Mt. sinai sept/oct 4 (page 279)
The Modern Age of Acne Therapy:
A Review of Current Treatment Options
This review of current acne treatments begins with the crucial discovery in 1979 of isotretinoin treat-ment for nodulocystic acne. This drug’s approval in 1982 revolutionized therapy, since it was the firstoral acne-specific drug, and it provided prolonged remissions. In addition, it may prevent the emer-gence of resistant bacteria, a problem linked to the traditional use of antibiotics for acne.
Patients who are not candidates for isotretinoin therapy may benefit from one of the other drugs
or drug combinations reviewed, including the third-generation topical retinoids adapalene and
tazarotene, retinoic acid reformulated in new vehicles, azelaic acid, and topical antibiotics. Proper
selection and education of patients are essential, since serious consequences may result from poorly
monitored use of antibiotics and retinoids.Key Words:
Acne, review, therapy, treatment, isotretinoin, retinoid, antibiotic, azelaic acid, adapalene,
tazarotene, benzoyl peroxide.
Acne: Definition, Demographics and
THE PERIOD 1945–1995 has been named the“Golden Age of Treatment” in dermatology by
Acne is a chronic inflammatory condition of
Thomas B. Fitzpatrick (1). These fifty years
the pilosebaceous unit. The comedo, a plug of
saw a great number of therapeutic discoveries,
sebum and keratin lodged in the follicular duct,
ranging from penicillin for syphilis to topical
is its primary lesion. Comedones appear clini-
corticosteroids for psoriasis. In the field of
cally as blackheads and whiteheads. When a
acne treatment, the single most important event
closed comedo or microcomedo causes the fol-
probably was the 1979 report of prolonged re-
licular wall to rupture, an inflammatory reac-
missions of cystic acne attributable to 13-cis-
tion ensues, resulting in clinically evident
papules, pustules, nodules and cysts. The term
In 1982, the Food and Drug Administration
“cyst” is a misnomer that refers to a pus-filled
(FDA) approved the use of isotretinoin for
acne lesion greater than 5 mm in diameter, in
treating recalcitrant nodulocystic acne. Unlike
which the wall is composed of inflammatory
traditional antibiotic treatment, isotretinoin’s
sole approved indication is cystic acne. Its ef-
The typical clinical picture of acne is an
fect lasts months to years after a 20-week
eruption located on the face, with the upper
course, a claim that no other acne medication
trunk often being affected as well. Adolescents
can match. Also, its use does not promote an-
and young adults are most often afflicted, with
tibiotic-resistant bacteria, an important concern
estimates of 85 – 100% of those aged 12 – 24
being affected, at least intermittently, during
Since isotretinoin is reserved specifically
those years (4, 5). Within the adolescent group,
for severe acne, it has not made other acne
the frequency and severity of acne, as well as
treatments obsolete. Yet it appears to provide an
its tendency toward scarring, is greater in males
acne treatment that is comfortable, safe, effec-
than in females. However, the persistence of
acne into adulthood is more common in females(6).
Contrary to popular belief, hygiene plays at
most a minor role in the etiology of acne, and
Assistant Clinical Professor of Dermatology, The Mount Sinai
diet appears to have little or no influence.
