal-

derived products, the vast majority of HA products are bacterial derived.

Until recently, no HA products on the market contained lidocaine and,

therefore, were more painful than fillers that contain lidocaine. However,

lidocaine-containing injectables, such as Prevelle Silk, have recently entered

the market. Because of their nonallergenic nature and manufacturing, HA

fillers do not require prior testing and can be stored at room temperature.

Their advantages over collagen products are longer duration (6–12 months),

better pliability, and less immunogenic and allergic side effects. On the

whole, side effects of various HA fillers are similar, mild, and rare; these

include bruising, temporary swelling, lumps, acneiform eruptions, and,

rarely, acute hypersensitivity. In addition, arterial occlusion, thought to be

due to swelling of the HA implant, causing vascular compromise, can rarely

occur.130,177,193

A major advantage of HA fillers is that if skin nodules do arise, these

reactions can be easily dissolved with intralesional hyaluronidase. The

disadvantages of the currently available HA fillers are increased pain on


injection and post-procedure edema, erythema, and ecchymoses as

compared to CosmoPlast injections.191 HA fillers do not require skin testing

and the risk of allergy with all products that are FDA approved is minimal.

Cost, availability, duration of correction, and size of the required needle for

injection all play a role in product selection and manufacturers all strive to

create an affordable, long-lasting product that can be injected with a 30-

gauge or smaller needle. However, there are other, less obvious, scientific

considerations to be taken into account when choosing a filler. The stiffness

or G* (G prime) of a product is one of the most important considerations. G*

is a measurement of gel hardness. It is obtained when a gel is placed on a

plate. A second plate is placed over the gel and a lateral force is applied. The

measurement of resistance to deformation is known as the elastic modulus

or the G*. Together with the cohesivity of the product, G* values could be

used to determine the appropriate placement of an HA dermal filler. For

example, more robust products (higher G* values and higher cohesivities)

such as Juvéderm Ultra Plus and Perlane, in the primary author’s opinion,

should be used in deeper lines, such as nasolabial folds and marionette lines,

as well as to lift the lateral brow, to correct the nasal bridge, to give the ear

lobe youthful volume, to evert the nipples, and to raise the nasal tip. More

fluid products such as Juvéderm Ultra and Restylane are better suited to be

used over large areas such as the cheekbones and cheeks. Low G* products

such as Hylaform and Juvéderm Ultra are necessary in areas that require a

softer agent, such as the body of the lip or the tear trough. As new products

reach the market, knowing the G* will help practitioners match fillers with

indications.194-197


The concentration of HA in a product is important to consider as well. Many

authorities believe that the higher the concentration of HA, the stiffer the

product and the longer its duration. This is true in general when comparing

products within a brand, for example, when comparing Juvéderm 18 to

Juvéderm 24. However, this does not hold true across brands because not all

of the HA in the dermal fillers is cross-linked. Many HA fillers contain

uncross-linked HA and lightly cross-linked chains and fragments. The

uncross-linked HA, fragments of HA, and lightly cross-linked HA are included

in the overall concentration measurement but only remain in the skin for a

limited time and should minimally contribute to the longevity of the filler.

The uncross-linked HA does help decrease extrusion force and make

injection easier, which is the main reason it is included. Therefore, the fact

that Restylane contains 20 mg of HA/cc and Juvéderm contains 24 mg of

HA/cc does not give a provider enough information to decide which filler will

have longer duration. It is actually the amount of modified HA that plays the

primary role in duration.198-200

The type of modification (cross-linking) and the cross-linking agent used is

also important. Cross-linking can be best visualized by imagining a ladder.

Each side of the ladder is an HA chain. The rungs of the ladder are the cross-

links. When the “rungs” of the ladder attach to both sides of the ladder, the

agent is considered completely modified. However, the cross-linking agent

used may incompletely cross-link the chains of HA, leaving the sides of the

rungs unattached and resulting in incomplete modification. Such a product

might not be as durable as a completely modified product. In addition, there

are two types of rungs in the HA ladder. One is called an ether linkage and

the other is called an ester linkage. Ether linkages are formed by 1,4-

butanediol diglycidyl ether (BDDE, the cross-linking agent in Restylane and

Juvéderm) and divinyl sulfone (DVS, the agent used in Prevelle Silk,


Captique, and Hylaform). The cross-linking agent used in Prevelle Dura,

1,2,7,8 diepoxyoctane (DEO), forms both ether and ester linkages (known

as “double cross-linking”). It is unknown at this time what advantages, if

any, ether linkages impart to a dermal filler.191,195,201,202

The hydration status of the filler once it is packaged in the syringe also

affects filler performance. HA is well known to bind up to 1000 times its

weight in water. The amount of water bound to the HA prior to its packaging

in the syringe determines how much more water the filler can absorb once it

is injected into the skin. In other words, fillers that are completely hydrated

in the syringe will bind less water on injection and the volume will expand

less upon injection as compared to fillers that are not completely hydrated in

the syringe. Fillers that are not completely hydrated in the syringe will swell

somewhat within 24 hours after correction; therefore, it is prudent to slightly

under-correct with these substances. In addition, patients can be told that

they will “look even better” 24 hours after the injection. Restylane and

Juvéderm are not completely hydrated in the syringe while Captique and

Hylaform are close to being fully hydrated.198,203,204

Another process that may affect the performance of the filler is referred to

as “sizing technology.” This term is used by Allergan to differentiate

Juvéderm from the other HA fillers. When an HA filler is cross-linked, the

chains of modified sugars form a gel. In the process of manufacturing

Restylane, Restylane Fine Line, Restylane Lip, Restylane Touch, Perlane, and

Restylane Sub-Q, this gel is extruded through a screen. This produces

various sizes of the gel that are considered “sized.” The large pieces become

Perlane or Restylane Sub-Q, while the small pieces are marketed as

Restylane Fine Line or Restylane Lip. The medium-sized pieces are

Restylane. The larger pieces yield products that are best used in the mid to


lower dermis while the small pieces such as Restylane Fine Line can be used

more superficially. The Juvéderm family of products is not sized. In other

words, Juvéderm is not pushed through a screen and broken into sized

pieces and, therefore, it consists of randomly sized and shaped pieces. It is

unknown at this time what role sizing technology plays, if any, in the

performance of a filler.205,206

There are many factors that must be understood in order to make the most

suitable choice of HA filler. There are no peer-reviewed publications that

review the above mentioned properties so it is difficult at this point to know

how important these various characteristics are in choosing a filler. More

data needs to be collected to properly ascertain if, for example, sizing

technology makes a difference or if ester bonds last longer than ether bonds.

These distinctions will become clearer and more important as more HA fillers

are introduced onto the market and more data are collected. The table below

lists and discusses the individual HA brands in terms of their properties,

indications, methods of administration, potential risks and

benefits.130,166,189,195,196,198,205-210

Restylane Restylane (Medicis, Scottsdale, AZ) was the first nonanimal HA

product approved in the US. It is a NASHA gel formulated through

fermentation, with sugar present, in bacterial cultures of equine

streptococci. Restylane has a higher concentration of HA compared

to Hylaform and Captique and the highest G´of the fillers currently

on the market, denoting that it is a slightly stiffer product. It is the

most popular of the HA fillers in the U.S.

Restylane is popular to use because of its safety profile, brand

recognition, and ease of injection. It is composed of approximately 100,000 particles/mL (approximately 250 m on average) and

contains 20 mg/mL of HA. Restylane is indicated for middermal

wrinkle reduction and was the first HA filler approved in the U.S. in

2003. The FDA more recently approved Perlane, another product in

the Restylane family, to use for significantly deeper folds and

furrows.


Restylane is made of medium-sized particles of HA gel, while

Perlane is composed of larger HA gel particles (approximately 1000 m), but with the same HA concentration.

The Restylane family of products also includes Restylane Fine Line,

Restylane Touch, Restylane Lip, and Restylane Sub-Q, which are not

currently approved for use in the US. These products have the same

formulation as Restylane and differ only in their particle size.

Restylane and Perlane are packaged as transparent gels, with a

shelf life of 18 months, and stored at room temperature. Restylane

is enclosed in 0.4- and 1-mL syringes while Perlane is packaged in a

0.7-mL syringe; both are injected via a 27-gauge needle. Restylane

is implanted using linear threading anterograde or retrograde

techniques. It is important to avoid injecting at withdrawal of the

needle, which can result in superficial injection, creating blue-

colored nodules.

A fanning threading technique can also be employed with Restylane

at the nasolabial fold or lip commissures. The stiffness of Restylane

renders it well suited for moderate to deep wrinkles and it is this

quality among other factors that is thought to impart greater

longevity in human tissue as compared to Hylaform and Captique.