Address all correspondence to S. Bershad, 28 South Moun-
However, true acne can be exacerbated by ex-
ternal factors such as friction (“acne mechan-
THE MOUNT SINAI JOURNAL OF MEDICINE Vol. 68 Nos. 4 & 5 September/October 2001
ica”) (7) and pore-clogging cosmetics (“acne
tions in this group include topical tretinoin,
cosmetica”) (8). The etiology of acne lies in a
adapalene and tazarotene, as well as oral
confluence of several factors which together
isotretinoin. Considerable current research is
produce clinical acne. Research suggests that
genetic control, along with the stimulation of
Tretinoin preceded the others in this class
androgenic hormones, is responsible for abnor-
by a decade or more, becoming available as a
mal sebum secretion (9, 10). The latter, to-
topical acne treatment in the United States in
gether with faulty corneocyte occlusion of the
1971. Tretinoin exerts its effects by increasing
pilosebaceous orifice, produces comedonal
the turnover of follicular epithelial cells, thus
acne (11). The anaerobic diphtheroid Propioni-
normalizing keratinization (13). This leads to
is believed to play a pivotal
the extrusion of comedones and also accelerates
role in converting comedonal acne to inflamma-
tory acne. Previously P. acnes
was thought to
incite inflammation by breaking down neutral
Early formulations of tretinoin tended to
sebaceous lipids into free fatty acids, but newer
cause excessive skin irritation, due to the high
research favors a direct role for P. acnes
concentration of the active ingredient in a pen-
etrating hydroalcoholic vehicle. Now availableare a number of formulations which utilize a
Treatment of Acne
lower tretinoin concentration (0.025%) andcream vehicles which are designed to be more
Today’s therapeutic modalities for acne are
emollient and less penetrating. Two of the
aimed at one or more of its pathogenic precipi-
newest topical tretinoin products are based on
tants, which include androgenic hormonal stimu-
slow-release delivery systems (15). One of
lation, hypersecretion of sebum, faulty occlusion
these contains tretinoin (0.025%) in a gel or
of the follicular orifice, P. acnes
cream base containing polyolprepolymer-2, a
and inflammation. Combination therapy, there-
large-polymer compound that delays absorption
fore, is the usual approach, with isotretinoin
of the active ingredient into epidermal cells.
treatment being the notable exception.
The second formulation designed to slow deliv-ery is a tretinoin (0.1%) gel, in which the active
ingredient is incorporated into microsponges,which are macroporous beads 10 – 25 microns
principal manifestations of acne, there is no
substitute for the immediate results achieved
tretinoin in dermatology practice is often lim-
with acne surgery, which is the manual extrac-
ited by local skin irritation. In addition, the
tion of impacted comedones, performed in the
onset of improvement is relatively delayed and
physician’s office. Most patients benefit by
variable — one to three months is common
having this procedure performed at 3 – 6 week
(16). Some patients experience clinical wors-
intervals until topical medications take effect.
ening after 2 – 4 weeks of treatment (17), when
Patients should be discouraged from attempting
the extrusion of comedones can elicit a pustular
this at home, due to the risk of infection and the
reaction. Tretinoin also increases sun sensitiv-
potential for scarring due to excessive trauma to
ity, necessitating regular sunblock use.
The most effective topical medications for
matic retinoids, adapalene and tazarotene, may
comedonal acne are the so-called keratolytic
provide therapeutic advantages over tretinoin.
agents, which target faulty occlusion of the fol-
These new agents have molecular configura-
tions that are selective for nuclear retinoic acid
retinoids, azelaic acid, and the alpha-hydroxy
receptors. It is theorized that these receptors,
when activated, affect keratinocyte differentia-tion and block inflammation (17 – 19).
Adapalene is a synthetic naphthoic acid de-
rivative. Its mechanism of action is twofold:
Topical Vitamin A acid (tretinoin, all-trans-
first, it inhibits comedo formation through its
retinoic acid) and its synthetic analogs, termed
ability to bind to retinoic acid receptors and
retinoids, comprise the most potent group of
modulate cell differentiation; and second, it
currently available keratolytic agents. Medica-
possesses direct anti-inflammatory activity
Vol. 68 Nos. 4 & 5
(20). Adapalene is available in gel, solution
Figure) (23). There was no control group in
and cream formulations containing 0.1% active
this early study, but subsequent vehicle-con-
trolled clinical trials support the efficacy of this
In a multicenter study of more than 300 pa-
tients, adapalene (0.1% gel) was compared totretinoin (0.025% gel) for efficacy and side ef-
fects. Adapalene produced significantly greaterlesion reduction than tretinoin and caused less
Azelaic acid is a naturally occurring dicar-
boxylic acid. Available in a 20% cream formu-
Adapalene shares with other retinoids the
lation, it has been demonstrated to prevent fol-
adverse effect, in certain patients, of an inflam-
licular hyperkeratosis, thereby inhibiting come-
matory acne flare toward the end of the first
dogenesis (14). It also has antimicrobial activ-
month of therapy. This risk can be reduced by
ity, being bacteriostatic against P. acnes
introducing adapalene or tretinoin gradually.