The cosmetic effects of Restylane are thought to last over 6

months; Perlane delivers a durability of 6 to 9 months. Product

stiffness makes Restylane and Perlane more suitable for moderate

and deep wrinkles than for use in the body of the lips or the tear

trough.

Restylane is ideal to fill nasolabial and marionette lines, chin and

jowl depressions, nasal deformities, and for nasal tip-lift as well as

acne scars and other defects. Bruising is associated with all HA

fillers. However, the stiffness is a downside if a poorly skilled

physician uses the product, with bumps and blue blebs possibly

arising from improper injection technique. Injection into the tear

trough may result in visible blebs. Slower injection of any HA filler

will limit the risk of inflammation.

Restylane can be used in the vermilion border to augment the shape

of the lip. Restylane and Perlane may be a poor choice for the body

of the lips. However, outside the U.S., Restylane Lip is available and

is a better choice for use in this area. As with other fillers that do

not contain an anesthetic, the injection of Restylane can be painful.

The use of topical anesthetics and/or dental nerve blocks is

recommended to reduce the pain on injection. Restylane tends to

sting less after injection when compared to Juvéderm. It is unknown

why this occurs as they are both the same pH of approximately 7.0.

Juvéderm Juvéderm (Allergan, Irvine, CA), is manufactured by a bacterial

fermentation process similar to that used for other stabilized

bacterial-based HA filler and was approved by the FDA in late 2006.

There are many products in the Juvéderm line (Juvéderm 18,

Juvéderm 24, Juvéderm 24 HV, Juvéderm 30, and Juvéderm 30


HV), but only Juvéderm 24 HV (also known as Juvéderm Ultra) and

Juvéderm 30 HV (also known as Juvéderm Ultra Plus) are currently

approved by the FDA and sold in the U.S.

All the products in the line vary by the amount of HA concentration,

the amount of cross-linking, and the regularity of the cross-linking.

Both Juvéderm Ultra and Ultra Plus consist of 24 mg/cc of HA, but

Juvéderm Ultra Plus has a higher degree of cross-linking than

Juvéderm Ultra, which makes Ultra Plus more suitable for the

deepest facial grooves and furrows. Unlike Restylane, which consists

of stiff and a fairly narrow range of particle sizes, Juvéderm is a

smooth consistency gel composed of a broad range of particles of

various sizes and shapes (referred to as “Hyalacross technology”).

Juvéderm products are packaged as a clear gel in 0.8-mL syringes.

They are stored at room temperature.

Juvéderm Ultra is injected into the middermis via a 30-gauge needle

while Juvéderm Ultra Plus is implanted deeper via a 27- gauge

needle. The needles must be tightly attached to the Luer-lock

syringe to prevent detachment during injections. Various techniques

of injection can be used with Juvéderm, including serial puncture

and tunneling. Juvéderm Ultra and Ultra Plus are in the medium

range of stiffness; therefore, they can be used in any wrinkles,

moderate or deep, and to correct scars.

Juvéderm Ultra is easily placed in the vermilion border or the body

of the lips. The high concentration of HA in Juvéderm Ultra and Ultra

Plus and the high degree of cross-linking results in longer-lasting

aesthetic effects as compared to products such as Hylaform. As

other HA products, these agents have an overall low, mild, and

transient adverse-event profile. Juvéderm is not completely

hydrated in the syringe, so it will slightly expand after injection as it

absorbs more water. This is important to remember when injecting

the body of the lips, which should be slightly undercorrected to

allow for the expansion.

Similar to Restylane, the longevity of Juvéderm Ultra is about 6 to 9

months and Ultra Plus may last up to 12 months. All HA products

can cause erythema, swelling, and bruising after implantation. Pain

during injection caused by lack of anesthetic can be alleviated with

the use of topical or regional anesthesia. Juvéderm can be placed

with care in the tear trough area, but the proximity to the eye is

unnerving with the risk of the needle popping off, so injections

should be very slow with only moderate extrusion force.

The needle is more likely to pop off when the syringe is almost

empty; therefore, the tear trough area should be injected with a

new syringe and the last part of the syringe can be saved for less

dangerous areas such as the nasolabial folds. As with all fillers, the

skill and experience of the physician is crucial for optimal outcome.

If Juvéderm is injected too superficially, it can create a bluish hue.

Caution should be taken in overinjecting the vermilion border and

creating an unnatural “duck bill” appearance. In addition, superficial


placement of Juvéderm in the tear trough defects can result in blue

nodules. Blue nodules and unwanted bulges can be corrected with

the use of hyaluronidase.

Prevelle Silk

Prevelle Silk is sold by the Mentor Corp. (Santa Barbara, CA). This

bacterial-derived product is similar to the Captique formulation with

moderate softness illustrated by its G´ in the middle of the

spectrum. This product is softer than Restylane and is similar in

softness to Juvéderm. Prevelle Silk has a higher degree of cross-

linking density than Hylaform and therefore is slightly stiffer than

Hylaform. The gel contains 5.5 mg/mL of cross-linked HA with an average particle size of 300 m. Prevelle is suitable for treating

shallow to moderate wrinkles, lips, and scars.

The longevity of the product is unknown but reported to be about 4

months. Prevelle Silk contains 0.3% lidocaine. It was approved in

the United States in 2008. This product is suitable for use in the lips

since it generates less pain during injections. Side effects, which are

rare and relatively mild, include redness, swelling, and pruritus. This

product is softer than other products on the market since Hylaform

and Captique were discontinued. It can be used in any moderate to

deep facial wrinkles, the body of the lip, and periorbital areas.

Prevelle Silk is the first lidocaine-containing HA in the United States.

Longevity of the correction is not known but thought to be 4-6

months.

Prevelle Dura

Prevelle Dura (Mentor Corp.) is another bacterial-derived filler

approved for the US market in 2008. It is composed of 220-μm HA

particles cross-linked with DEO. As mentioned previously, DEO

cross-linking results in both ether bonds and ester bonds, known as

double cross-linking. These ester bonds may confer better stability

and longer duration but this has not yet been proven. Prevelle Dura

is touted for suitability in any dermal layer to correct middermal and

deep rhytides.

The G* (stiffness) of this product is 900 Da, which renders it slightly

stiffer than Restylane. Preliminary studies demonstrate the safety of

this product; however, more trials need to be performed to establish

its strengths and weaknesses. Based on double cross-linking

technology, the company claims that this device may last longer

than previous HA fillers; however, this has not been proven. The

role of the double cross-linking technology in terms of duration of

the filler has not been ascertained. Prevelle Dura is slightly more

viscous and, therefore, requires more pressure on injection.

Hyaluronidase


Hyaluronidase is a soluble enzyme that hydrolyzes HA, other GAGs, and

other connective tissue components in the skin and vitreous humor of the

eye. The FDA has approved Vitrase and Amphadase for enhancement of

injectable drug absorption and resorption of radiopaque agents. However,

effective off-label uses include wound care and postsurgical flap care among

other uses.175,178

Several reports have indicated the usefulness of hyaluronidase to dissolve

HA filler overcorrection for symmetric contouring, as well as to manage

impending tissue necrosis because of HA skin injections. Specifically, there

were two cases of imminent tissue necrosis caused by intra-arterial injection

of HA and surrounding tissue compression of vital vessel, which resolved

with employment of hyaluronidase. After using other appropriate techniques

to manage impending tissue necrosis including systemic aspirin, Nitro BID

under occlusion, and hot compresses (with massage) without significant

response, the authors injected 30 units of hyaluronidase into deep dermal

tissue and subcutis using a serial puncture method along the distribution of

affected arteries, which led to the resolution of symptoms within a day.

Although early reports have recommended the utility of hyaluronidase only

within 16 minutes of the critical event, studies reported successful responses

after several days. Furthermore, the effectiveness of hyaluronidase for bluish

(Tyndall) manifestations and asymmetric lumpiness from HA overcorrection

has also been reported at various concentrations. Because of the described

benefits of hyaluronidase for the treatment of complications of the popular

HA fillers, it has been recommended as a necessary agent to keep in an

aesthetic physician’s office.211-213

Hyaluronidase is a clear liquid that is stored in the refrigerator and

reconstituted with 1 mL of normal saline to generate 150 units. Very rare


adverse acute and delayed-type hypersensitivity reactions to hyaluronidase

have been reported, so it may be prudent to perform a skin test prior to the

use of this agent. Injection of hyaluronidase into patients with an allergy to

hymenoptera stings and thimerosal is contraindicated.214

Semi-permanent Fillers

Fat, Radiesse, and Sculptra are considered semitransitory because they are

partly biostimulatory and partially biodegradable; this balance allows them

to last approximately 1 to 3 years. The adverse events associated with semi-

permanent fillers include rare granuloma formations. The aesthetic effects of

these fillers are best preserved with annual touch-up sessions. These are

outlined in the table below.175, 176, 215, 181, 180, 184, 185, 200, 216, 217

Autologous

Fat

Originating in the 1890s, transplantation of fat from a patient’s excess

adipose areas to other skin defects is the oldest soft tissue

augmentation method. Fat injection filling has gained recognition for

several reasons. Naturally, the patient’s own cells are unlikely to

cause sensitivity or inflammation and are therefore considered

supremely biocompatible. Furthermore, the technique of fat

implantation has undergone remarkable polishing over many years,

especially with the advent of harvesting subcutis through liposuction.