The retinoid is generally applied 2 – 3 times per
it does not appear to induce resistant P. acnes
week initially, and increasing to nightly use
over a period of about 2 months. Oral or topi-
Clinically, azelaic acid 20% cream has been
cal antibiotics are often combined with retinoid
shown to have efficacy comparable to other
therapy, due to their ability to inhibit the in-
topical medications (25). It is associated with a
low rate of adverse effects, the most common
Tazarotene, a synthetic acetylenic retinoid,
being local itching and burning sensations.
was introduced in 1997 as a gel to treat psoria-sis. After topical application, it is rapidly con-
verted to its active metabolite, tazarotenic acid.
Two large clinical studies found tazarotene
0.1% gel to be more effective than vehicle in
hydroxy group on their second (alpha) carbon.
the treatment of acne (22), but erythema and ir-
These occur naturally in sugar cane, fruits, and
milk products. The most useful AHAs in der-
tazarotene cream is now available as well. A
matological practice are glycolic acid, lactic
new method of acne treatment, called short-
acid, and gluconic acid (gluconolactone).
contact tazarotene therapy, has been developed
by the author. This method involves applica-
AHAs facilitate desquamation of the stratum
tions once or twice daily of tazarotene (0.1%)
corneum (26). This finding has led to the clin-
gel for 2 – 5 minutes per application, followed
ical use of AHAs in the treatment of comedonal
by thorough rinsing with warm water. In a pilot
acne. Because these compounds are not patent-
study of this method, 20 patients with facial
protected drugs under strict FDA control, large
acne applied open-label tazarotene 0.1% gel
well-controlled trials are lacking. However,
using the short-contact method. Fourteen pa-
there is evidence suggesting acne improvement
tients (70%) achieved at least 50% reduction in
with AHAs, especially glycolic acid and glu-
acne lesions within 12 weeks of therapy (see
A 17-year-old patient, previously untreated for acne. (B)
After 7 weeks of short- contact tazarotene therapy
ment consist mainly of 5 – 10% glycolic acid inwater-based lotions or hydroalcoholic solu-
tions. Peeling agents containing 30 – 50% gly-
erythromycin have been available as hydroal-
colic acid may be used in the office setting
coholic solutions for about two decades.
Newer formulations intended to reduce skin ir-
ritation include hydrophilic gels and lotions.
their therapeutic usefulness in part due to the
The 1990s have seen an increase in the popu-
lower likelihood of causing skin irritation.
larity of the pledget application system, which
is often more convenient than the traditional
found their way into the treatment of mild
acne, particularly in pre-adolescents and
colonization of P. acnes
, and they may also pos-sess direct anti-inflammatory effects via sup-
pression of neutrophil chemotaxis (36, 37).
A clinical study showed that two different
topical solutions, one containing 1.5% ery-
acne is the comedo, a majority of acne patients
thromycin and the other containing 1% clin-
can benefit by using keratolytic agents. In ad-
damycin, were therapeutically equivalent for
dition, when the predominant lesion type is the
acne (37). Further, in a double-blind clinical
inflammatory papule or pustule, the traditional
trial, therapy with clindamycin 1% solution was
mainstays of treatment are topical and systemic
found to be as effective as oral tetracycline 250
“Combination therapy” for acne is gener-
Two fixed combination gels, the first con-
ally defined as ongoing treatment with two or
taining erythromycin 3% with benzoyl peroxide
more agents applied at different times. Com-
5% and the second containing clindamycin 1%
monly, a topical antibiotic is applied in the
with benzoyl peroxide 5%, have been found to
morning and a keratolytic agent is applied at
be superior to their individual components for
bedtime. Because antibiotic-resistant P. acnes
acne treatment (32, 39, 40). An added advan-
and staphylococci are well documented (29,
tage of these combinations may be a reduction
30), a better regimen might be twice-daily an-
in drug-resistant P. acnes
(29). Erythromycin is
tibiotic followed by a keratolytic agent at bed-
also available as a 2% solution with zinc, a sup-
time. If two agents are applied at the same
pressor of inflammation. A recent study sug-
time, care must be taken to ensure that the two
gests that zinc may act mainly as an inhibitor to
are compatible and that they are not thereby di-
penetration, leaving the antibiotic on the skin
luted to ineffective strengths. For example,
surface longer (41). The clinical correlate of
tretinoin is inactivated by benzoyl peroxide,
while adapalene and tazarotene are not.