The procedure is a multistep process, whereby the fat cells are

obtained from the buttock, thigh, and abdominal regions, then

segregated, stored (refrigerated up to 18 months), and injected back

into the patient’s subcutis on the face, hands, and any other areas

requiring volume enhancement.

As anticipated, this process is more invasive, time-consuming, both

for the clinician to prepare and perform as well as the patient to

recover from, as well as more costly. In effect, the optimal efficacy

with minimal adverse effects is mainly achieved in the hands of a

qualified dermasurgeon. Approximately 0.1 cc aliquots of fat are

inserted into subcutis through a 17- to 18-gauge needle via a

tunneling technique, without overcorrection. Postprocedure massage is

recommended for proper shaping of contours.

Because of its autologous character, lipotransfer is unlikely to cause

sensitivity and reactivity of the tissue, minimizing potential long-term

side effects and obviating prior testing. Nasolabial folds, sunken

cheeks, tear troughs, marionette lines, scars, and lips are the most

appropriate areas of correction with fat. Furthermore, fat transfer

provides a reported duration of about 12 months; although the


concrete duration is controversial.

The injectable material used is the patient’s own tissue, so its use

decreases the amount of money spent on the actual filler. The

procedure also has an attractive double-gain, where two cosmetic

areas can be simultaneously addressed, lipoexcess and lipodystrophy.

Stem cells have been isolated from fat cells. It is believed that the

stem cells found in fat lead to increased skin rejuvenation. When

performed by a skilled physician, the results of lipotransfer are

remarkable. Fat injections require prophylactic local or regional

anesthesia.

Because of the fact that the procedure is more surgically invasive,

more complex preparations and settings are required with longer and

more frequent office visits. Although the harvesting portion can cause

a longer recovery time and an increased risk of side effects (i.e.,

infection, scarring), the actual injection has a similar adverse event

profile to the other fillers (i.e., edema, redness, bruising, and

discomfort lasting a few days).

Another variable to consider when selecting candidates for this

procedure is to ensure that the patient has a sufficient graft supply. In

some patients, the fat injections last several years and in other

patients the injections last merely months. Many tricks are employed

to try and increase longevity, but at this time there are no guarantees.

Radiesse

Radiesse (BioForm Medical, San Mateo, CA) was approved by the FDA

in 2006 for the correction of moderate to severe folds and wrinkles

along with HIV-associated lipoatrophy. It is composed of 30% calcium

hydroxylapatite (CaHA) microspheres (25–45 μm) suspended in an

aqueous gel carrier (1.3% sodium carboxymethyl cellulose, 6.4%

glycerin, and 36.6% sterile water). As the gel carrier of this filler

dissipates in several months, the microspheres stimulate cutaneous

cells to generate focal foreign body reaction and neocollagenesis. This

leads to envelopment of the microspheres by fibrin, collagen, and

fibroblasts, and slows the degradation by macrophages and

metabolism into calcium and phosphate ions. Because of a similar

mineral constitution as human bones, and no foreign antigenic

properties, CaHA is particularly biocompatible.

It is critical for patients to be aware that Radiesse is a radioopaque

material that can be visualized and misinterpreted on facial

radiographs, but importantly, it does not radiographically mask

surrounding tissues. Radiesse is a white material packaged in a 1-mL

syringe and injected via a 25- to 27-gauge and 11/4-inch needle into

the deep dermis or subcutis without overcorrection. The product

should be stored at room temperature. A reasonable injection method

for Radiesse is tunneling or crisscross threading techniques.

A placement of Radiesse in the supraperiosteal plane yields better

control and ability to contour skin with this stiffer filler. Since Radiesse

is immunologically inert, it does not require skin testing. With more


than 20 years of use as implantable devices for otolaryngology and

orthopedic specialties, CaHA possesses an excellent safety record.

The average duration of Radiesse is 9 to 18 months. The proper

locations of injection include the nasolabial folds, marionette lines,

prejowl sulcus, and cheek depressions.

Unlike Sculptra, where time is necessary to build up new collagen,

Radiesse offers the advantage of immediate wrinkle ablation.

Interestingly, although Radiesse induces foreign body reaction, it is

not known to cause granuloma formation. In its gel form, the device is

also quite pliable, permitting timely manipulation and appropriate

modification. In addition, it can be combined with other fillers, such as

Sculptra, HA, and collagen.

The main drawback of Radiesse is that it is not reversible like HAs.

Radiesse also does not contain an anesthetic and because of its high

viscosity, requires administration through a high-bore needle.

However, Radiesse can be combined with lidocaine in the syringe to

decrease pain on injection. Hence, the use of topical or regional

anesthesia is recommended. Minimal side effects such as ecchymoses,

edema, and erythema appear soon after Radiesse injection and are

transitory. Rare nodules have also been associated with Radiesse and

can be managed with intralesional steroids or excision.

Similar to Sculptra, an implantation of Radiesse in the superficial and

mobile wrinkles (i.e., lips and periorbital area) and the body of the lips

is discouraged because of the palpable and visible white papules that

can develop (also known as “popcorn lips”). Radiesse should not be

performed in the nose of a patient anticipating rhinoplasty. Several

facial plastic surgeons have given anecdotal reports in lectures

suggesting that this complicates rhinoplasty surgery. An HA or

collagen filler would be a more appropriate choice in preoperative

rhinoplasty patients.

Sculptra

Sculptra is a synthetic, biodegradable, biocompatible, immunologically

inert peptide polymer (also known as NewFill). Sculptra (Dermik

Laboratories, Sanofi-Aventis, Bridgewater, NJ) is composed of poly-L-

lactic acid (PLLA) microspheres, sodium carboxymethylcellulose, and

nonpyrogenic mannitol and is manufactured from powdered,

absorbable suture material (i.e., Vycryl). This agent is not a true

dermal filler because it does not fill the dermis the way collagen and

HA do but, rather, it promotes the production of new and organized

collagen in the dermis. Many physicians refer to it as a “dermal

stimulator.”

Sculptra is thought to foster neocollagenesis by stimulating fibroblasts

and gradually restoring facial volume. However, Sculptra is eventually

cleared from the skin via phagocytic digestion. In the U.S., the FDA

approved Sculptra in 2004 for the treatment of HIV-associated facial

lipoatrophy, but it has been used off-label for cosmesis, and Dermik is

currently applying for approval for its use in facial rejuvenation.

NewFill has been used in Europe and Asia for many years.


When it was first introduced, NewFill was diluted with a lower amount

of saline and many granules and nodules were reported. This led to

new recommendations to dilute one bottle with 5 to 10 cc of sterile

water and massage after application. With the new recommendations,

adverse events have been minimal.

Freeze-dried Sculptra powder is stored at room temperature and

reconstituted approximately 2 to 4 hours prior to injection. The

package label states that the product should be used within 72 hours.

In our practice, we prefer using Sculptra that has been reconstituted

for at least 2 days because the solution is easy to work with and

results in less needle clogging.

Sculptra is reconstituted and kept in the refrigerator for 2 days to 2

weeks. Although the package label recommends that the formulation

be reconstituted with 5 cc of sterile water, many physicians

reconstitute with 4 mL of sterile water and 1 mL of 2% lidocaine with

epinephrine. The lidocaine decreases pain while the epinephrine

reduces bruising.

Strong agitation of the filed syringes is recommended directly before

injection to homogenize the white suspension. (Sculptra tends to

settle in the bottom of the syringe.) By means of tunneling and

threading techniques, a 25- or 26-gauge needle is utilized to implant

Sculptra into overlapping deep dermal and subcutaneous layers of the

skin.

The mechanism of action and proper technique of injecting Sculptra

require practitioners to restore volume to a selected treatment plane

rather than a specific wrinkle. Indeed, injecting Sculptra is more

similar to fat injection procedures than collagen or HA injections,

because it serves to sculpt the prominent hollows and deep grooves

associated with loss of deep soft tissue. In addition, specialized

training to use Sculptra is required prior to injections.

Small and exact aliquots of Sculptra are injected in the correct tissue

plane without overcorrection. In general, 2 to 3 cc of the product are

used for patients in their thirties, 4 cc for patients in their forties, and

5 cc or more for older patients. The cost is approximately $230 per

syringe. Once Sculptra is injected, there is a transient period lasting

about 1 hour during which the patient can see a slight effect because

of the volume of fluid injected. Once this resolves, results are not seen

until about 4 weeks after treatment when results may begin to

appear. Injections are performed on a monthly basis until desired

results have been obtained.

The number of injection sessions required varies greatly from person

to person and it is difficult to predict the total number of sessions

needed. Injections are performed 3 to 6 weeks apart. Anecdotal

reports state that premenopausal women and postmenopausal women

on hormone replacement therapy (HRT) require fewer sessions than

postmenopausal women not on HRT. Postmenopausal women not on


HRT may require up to eight sessions.

Men tend to correct more quickly than women for unknown reasons.

After the procedure, the patient’s skin is strenuously massaged with

topical arnica (for its anticoagulant properties) for about 5 minutes to

reduce bruising, pain, and nodule formation.

Patients should be told to massage the treated area for 5 minutes

every night for five nights. Sculptra treatments can be combined with

other fillers for instant gratification. In this case, Sculptra is injected

first, the massage with arnica is performed, and then the HA or

collagen filler is applied in the treatment area. Sculptra is often used

in the cheeks and cheekbone area while an HA filler is used in the

nasolabial folds, marionette lines, and the lips. Alternatively, a course

of three to four Sculptra treatments is used and then an HA filler is

used after Sculptra at the last visit. Sculptra should always be used

first, then massaged, before the HA is injected so that the lidocaine

and epinephrine in the Sculptra will reduce the pain and bruising of

the HA injection, and the massaging will not affect the placement of

the HA filler. Sculptra does not require prior skin testing. It is ideal for

treating volume loss in the cheeks, nasolabial folds, and the malar

area.

Once the desired result is achieved, results last about 18 to 24

months. The correction is very natural looking. Having been used

successfully in various medical devices for more than 30 years, PLLA

has an established safety record. Moreover, new product guidelines

and injection techniques (i.e., using a more dilute product, avoiding

overcorrection, not injecting too superficially, and postinjection

massage) have reduced the incidence of side effects (i.e., formation of

granulomas and nodules) as compared to when the product was

originally packaged as NewFill.

Sculptra injection results are not immediate and multiple courses are

required to achieve the optimal cosmetic effect, with the number of

treatments depending on volume of the defect being treated.

Preinjection reconstitution can contribute to scheduling limitations

because it must be made at least 2 hours in advance. Injecting

suspension can be slightly difficult because of recurrent clogging of the

needles, which leads to frequent needle changes. Adverse events are

rare, but PLLA can cause postinjection site pain, bruising, and

swelling, as compared to other products, partly because of the larger

needle used. Adding lidocaine to the diluent mitigates injection pain.

Ecchymoses can be reduced by mixing epinephrine into the PLLA

suspension and taking bromelain supplements (500 mg twice daily)

after injection.

Hyperkinetic areas (i.e., crow’s feet and the corner of the mouth) and

regions with thin skin (i.e., around the eyes, smoker’s lines above the

lips) should not be treated with Sculptra because of irregular papules

that can emerge. Most lumps that do arise are from superficial

administration of Sculptra and are not visible, although they are

palpable by the patient. Reassuring patients that these lumps are


transient in nature is important. Nodule and hematoma formation are

the other rare adverse effects that have been reported, but are less

likely if the new injection guidelines are followed. Sculptra injection

technique is very different than that of HA fillers and the learning

curve is higher. In addition, there is lack of reversibility as with HA

fillers. Specialized training is required by the manufacturers of

Sculptra before they will sell the product to a physician.

Permanent Fillers

Although the current momentum in the cosmetic market is toward the less

invasive procedures, which are safer, permanent fillers are very popular

outside the U.S. because of the lower cost. Many of these products are used

by unskilled practitioners and lead to disfiguring results. If practitioners are

to use a permanent filler, they should be skilled in the technique and certain

of the patient’s expectations. In the primary author’s opinion, it is best to

use a temporary filler first, to make sure that a patient is pleased, before

proceeding to a permanent or semi-permanent option.

Newer fillers (i.e., Artefill) as well as older fillers (i.e., silicone) are being

used for this purpose. These nonbiodegradable fillers stay enclosed by the

skin for an indeterminate and lasting period of time. However, these fillers

are not to be used for and by the lighthearted. They are associated with

rare, significant side effects such as granulomas, migration, and asymmetry

and are best implanted into a patient experienced with prior soft tissue

augmentations and by a proficient provider.

Remember, as with anything enduring, if one is not pleased with the results,

one has to live with long-term consequences. The following table outlines

the list of fillers.176,192,208,209,216,218-221

Artefill

In October 2006, the FDA approved the novel permanent filler Artefill

(Artes Medical, Inc., San Diego, CA) for the correction of nasolabial

folds. Artefill is constituted with 20% homogenous

polymethylmethacrylate (PMMA) suspended in equilibrium with partly

denatured 3.5% bovine collagen (from enclosed US cattle herds) and


0.3% lidocaine.

As opposed to the original European product, Artecoll, which contained

different size microspheres of PMMA that potentially contributed to a

higher risk of granulomas, Artefill is composed of uniform size PMMA microspheres (30–50 m) that are less likely to result in the formation

of granulomas.

Small size, uniformity, and smoothness are refined characteristics of

Artefill that promote biocompatibility and resistance tphagocytic

degradation and migration as well as ensure encapsulation by patients’

collagen leading to lasting nonimmunogenic results.

Artefill is packaged in a kit of three 0.8-mL and two 0.4-mL syringes

that are injected through a 26-gauge needle into subdermal and

subcutaneous space via a tunneling technique without overcorrection.

After injection, gentle massage is recommended to evenly distribute

material in the skin and prevent clumping. Artefill must be stored via refrigeration (2 C–10 C) and warmed before use. In order to achieve

optimal correction of rhytides, two to three treatment sessions, a few

months apart, are suggested.

Like Sculptra, specific injection training for Artefill is required. Artefill

offers the dual action of immediate wrinkle correction from collagen

(lasting about 1–3 months) and permanent deep-fold ablation from

PMMA (lasting for more than 5 years).

The long-term efficacy is believed to be because of the stimulatory

influence of PMMA on the surrounding skin, causing fibroblast and

collagen proliferation around the material starting at 1 month.

Although approved only for nasolabial folds, PMMA has also been

successfully used in other deeper defects (e.g., the cheek and malar

regions). Lidocaine content eliminates the necessity for alternative

anesthesia and alleviates intrainjection discomfort. As compared to the

standard of bovine collagen, PMMA filler has been found to be superior

in efficacy with a comparable safety profile. Widely used in implantable

medical devices for more than 50 years, PMMA has a long safety

record.

Artefill contains bovine collagen; therefore, skin testing prior to

injections is strongly advised to reduce the incidence of

hypersensitivity. This means that patients cannot be treated on the

initial office visit. Furthermore, because of Artefill’s higher viscosity,

more administration pressure is required by the clinician, and the

product is more difficult to inject than collagen and HA fillers.

Although the majority of side effects caused by Artefill are mild and

transient (i.e., swelling, redness, hyper sensitivity, and temporary

lumpiness, which is amenable to massage), rare moderate-to-severe

effects have been reported (i.e., granuloma and inflamed nodule

formation, manageable with intralesional steroids or excision). Because

of the reported lumpiness with this product, it is currently discouraged

for lip augmentation or any superficial wrinkle correction.


Having to inject through a larger bore needle may induce more

posttreatment edema and ecchymoses, which require slightly longer

downtime. The disadvantage of implanting permanent fillers such as

Artefill is the inability to foretell the long-term appearance of the

patient; since the skin changes with age, the natural look may be

altered. Time will tell the exact risk-to-benefit ratio of this filler.

Silicone

Silicone is composed of dimethylsiloxane chains linked by oxygen with

varied viscosity based on the length of the polymer. Used in patients

since the 1940s, the liquid form of this product is one of the oldest soft

tissue augmentation materials.

The use of this injectable filler is fraught with controversy because the

initial unpurified product was associated with long-term disfiguring side

effects, including migration and granuloma formation. It was illegal to

perform silicone injections in the U.S. in some states until recently.

However, because of the purification of liquid silicone and honing of the

injection technique, this soft tissue filler has returned and is very

popular in Brazil.