Other topical antibiotics that are useful in
acne treatment include metronidazole, elemen-
tal sulfur and sulfur compounds. These may actmainly as direct inhibitors of inflammation;
Benzoyl peroxide is a potent bactericidal
they are generally considered to be more useful
agent that is widely available in prescription
in treating acne rosacea, a condition with early
and non-prescription acne products, including
inflammation, than true acne, which starts with
gels, lotions and cleansers. In concentrations of
2.5 – 10%, it effectively reduces P. acnes
andfree fatty acids in sebum (31). There is evi-
dence that it reduces comedones (14, 32), in ad-dition to improving inflammatory acne (33).
There has been little change in systemic an-
tibiotic therapy for acne in recent years. Oral
and bleaching of the skin and fabrics. Occa-
drugs are indicated for moderate-to-severe
sionally, true contact allergy occurs. Recent
forms of acne, particularly those with a poten-
concerns that benzoyl peroxide enhances car-
cinogenesis in laboratory animals (34) are
Effective systemic therapies for acne in-
thought to be of little relevance to humans by
clude: tetracycline and its relatives minocycline
and doxycycline; erythromycin; azithromycin;
Vol. 68 Nos. 4 & 5
and trimethoprim alone or in combination with
nation has low intrinsic androgenicity and min-
sulfamethoxazole (42). Traditionally, systemic
antibiotic treatment has been initiated in the
modest-to-low-dose range, which is then ta-
during treatment with norgestimate/ethinyl estra-
pered over a period of weeks to months. It may
diol might take 3 – 4 months to become apparent
be time to reconsider this strategy, in recogni-
(49). The principal adverse effect noted in this
tion of the increase in antibiotic-resistant bacte-
study was nausea. As expected, OC treatment
ria, which occurs not only in acne patients, but
was protective against pregnancy and appeared
also in their household contacts (29). A sug-
to alleviate dysmenorrhea, which was more com-
gested alternative is full-dose antibiotic treat-
mon in the control group. The chief limitation of
ment for 2 – 3 weeks, given at several-month in-
anti-androgen therapy for acne is the obvious
one: it cannot be used with male patients.
An alternative drug for treating hormonal
fects, the most notable in this category being:
acne in women is spironolactone (51), which
phototoxicity from the tetracycline group, espe-
can be combined with OC therapy. Other anti-
cially doxycycline; vertigo-like dizziness from
androgenic therapies that may prove useful in
minocycline; gastrointestinal distress from ery-
the future include cyproterone acetate, flu-
tamide, finasteride, and gonadotropin-releasing
Stephens-Johnson syndrome, from trimetho-
prim-sulfamethoxazole. In addition, all oral an-tibiotics predispose to Candida
A recent study of the safety of the tetracy-
All of the treatments mentioned previously
cline-related antibiotics showed minocycline to
can be used with some success in severe, nodu-
have a greater tendency than tetracycline and
locystic acne. Particularly useful are oral an-
doxycycline to cause rare adverse effects, in-
tibiotics combined with topical keratolytic
cluding hypersensitivity reactions, serum-sick-
agents, as well as hormonal therapy in women.
ness-like reactions, drug-induced lupus, and
While oral and intralesional corticosteroids are
single organ failure (43). While minocycline is
useful as temporary measures to help control
generally considered safe for long-term use
severe outbreaks (54), chronic corticosteroid
(44), these rare but serious reactions, as well as
its higher cost, must be taken into account.