At the turn of the 21st century, the FDA approved two forms of

medical-grade silicone oils: ADATO (or Silol 5000, Bausch & Lomb

Surgical, Inc., San Dimas, CA) with 5000 centistoke (cs) viscosity and

Silikon 1000 (Alcon Laboratories, Inc., Fort Worth, TX) with 1000 cs

viscosity. These are both indicated for the ophthalmologic uses of

retinal temponade and detachment. Although neither of these products

have been approved by the FDA as skin injectables, they are used off-

label. Furthermore, there are ongoing studies in the U.S. assessing the

safety and efficacy of SilSkin (a 1000 cs, highly purified

polydimethylsiloxane, OFAS Therapeutic Silicone Technologies, Inc.,

New York, NY) for the correction of nasolabial folds and HIV-associated

lipoatrophy. Pilot studies in patients with HIV-lipoatrophy have

revealed satisfactory results with minimal side effects.

Similar to PMMA and PLLA, silicone oil biostimulates the surrounding

skin to slowly generate a focal fibro-granulomatous reaction that leads

to a permanent volumizing. Zappi et al., analyzed the microscopic

biologic behavior of liquid silicone and concluded that it was an

effective, durable (up to 23 years), and immunologically compatible

filler Silikon 1000 is the preferred injectable filler over ADATO because

of its lower viscosity and therefore easier injectability. It is stored at

room temperature and packaged as clear oil. The proficiency in the

injection technique is the crucial variable in achieving successful soft

tissue augmentation with silicone. The favored technique is a serial

puncture of micro droplets and subdermal implantation of 0.01 to 0.02

mL silicone aliquots at 2- to 4-mm intervals using a glass syringe with

a 30-mL needle.3 2, 5 2 The key is not to overcorrect. Instead,

patients should anticipate steady changes with multiple treatment

sessions, 1 to 2 months apart, in order to achieve the most natural and

safe outcome in several months. Since it is immunologically inert, no

prior skin testing is required.


Practitioners with experience in using Silikon have reported its value in

correcting wrinkles and scars, augmenting lips, and panfacial

contouring of deeper folds and valleys. Its low cost and longevity are

obvious benefits. As with any temporary filler, potential long-term

consequences should be broached when discussing this treatment

option with patients.

Most side effects associated with medical-grade silicone injectables are

minimal and include anticipated temporary pain, edema, bruising, and

redness. The pain is likely because of the absence of anesthetic as part

of the product formulation, so appropriate pre-procedure anesthesia

should be provided. However, it is important to keep in mind that rare

reports of appropriately injected, purified silicone causing significant

nodules, granulomas, cellulitis, and ulceration also exist.

The skill of the physician is crucial as this is a permanent filler. The

primary author has seen myriad unhappy patients who have lumps and

asymmetry after treatment by other physicians. In addition, many

patients who are treated by nonphysicians are treated with impure

silicone. This results in disfiguring edema and long-term complications.

In some clinics, an attempt is made to treat complications of silicone

injections by non-physicians with injectable steroids, tacrolimus,

cyclosporine, and Aldara with minimal and short-term improvement.

Surgical excision has remained the only effective long-term treatment.

Polytetrafluor

oethylene

Approved by the FDA in the 1990s for the purpose of soft tissue

augmentation, several forms of expanded polytetrafluoroethylene

(PTFE) are currently on the market: Gore-Tex strings or strands (Gore

Advanced Technologies Worldwide, Newark, DE); Soft-Form and

UltraSoft tubes (Tissue Technologies, Inc., San Francisco, CA); and

newer dual porous, soft, varied-shape Advanta (Atrium Medical

Corporation, Hudson, NH).

PTFE is a synthetic material used in medical devices since the 1970s

with a good safety record. These are spongy products that provide

significant volume enhancement and stimulate local tissue fibrosis and

integration, which relays permanence and stability. PTFE is

biocompatible with rare instances of inflammatory reactions. The

extended PTFE subdermal implants require a more invasive procedure

via surgical implantation, which translates to higher procedural risks

and the necessity for a more specialized setting and training. Because

of these complex features and generally lower physician satisfaction,

the use of these devices by cosmetic dermatologists is not popular.

Benefits PTFE fillers have been shown to impart an enduring correction

of the nasolabial folds, marionette lines, malar and mandibular deficits,

and enhancement of the lips.

Additionally, these products do not require prior testing because of

immunologic inertness. Although the implants are considered

permanent, if patients are dissatisfied with their image alterations, the

products can be removed in bulk within 3 months. The side effects of


bleeding, bruising, redness, postoperative pain, scarring, palpability,

and secondary infection occur more frequently with PTFE fillers as

compared to HA fillers and the recovery time is longer. These products

have high displacement and extrusion rates and an unnaturally stiff

appearance. In addition, they can shrink with time leading to an

asymmetric correction.

Advancements in Fillers

As noninvasive cosmetic interventions have become more prominent, the

manufacturing market has responded by developing newer products. In fact,

there are so many products to consider, it has become ever more

challenging for regulatory organizations, physicians, and patients to discern

their differences. While some clinicians opt to jump on the bandwagon and

use novel filling agents by interpreting newer as better, others await

satisfactory clinical evidence before integrating these fillers into their

practices. It is crucial to appreciate the fact that the products once

proclaimed innovative have either stood the test of time, with manufacturers

reaping the rewards, or they have been superseded. The following table

provides an overview of the up and coming soft tissue augmentation

devices.176,187,202,218,222,223

Evolence

Evolence (Colbar LifeScience Ltd., Herzliya, Israel) is cross-linked

porcine-derived collagen (30 mg/mL concentration). Because of the

greater biologic similarity between pig and human skin versus bovine

and human skin, this filler has potentially lower immunogenicity than

bovine collagen fillers, with no pre-procedure sensitivity testing required.

It is currently only approved in Europe and Israel as two products,

Evolence and Evolence Breeze (finer version), for soft tissue

augmentation.

Evolence is injected through a 25- to 27-gauge 1.25- to 1.5-inch needle

into mid-depth dermal space using tunneling and cross-hatching

techniques, while Evolence Breeze is injected in 0.1-mL aliquots via a 31-

gauge needle using a serial puncture technique into the superficial

dermis; overcorrection is to be avoided. Postimplantation massage is

advised to enhance molding. Without prior allergy testing needed, these

products can be injected on the first visit. Special cross-linking

technology, Glymatrix, yields a more stable collagen product that creates

immediate effects potentially lasting for up to 1 year. Evolence products

may be used in combination with other agents such as HA fillers. This

collagen filler is stored at room temperature.


A recent study comparing the safety and efficacy of Evolence and

Restylane showed that Evolence performed similarly to Restylane.

Evolence does not contain lidocaine as other collagen fillers do. It is more

difficult to inject than Restylane and Juvéderm. Needle jamming has

been noted on occasion, which makes injections a bit awkward.

Religious beliefs have to be considered prior to implantation because this

product contains porcine collagen, which may be rejected on religious

grounds by Jewish and Muslim patients. The FDA had not yet approved

this product at the time of publication, but approval is expected shortly.

Although postprocedure side effects of porcine collagen fillers are

comparable to HA fillers (i.e., transient edema, erythema, pain,

ecchymoses), the development of infrequent lumps and nodules that last

several months has also been noted. These papules can be treated with

massage and intralesional corticosteroids. Because of these side effects,

injecting Evolence into thin skin areas should be avoided.

This filler is new and does not have the years of experience associated

with other collagen and HA fillers. Its use should be approached with

caution.

Isolagen Although presently approved in the UK, Isolagen (Isolagen Inc., Exton,

PA) is undergoing clinical studies in the US to obtain FDA approval.

Utilizing the patient’s skin, fibroblasts are cultured and stimulated to

generate injectable material for aesthetic augmentation. The appeal of

Isolagen is that it uses a minimally invasive harvesting technique,

employing very little tissue (a 3-mm skin punch biopsy from a non-

cosmetic area), to produce an individual, immunologically inert supply of

volume-enhancing product. About 2 months after harvesting, a 1 to 2 cm

3 amount of product is created and injected at about 2-week intervals in

several sessions to provide longer-lasting results.

This product may contain fibroblasts that could confer long-term benefits

not found with other fillers. The crucial benefits of Isolagen are

biocompatibility and safety. This product contains the donor’s own

fibroblasts, which may provide ameliorative effects by increasing the

production of desired cytokines and growth factors, stimulating collagen

and elastin production. Correction is believed, but not proven, to last

about 6 to 12 months. As other collagen fillers, it is injected at superficial

and moderate dermal depth to treat rhytides and nasolabial folds as well

as the lips. This product is particularly expensive because of the specific

engineering technique of cultured autologous fibroblasts and collagen.

There is a waiting period of 2 months and the product derived from the

biopsy is relatively sparse. However, this product can be used in

conjunction with other fillers to make up the volume difference. Special

product shipping, handling and storage, as well as a narrow time-frame

of implantation (within 24 h of Isolagen delivery) are limitations. The

side effects of the product have not been clarified, but are likely similar

to other fillers on the market.


Laresse

Laresse is a novel dermal filler composed of two polymers in solution,

carboxymethyl cellulose (CMC) and polyethylene oxide (PEO), both of

which are hydrophilic. The product is a viscoelastic gel that is injected

into the dermis as a space-filling substance. Although the clinical data

are limited, it has been available in the UK since mid- 2006 and has

become a competitor to cross-linked HA products.

Since Laresse is not cross-linked, it is smoother to inject than HA fillers

and imparts a soft contour to the dermis. Skin testing is not required

with this product. The components have been used in numerous

injectable therapeutics and medical devices and are known to be

immunologically inert. Laresse is easily injected and is reported to

produce less pain on injection than other fillers.

The product is particularly smooth and natural feeling in the skin and it

has been used in nasolabial folds and other superficial wrinkles. Because

of its ability to stabilize and compact in higher concentrations without a

need for cross-linking, it is hypothesized that Laresse will have longer

durability than HA fillers.

However, no studies have been published in the US to support these

claims. Although studies have shown that Laresse lasts 6 months in

some patients, limited clinical studies have been performed so its

duration will become evident as it becomes available in the marketplace.

The extent of its potential applications in facial augmentation is unclear

as the product has been used clinically only since 2007 and its use in the

hands of practitioners is still being evaluated. Laresse does not contain

lidocaine and, therefore, preprocedure anesthesia is usually topical or a

nerve block, similar to HA fillers. Side effects are analogous to the HA

fillers and consist mainly of transient swelling, bruising, and redness.

Other adverse events are yet to be revealed as the FDA is investigating

Laresse.

Aquamid

A novel permanent filler, Aquamid (Ferrosan A/S-Contura International

SA, Cophenhagen, Denmark) has been approved and used in Europe,

South America, and the Middle East for the past few years. Aquamid is

composed of 97.5% pyrogenic water linked to 2.5% cross-linked

polyacrylamide polymer. When it is introduced into skin tissue,

acrylamide stimulates fibrotic and localized foreign-body reactions.

The gel is packaged in a 1-mL syringe and stored at room temperature.

It is injected through a 27-gauge needle using a threading technique

without overcorrection. The material is inert, obviating prior sensitivity

testing. Aquamid is biocompatible and nonabsorbable, which yields an

inert and durable device that can last indefinitely. Aquamid has shown

efficacy in lip augmentation, correction of nasolabial folds, depressed

mouth commissures, as well as glabellar and perioral rhytides.

Lacking lidocaine content, Aquamid requires local or regional anesthesia

prior to the procedure. Although postimplantation side effects are similar

to those of HA fillers (e.g., temporary erythema, edema, redness), rare

long-term and more severe adverse effects are more prominent with

Aquamid. The primary author has seen several patients treated in South


America with prolonged swelling and edema. The exact duration of

Aquamid in the skin is still unclear, with most recent studies

demonstrating about 2-year durability. Rare hematomas, lumps,

granulomas, and indurations do occur with the use of Aquamid. Use of

this filler should be discouraged until more safety data are gathered.

Determining Which Filler to Use

There are many filler options available, so deciding on which filler to use is

difficult. The A, B, C, D approach can help. “A” stands for assess the patient.

Determine which areas can be treated with the greatest potential for

improvement. Look at the entire face and decide where to get the “best

bang for the buck.” For example, if the patient has prominent nasolabial

folds, there are two main options: treating the nasolabial folds, or treating

the cheek or cheekbone area to add volume that will improve the fold by

pulling the skin back. A patient with large round cheeks would do better to

have the nasolabial fold treated, while a patient with thin cheeks and facial

volume loss would have a better result if the cheeks were treated. As a

practitioner, it is important to form your own impression first before the

patient tells you their thoughts. In some cases you may notice factors that

the patient does not even realize are contributing to an aged appearance.

These observational skills are developed with experience.194

Once you have an idea of what areas would make the most significant

impact if treated, then move to the “B” section, which is budget. It is crucial

to determine how much money the patient is willing to spend. It is often the

case that the budget is lower than what is necessary, so the physician must

determine what areas to treat to achieve the best cosmetic effect possible

within the patient’s budget. In addition, the practitioner must consider the

patient’s time budget or schedule. For example, if a patient is visiting from

another country and planning to leave the following day, a course of

Sculptra injections is not an option.194,202


Once the time and financial budget have been determined, the practitioner

should talk to the patient about other considerations. The most important

question is what bothers them about their face. It is often different than

what the physician sees. Patient happiness is contingent on improving what

they see as the problems on their face, not what bothers the medical

provider. The following or similar questions may be appropriate to frame

such a discussion, then, in the attempt to identify the most suitable filler for

a patient: What have you tried before? Were you satisfied with the results?

Why or why not? What concerns do you have? Are you a frequent bruiser?

Are you worried that your lips will look too big? Do you hate it when your

lipstick bleeds up into the lines on the top lip? Do you have any religious

restrictions? Do you have any events coming up? What amount of downtime

can you tolerate? These are all critical issues in determining the most

appropriate filler. Once all this information has been gathered, the physician

must choose a filling device that meets all the criteria. It is a relatively easy

choice after the preceding questions have been answered. In addition, the

physician should have many filler choices on hand to give the patient the

best result.178,222,224

Injection Technique

Injection technique varies from filler to filler. Most physicians use either an

anterograde, retrograde, or serial puncture technique. Most collagen and HA

fillers are injected at a 45-degree angle. It is important to be individually

trained on the injection techniques of each filler. Fillers can be used in

combination with botulinum toxins and other cosmetic procedures. Fillers

can also be injected in other areas of the body such as the hands. Many

injection techniques can be used. However, it is difficult to teach various

techniques without video and live demonstrations.181


Sclerotherapy

Sclerotherapy is successfully used to treat both functional and cosmetic vein

disorders. When it performs as expected, the sclerosant significantly

damages the endothelial lining of the vessel wall being treated and results in

inflammation, fibrosis, and in the eventual obliteration of the vessel.

Hyperosmotic agents, such as hypertonic saline, produce endothelial damage

through dehydration. Detergents, such as sodium tetradecyl sulfate, sodium

morrhuate, ethanolamine oleate, and polidocanol, cause vascular injury by

altering the surface tension around endothelial cells, diminishing their ability

to adhere to one another.225

Foamed sclerosants (either sodium tetradecyl sulfate or polidocanol mixed

with air) are mainly used to treat functional vein disorders, such as chronic

venous insufficiency and venous ulceration under duplex-guided ultrasound.

This approach has been very successful for the medical sclerotherapy

patient. The most common sclerosing agent used in dermatology is

hypertonic saline, although it is approved as an abortifacient rather than a

sclerotherapy agent.226

It is important to know the risk profiles of commonly used sclerosants.

Hypertonic saline is associated with burning and cramping upon injection

and an increased risk of ulcerative necrosis secondary to extravasation.

Sodium tetradecyl sulfate has also been associated with hyperpigmentation,

pain upon extravasation, and skin necrosis. Rarely, sodium tetradecyl sulfate

and, even more rarely, polidocanol have been associated with allergic

hypersensitivity reactions. The optimal concentration of sclerosant may vary

with the diameter of the vessel being treated, with a greater concentration

of sclerosant being required for vessels of larger diameter. If the sclerosant

is too weak, insufficient damage to the endothelium results and a thrombus


may form that eventually recanalizes. If the sclerosant is too strong, then

ulceration and hyperpigmentation can occur because of extravasation of the

sclerosant.227

Shelf Life Of Pharmacological Agents

The longevity of a pharmacologic agent

is governed by its shelf life. Shelf life of a

drug is the duration from the time the

product is manufactured till the potency

of the drug has been reduced by 10%.

This limit is usually considered

acceptable in practice; more stringent

standard is required if the degradation

products are more toxic or irritative than

the parent drugs.2

The shelf life of pharmacological agents will vary depending on a number of

factors. Each preparation will include detailed information regarding the

expected shelf life, with recommendations for storage and proper use.

Products with a shelf life of more than 3 years are considered to be 'stable'

as these are expected to sold and used within his period. Products with a

shorter half-life should be labeled with expiration date.1

As a guide to good pharmaceutical practice it is suggested that mixtures

recommended to be 'freshly prepared' should be prepared not more than 24

hours before issue to the patient. Mixtures recommended to be 'recently

prepared' should be stored in unopened bottles in the dispensary for not

more than 3 months. Should there be any doubt, the pharmacist should be


consulted.4 There are a number of environmental factors that can affect the

shelf life of a drug. These are briefly outlined below.5

pH: the pH affects rate of chemical reaction and hence longevity of a

drug.

Temperature: An increase in temperature usually increases the rate of

chemical reaction. Storage of a medicine in a cool place (below 15 C)

will prolong the shelf life. Refrigeration may prolong shelf life of a

medicament that is unstable in room temperature but solid particles

may grow and precipitate in a suspension. The temperatures suitable

for storage of topical drugs lie in the range of 15-25 C.