Numerous studies have shown a direct cor-
isotretinoin (13-cis-retinoic acid) remains the
relation between serum androgen levels and
treatment of choice for recalcitrant nodulocystic
acne (45, 46). Androgens increase sebaceous
acne and the more severe variant, acne conglo-
gland activity and may also cause hyperkerato-
bata (55). Isotretinoin causes de-differentiation
sis of the pilosebaceous gland (47). It has also
of the sebaceous gland, suppressing sebum pro-
been hypothesized that sebaceous glands of
duction to pre-adolescent levels (56). As with
acne-prone individuals are hyperresponsive to
other retinoids, it also promotes shedding of
keratinocytes. In addition, colonization with P.
subsides, due to disappearance of sebum.
successfully in acne treatment for decades, this
Isotretinoin’s clinical effect on acne is dra-
mode of therapy for female patients made a re-
matic, often reducing lesion counts by 90% or
cent breakthrough. For the first time, in 1997,
more within three months. Its results are pro-
the FDA approved a triphasic, combination oral
longed, with one 20-week course producing sig-
contraceptive (OC), which contains norgesti-
nificant improvement for 3 years or longer in
mate 0.215 mg and ethinyl estradiol 0.035 mg,
to be used specifically for acne treatment. This
The usual dosage range of isotretinoin is
decision followed a large, multicenter study
0.5 – 2.0 mg/kg/day. Studies have shown doses
which showed that this OC reduced acne lesion
as low as 0.1 mg/kg/day to be effective, but
counts by more than 50% in female subjects,
acne relapse rates are high, approaching 50%,
compared with lesion reductions of about 26%
at this dose (58). As a predictor of the final out-
in controls (49). The progestin in this combi-
come, researchers have observed that the 20-
week cumulative dose is more important than
Patients on isotretinoin may experience a
the daily dose. In 1997, a consensus regarding
temporary flare-up of acne after 2 – 4 weeks of
isotretinoin dosage was reached among interna-
therapy. As is the case with topical retinoids,
tional acne experts (59). Their guidelines rec-
gradual introduction of the drug, along with pa-
ommend a cumulative dose of 120 mg per kilo-
tience, usually leads to a favorable outcome. A
gram of body weight over a single 20-week
rare but troubling event that may occur during
course of therapy, using the original oral formu-
isotretinoin therapy is the onset of acne fulmi-
lation of isotretinoin. Currently, an ultrami-
nans (65). This condition is a painful, severe
cronized form of oral isotretinoin is being intro-
exacerbation of cystic acne with exuberant
duced for the purpose of more efficient absorp-
granulation tissue and scarring. Acne fulmi-
tion of the active ingredient. It is unclear how
nans can be managed with variable success by
this new product may impact dosing guidelines.
temporarily decreasing the isotretinoin dose
Because isotretinoin has a half-life of 10 – 20
and treating concurrently with a short course of
hours, 24-hour dosing intervals are adequate, but
systemic corticosteroid (66). Dapsone may also
twice-daily dosing may reduce side effects.
Tetracycline derivatives and vitamin prepa-
course of isotretinoin, practitioners who follow
rations containing vitamin A should be avoided
cumulative dosing guidelines may choose to vary
during isotretinoin therapy, since these medica-
the length of treatment slightly. FDA guidelines,
tions may increase the risk of pseudotumor
however, still include an 8-week drug-free period
cerebri (44), a rare side effect of isotretinoin.
isotretinoin are its teratogenicity and its effect
sense supports the concept of “pulse-dosing”
on serum lipids. The former cannot be overem-
with isotretinoin. It is likely that the risk of ter-
phasized: the risk of birth defects mandates
atogenicity, isotretinoin’s most serious side ef-
careful patient selection, contraceptive counsel-
fect (60), would increase when drug treatment
ing, and strict monitoring of women who may
is prolonged, interrupted or inadequately moni-
become pregnant. Isotretinoin is not muta-
tored. In a recent study of intermittent dosing
genic, and federal guidelines suggest that preg-
with isotretinoin for one week each month over
nancy is safe one month after drug cessation.
6 months, resolution of acne was impressive,
about 90%, but the 12-month relapse rate was
isotretinoin therapy due to its teratogenic po-
tential. Two negative pregnancy tests are now
Adverse effects from isotretinoin are seen
required prior to initiation of isotretinoin ther-
in virtually 100% of its users but generally sub-
apy, and monthly testing is mandatory for sexu-
side one to three weeks after cessation of ther-
ally active females during treatment.