Oxygen: Many drugs show slow oxidation in the presence of

atmospheric oxygen. If the rate of degradation is significant, the

addition of an antioxidant may be needed.

Light: Can induce photochemical degradation. This can be reduced by

the use of light-resistant containers or, more effectively, by storage in

the dark.

Humidity: Low humidity may be responsible for the powdering of

granular solids containing effervescent salts and for the 'drying out' of

creams. High humidity brings about the deterioration of effervescent

tablets and solid preparations that contain hygroscopic materials. The

adverse effects of humidity can be avoided by the use of moisture-

proof containers.

Pharmaceutical containers:


o The basic requirement for a container is that it should not

interact with the formulation. Glass, plastics are commonly used

components of containers. Glass containers have some

disadvantages, i.e., leaching of alkali and insoluble flakes into

the formulation; these can be offset by the choice of an

appropriate glass material.

Plastic containers are convenient to handle but the major

disadvantage is the two-way permeation or 'breathing' through

the container walls. Volatile oils, perfumes and flavoring agents

can permeate through plastics to some extent. Components of

emulsions and creams have been reported to migrate through

the walls of some plastics causing either a deleterious change in

the formulation or collapse of the container. Loss of moisture

from a formulation is also common.

o Closure must form an effective seal for the container. It must

not react chemically or physically with the formulation. Rubber is

a common component of stoppers, cap liners, and parts of

dropper assemblies. Absorption of the active ingredients,

preservatives into the rubber and the extraction of one or more

components of rubber into the formulation is a common

problem.

o The application of an epoxy lining to the rubber closure reduces

the amount of leached extractives but has no effect on the

absorption of the preservative from the solution. Teflon-coated

rubber stoppers may prevent most of the leaching and

absorption.


Summary

In the course of a day, dermatologists see a wide variety of patients with

concerns ranging from serious medical conditions like cancer to cosmetic

issues that impact the patient's physical and emotional health. As with most

other specialties, pharmacological agents can be a useful resource for

treating dermatological concerns involving the hair, nails, and skin. There

are a wide variety of pharmacological agents that can be utilized in treating

dermatological issues, and they are typically delivered either topically or

percutaneously. As with any medical treatment, the purpose of these

pharmacological agents is to provide relief for the patient's issue with a

minimal amount of pain and other side effects.

The mechanisms of potential toxicity of skin products and the depth of injury

are important for health providers to understand and to educate patients

about during their course of care. Dermatology drug treatments may also

require follow up by the health provider since irritation and damage can

appear even after a drug has been discontinued.

Initial consultation, discussion of the treatment options, and, importantly,

the patient’s history helps to determine the best dermatology treatment and

prevention of potential contraindications to treatment. Evolving marketplace

influences and an overlap of dermatology specialties influence patient care

outcomes. The practice of dermatology is continuously evolving with many

new products and therapies that pose both health benefits and risks for

which health professionals must be continuously informed.


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a) Tapering down

b) Rebound effect

c) Tachyphylaxis

d) Topical nonadherence


a) medical and cosmetic dermatology.

b) surgical and cosmetic dermatology.

c) dermatology and general medicine.

d) dermatology and surgery.


corticosteroids.

a) Infants

b) Individuals who are underweight

c) Women

d) The elderly



a) True


b) False


a) Oil

b) Liquids

c) Anti-infective agents

d) Powders

6. The term ___________ refers to the inactive part of a topical preparation

that brings a drug into contact with the skin.

a) lidocaine

b) vehicle

c) prilocaine

d) astringents

7. Vehicle selection for topical dermatologic treatment is guided by

a) location of application

b) cosmetic effects

c) convenience

d) all of the above

8. Most powders contain zinc oxide for its

a) lubricating and drying properties

b) improved adherence to the skin

c) composition of magnesium silicate

d) antiseptic and covering properties

9. A poultice, also referred to as a ______________, is a wet solid mass of

particles, sometimes heated, that is applied to diseased skin.

a) talc

b) cataplasm


c) calamine

d) magnesium silicate

10. In pharmaceutical terms, oil-in-water emulsion bases are

a) creams.

b) poultices.

c) specifically used for conditions on the palms and soles. p. 4

d) composed of magnesium silicate.

11. True/False: Under normal conditions, up to 99% of the applied topical

corticosteroid is cleared from the skin, and only 1% is therapeutically active.

a) True

b) False

12. The most important element in topical therapy is

a) the retinoid preparation.

b) the patient’s age.

c) educating the patient about skin irritation.

d) the patient’s gender.

13. Which of the following is/are not a stabilizer (nontherapeutic ingredient):

a) preservatives

b) antioxidants

c) chelating agents

d) corticosteroids

14. _________________ is the principal solvent for cleansing.

a) Soap

b) Water

c) Isotonic saline

d) Aluminum chloride


15. True/False: When applying a topical treatment, the patient should avoid

vigorous rubbing or massaging of the drug into the skin.

a) True

b) False

16. Irritant contact dermatitis, caused by a topical drug may be reduced by

a) lessening the drugs penetration properties.

b) using a less concentrated preparation over a greater period of time.

c) cessation of the drug’s use.

d) None of the above.

17. True/False: In some instances, though, skin irritancy might be central

to drug efficacy.

a) True

b) False

18. Topical steroids cause capillaries in the superficial dermis to

a) constrict, thus reducing erythema.

b) expand, thus increasing erythema.

c) enlarge the thickness of the stratum corneum.

d) expand vascular supply to the area.

19. ______________ are triphasic liquids composed of oil, organic solvents

and water.

a) Shake lotions

b) Foams

c) Suspensions (lotions)

d) Aqueous solutions


20. Topical corticosteroids are recommended for

a) their anti-inflammatory activity in inflammatory skin diseases.

b) their antimitotic effects.

c) their capacity to decrease the synthesis of connective tissue

molecules.

d) All of the above.

21. True/False: Results from large-scale surveys show that patients or

caregivers overestimate the actual risks of topical corticosteroids leading to

treatment noncompliance.

a) True

b) False

22. Liniments have many uses but they do not include:

a) use as a counterirritant.

b) use as an antipruritics.

c) use as a drying agent.

d) use as an analgesics.

23. The current evidence shows that

a) pregnant women should not use topical corticosteroids.

b) topical glucocorticoids are excreted in breast milk.

c) topical glucocorticoids should be used with caution in breastfeeding

mothers.

d) topical glucocorticoids may be used on the breasts before

breastfeeding.


24. True/False: With respect to dosage regimes in the application of potent

or moderately potent corticosteroids, there is a significant difference with

once versus twice daily dosages.

a) True

b) False

25. Which of the following side effects may result from the use of topical

corticosteroids:

a) steroid rosacea

b) acne

c) perioral dermatitis

d) All of the above

26. An oil-in-water emulsion

a) contains greater than 31% water.

b) contains less than 25% water.

c) is the one most commonly chosen to deliver a dermatologic drug.

d) a) and c)

27. ______________ formulations require no preservative additives.

a) Oil-in-water emulsion

b) Water-soluble bases

c) Paraben

d) Gel

28. True/False: There is no difference between “oil-in-water” and “water-in-

oil” emulsions; these names are interchangeable and describe the same

thing.


a) True

b) False

29. _______________ are nonstaining, greaseless, and easily washes off of

the skin.

a) Water-soluble bases

b) Water-in-oil emulsions

c) Hydrophilic (polar) compounds

d) Pastes

30. ______________ are simply the incorporation of high concentrations of

powders (up to 50%) into an ointment.

a) Nonaqueous gels

b) Solubilized therapeutics

c) Pastes

d) Cellulose derivatives

31. Gels are suitable for facial or hairy areas because

a) after application little residue is left behind.

b) they have protective or emollient properties.

c) they may be combined with high concentrations of propylene glycol.

d) they do not require preservatives.

32. Newer gel formulations may contain the viscoelastic _______________,

which can mitigate dermal irritation.

a) propylene glycol

b) glycerin

c) preservatives

d) polysaccharide hyaluronic acid


33. A hydroalcoholic solution with a concentration of alcohol of

approximately 50% is called a ____________.

a) Burow solution

b) collodion

c) tincture

d) liniment

34. Emollients containing urea or lactic acid are an example of a

a) suspension that is preferred for its uniform application.

b) suspension that requires shaking of the lotion before application.

c) Burow solution.

d) None of the above.

35. True/False: Flexible collodions have added castor oil and camphor and

are used, for example, to deliver 10% salicylic acid as a keratolytic agent.

a) True

b) False

36. Shake lotions are lotions to which

a) a powder is added to hydrate and warm dry skin.

b) triphasic liquids are added for their hydrating effect.

c) organic solvents are added for their hydrating effect.

d) a powder is added to increase the surface area of evaporation.