Serum lipid and lipoprotein alterations are
branes, and chapped lips (retinoid cheilitis) are
common, with elevation of triglycerides being
universal at therapeutic doses. Patches of
reported most frequently (67). Mean triglyc-
eczema (retinoid dermatitis) occur commonly,
eride levels have been shown to increase by
typically on the dorsal hand and forearm.
about 50% within 2 – 3 months on the drug, and
These complaints are managed with moisturiz-
cholesterol by about 15%. Overweight patients
ers, greasy topical corticosteroids, and dosage
have an increased risk of isotretinoin-induced
adjustment, if necessary. Skin fragility and sus-
hypertriglyceridemia. Blood work, including
ceptibility to sunburn are frequently reported.
fasting triglyceride and cholesterol levels,
Dry eyes, nosebleeds, hair shedding, myalgias
should be performed at baseline and at 2 – 4
week intervals during isotretinoin therapy (56).
Recently, several cases of psychological de-
Isotretinoin has been linked with premature
pression and even suicide have been reported
closure of the epiphyses of long bones in labo-
among patients taking isotretinoin (62). Para-
ratory animals (63). For this reason, some
doxically, previous studies had shown an im-
physicians prefer to reserve its use for patients
provement in well-being and self-esteem (63).
past their growth spurt. A baseline serum alka-
Whether isotretinoin plays a causal role with re-
line phosphatase level is often helpful to assess
gard to these symptoms is unclear, as a recent
the level of adolescent bone growth.
large, population-based study failed to show an
increased risk of depression in isotretinoin
isotretinoin treatment occurs in a significant
users compared with other acne patients (64).
Vol. 68 Nos. 4 & 5
within three years (57). Patients at particular
risk for recurrence are adolescents under the
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age of 18, women with hormonal acne (68), and
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patients whose cumulative dose is less than 100
2. Peck GL, Olsen TG, Yoder FW, et al. Prolonged remissions of
mg per kilogram (57). Relapses are usually
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minor and can be managed with conservative
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Discussion and Summary
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the patient may not understand or comply with
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the treatment regimen. And finally, the perfect
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drug for acne — one that is safe and efficacious
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for all varieties of the disorder — does not exist.
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Effective physician-patient communication is
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crucial if any regimen is to provide its maxi-
mum benefit. Patients must be educated to
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apply topical therapies to nonlesional skin as
well as to blemishes, and to understand that all
17. Gibson JR. Rationale for the development of new topical treat-
acne medications are essentially prophylactic.
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They should also be taught the importance of
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continuing treatment when the condition is at
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its best. Using topical and oral antibiotics in an
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may be. Topical therapy should be relied upon
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cacy and safety of adapalene gel 0.1% and tretinoin gel
when possible, to minimize side effects. Com-
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topical antibiotic is a rational approach. While
22. Data on file, Allergan Inc., 2525 Dupont Drive, Irvine, CA
oral antibiotics have an important role, care
must be taken to avoid their haphazard use.
23. Bershad S. Treatment of acne vulgaris with a novel short-con-
Isotretinoin has revolutionized acne therapy.
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Its use requires expert patient selection, educa-
emy of Dermatology. New York, Jul 1999.
tion, and monitoring. Until the next generation
24. Bojar RA, Holland KT, Cunliffe WJ. The in-vitro antimicrobial
of therapeutic options is realized, isotretinoin
effects of azelaic acid upon Propionibacterium acnes strain
remains the choice for difficult cystic acne.
P37. J Antimicrob Chemother 1991; 28(6):843 – 853.
25. Graupe K, Cunliffe WJ, Gollnick HP, Zaumseil RP. Efficacy and
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safety of topical azelaic acid (20 percent cream): An
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ASSESSMENT Applicant Name: ___________________________________________ Date: __ __ / __ __ / __ __ __ __ Notes: _______________________________________________________ _______________________________________________________ _______________________________________________________ _______________________________________________________ _____________________________________________
Pharmaceutical analysis and Quality control Ph-343 Submitted to: Submitted by: Date of submission: 20 – 02 - 07 APPLICATIONS OF HPLC 1.The wide verity of packing materials allows the separation ofmost chemical species. Chemical Separations can be accomplished using HPLC by utilizing the fact that certain compounds have differentmigration rates given a particular co