37. The following is/are true about the penetration of topical steroids:

a) side effects are less likely where the skin is thin.

b) increased penetration of the drug occurs where the skin is thin.


c) penetration of topical steroids through the palms is 36 times greater

than for the soles.


38. Elderly patients may have thin skin, which

a) allows for decreased penetration of topical glucocorticoids.

b) means they are less likely to have preexisting skin atrophy.

c) allows for increased penetration of topical glucocorticoids.

d) means that topical glucocorticoids should not be used.

39. Previous studies have demonstrated that foam vehicles, when compared

to other vehicles,

a) deliver active drug at a decreased rate.

b) act as an added barrier for the stratum corneum.

c) are not effective for drug delivery through the intercellular route.

d) are highly effective in delivering greater amount of active drug.

40. True/False: Foams have been associated with adverse side effects,

especially for localized conditions affecting the scalp.

a) True

b) False

41. Topical aerosols may be used to deliver drugs formulated as

a) solutions.

b) powders.

c) semisolids.


42. When applied to abraded or eczematized skin, which of the following

delivery forms is least irritating when applied?

a) aerosols


b) liniments

c) pastes

d) ointments

43. One of the drawbacks to aerosols is

a) low patient satisfaction.

b) excessive waste when dispensed.

c) the cost.

d) poor application, especially to hair-bearing areas.

44. True/False: Corticosteroids are thought to exert their potent anti-

inflammatory effects by inhibiting the release of phospholipase A2.

a) True

b) False

45. Increasing hydration of the stratum corneum can enhance absorption of

topical corticosteroids by

a) 98%.

b) four to five times.

c) ten times.

d) 50%.

46. A serious consequence of ceasing topical steroid therapy after an

extended treatment period can result in

a) an Addisonian crisis.

b) a placebo affect.

c) hemangiomas.

d) dry skin.


47. Hemangiomas of infancy show a good or partial response to treatment

with

a) sulfacetamide.

b) topical glucocorticoids.

c) metronidazole.

d) nitroimidazole.

48. Sulfacetamide is a topical sulfonamide used in the treatment of

a) psoriasis

b) eczema

c) hemangiomas.

d) rosacea and acne.

49. Which of the following is true of topical 5% dapsone gel?

a) It is not approved by the FDA for the treatment of acne.

b) If benzoyl peroxide is applied after it, a temporary orange/yellow

discoloration of skin and facial hair may occur.

c) It awaits FDA approval once the mechanism of action is understood.

d) It is used to treat skin disorders but not acne vulgaris.

50. Mechanisms for the anti-inflammatory effects of corticosteroids include:

a) blocking the release of arachidonic acid.

b) increasing the release of arachidonic acid from phospholipids.

c) Corticosteroids also decrease the release of interleukin-1α.

d) Encouraging the release of inflammatory cytokine, from keratinocytes.


Correct Answers:



Correct Answer: Tachyphylaxis


Correct Answer: medical and cosmetic dermatology


corticosteroids.

Correct Answer: Infants



Correct Answer: False


Correct Answer: Anti-infective agents


6. The term ___________ refers to the inactive part of a topical preparation

that brings a drug into contact with the skin.

Correct Answer: vehicle

7. Vehicle selection for topical dermatologic treatment is guided by

Correct Answer: all of the above

8. Most powders contain zinc oxide for its

Correct Answer: antiseptic and covering properties

9. A poultice, also referred to as a ______________, is a wet solid mass of

particles, sometimes heated, that is applied to diseased skin.

Correct Answer: cataplasm

10. In pharmaceutical terms, oil-in-water emulsion bases are

Correct Answer: specifically used for conditions on the palms and

soles.

11. True/False: Under normal conditions, up to 99% of the applied topical

corticosteroid is cleared from the skin, and only 1% is therapeutically active.

Correct Answer: True

12. The most important element in topical therapy is

Correct Answer: educating the patient about skin irritation.

13. Which of the following is/are not a stabilizer (nontherapeutic ingredient):

Correct Answer: corticosteroids

14. _________________ is the principal solvent for cleansing.


Correct Answer: Water

15. True/False: When applying a topical treatment, the patient should avoid

vigorous rubbing or massaging of the drug into the skin.


16. Irritant contact dermatitis, caused by a topical drug may be reduced by:

Correct Answer: using a less concentrated preparation over a greater

period of time.

17. True/False: In some instances, though, skin irritancy might be central to

drug efficacy.


18. Topical steroids cause capillaries in the superficial dermis to

Correct Answer: constrict, thus reducing erythema.

19. ______________ are triphasic liquids composed of oil, organic solvents

and water.

Correct Answer: Foams

20. Topical corticosteroids are recommended for

Correct Answer: All of the above.

21. True/False: Results from large-scale surveys show that patients or

caregivers overestimate the actual risks of topical corticosteroids leading to

treatment noncompliance.



22. Liniments have many uses but they do not include:

Correct Answer: use as a drying agent.

23. The current evidence shows that

Correct Answer: topical glucocorticoids should be used with caution in

breastfeeding mothers.

24. True/False: With respect to dosage regimes in the application of potent

or moderately potent corticosteroids, there is a significant difference with

once versus twice daily dosages.


25. Which of the following side effects may result from the use of topical

corticosteroids:

Correct Answer: All of the above

26. An oil-in-water emulsion

Correct Answer: a) and c)

27. ______________ formulations require no preservative additives.

Correct Answer: Water-soluble bases

28. True/False: There is no difference between “oil-in-water” and “water-in-

oil” emulsions; these names are interchangeable and describe the same

thing.



29. _______________ are nonstaining, greaseless, and easily washes off of

the skin.

Correct Answer: Water-soluble bases

30. ______________ are simply the incorporation of high concentrations of

powders (up to 50%) into an ointment.

Correct Answer: Pastes

31. Gels are suitable for facial or hairy areas because

Correct Answer: after application little residue is left behind.

32. Newer gel formulations may contain the viscoelastic _______________,

which can mitigate dermal irritation.

Correct Answer: polysaccharide hyaluronic acid

33. A hydroalcoholic solution with a concentration of alcohol of

approximately 50% is called a ____________.

Correct Answer: tincture

34. Emollients containing urea or lactic acid are an example of a

Correct Answer: suspension that requires shaking of the lotion before

application.

35. True/False: Flexible collodions have added castor oil and camphor and

are used, for example, to deliver 10% salicylic acid as a keratolytic agent.


36. Shake lotions are lotions to which


Correct Answer: a powder is added to increase the surface area of

evaporation.

37. The following is/are true about the penetration of topical steroids:

Correct Answer: increased penetration of the drug occurs where the

skin is thin.

38. Elderly patients may have thin skin, which

Correct Answer: allows for increased penetration of topical

glucocorticoids.

39. Previous studies have demonstrated that foam vehicles, when compared

to other vehicles,

Correct Answer: are highly effective in delivering greater amount of

active drug.

40. True/False: Foams have been associated with adverse side effects,

especially for localized conditions affecting the scalp.


41. Topical aerosols may be used to deliver drugs formulated as

Correct Answer: All of the above.

42. When applied to abraded or eczematized skin, which of the following

delivery forms is least irritating when applied?

Correct Answer: aerosols


43. One of the drawbacks to aerosols is

Correct Answer: the cost.

44. True/False: Corticosteroids are thought to exert their potent anti-

inflammatory effects by inhibiting the release of phospholipase A2.


45. Increasing hydration of the stratum corneum can enhance absorption of

topical corticosteroids by

Correct Answer: ten times.

46. A serious consequence of ceasing topical steroid therapy after an

extended treatment period can result in

Correct Answer: an Addisonian crisis.

47. Hemangiomas of infancy show a good or partial response to treatment

with

Correct Answer: topical glucocorticoids.

48. Sulfacetamide is a topical sulfonamide used in the treatment of

Correct Answer: rosacea and acne.

49. Which of the following is true of topical 5% dapsone gel?

Correct Answer: If benzoyl peroxide is applied after it, a temporary

orange/yellow discoloration of skin and facial hair may occur.

50. Mechanisms for the anti-inflammatory effects of corticosteroids include:


Correct Answer: Corticosteroids also decrease the release of

interleukin-1α.

References Section

The reference section of in-text citations include published works intended as

helpful material for further reading. Unpublished works and personal

communications are not included in this section, although may appear within

the study text.

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DERMATOLOGY PHARMACOLOGY - … nursece4less.com nursece4less.com nursece4less.com nursece4less.com 1 DERMATOLOGY PHARMACOLOGY Jassin M. Jouria, MD Dr. Jassin M. Jouria is a medical