Thu rnate,iaI nity be protected by Copyright to, Title 12 us. Code)
`
`DECEMBER 2012 (cid:9)
`
`1417 (cid:9)
`
`VOLUME 11
`
`(cid:149) Issui: 12
`
`CoI’YRIGIIT (D 2012 (cid:9)
`
`[/’.t (cid:9)
`
`l’h1t1 (cid:9)
`
`JOURNAL Oil Douns IN Di:luviAIoLoc;y
`
`The Efficacy and Tolerability of Dapsone 5% Gel in
`Female vs Male Patients With Facial Acne Vulgaris:
`Gender as a Clinically Relevant Outcome Variable
`
`Emil Tanghetti MD,’ Julie C. Harper MD," and Michael G. Oefelein MD(cid:176)
`’Center for Dermatology and Laser Surgery Sacramento, CA
`5T11c Dent a tol ogy a Id Skin Care Center of Birmingham, Birmiti i ighaiti, AL
`’l)igiftad Corporation, POwa) CA
`
`Background: Gender differences in skin and acne have been reported.
`Objective: To evaluate the effect of gender on the efficacy and tolerability of dapsone 5% gel.
`Methods:This was a pooled analysis of data from 2 identical phase 3 randomized, double-blind, and vehicle-controlled trials (DAP0203
`and DAP0204) of dapsone 5% gel conducted in the United States and Canada between November 2002 and September 2003. A total
`of 2,898 patients with acne vulgaris were included in the pooled analysis. Of these, 1,453 patients (753 female, 700 male) received
`dapsone 5% gel twice daily, and 1,445 patients (767 female, 678 male) received vehicle twice daily. End points included the mean
`percentage reduction from baseline in acne lesion counts and the proportion of patients achieving clinical success (Global Acne Assess-
`ment Scale score of 0, clear skin, or 1, almost clear skin). Assessments were performed at baseline and at weeks 2, 4, 6, 8, and 12.
`Results: The mean percentage reduction in acne lesion counts at 12 weeks was significantly greater in females than males in both
`treatment groups.The mean reduction in total lesion counts in dapsone-treated females and males was, respectively, 46.6% vs 35.8%
`)Puz.0001). Seductions in papulopustular and comedonal lesion counts were likewise significantly higher in female than male patients
`(each P<.0001). Significantly more dapsone-treated females than males achieved clinical success (48.6% vs 34.4%; P=.0003),
`Conclusion: The response to dapsone 5% gel appears to be influenced by gender, with female patients experiencing a significantly
`greater reduction in acne lesion counts and a significantly higher clinical success rate following 12 weeks of treatment. These data sug-
`gest that gender is a novel predictor of outcome that should be considered in acne clinical trial design and analysis.
`
`J Drugs Dermato/. 2012:11(12):1417-1421.
`
`riNTRODUCTION1
`
`Acne is a very common disease that remains prevalent
`
`in adults, with more adult women being afflicted than
`adult men.’ This raises the intriguing possibility that
`gender differences in skin may influence acne pathogenesis and
`response to acne treatment. Indeed, gender differences in skin,
`both its function and structure, have been the focus of consider-
`able research to understand more about skin disease pathogen-
`esis and response to treatment. For example, gender differences
`in skin surface pH have been reported, although findings have
`been inconsistent .2-7 It has also been shown that males have
`thicker skin than females,’ while females have thicker subcutane-
`ous tissues than males. 9 Skin thickness tends to decrease with
`age, especially in women, suggesting that estrogens play a role
`in maintaining skin, 10 Estrogens also have been implicated in
`regulating the composition of stratum corneum sphingolipids t1
`and cutaneous protein’ and in decreasing sebum production. 12 ’ 12
`In contrast, androgens appear to increase sebum production, 14
`possibly by influencing cell proliferation and lipogenesis in the
`sebaceous gland. 14 Sebum production and sebaceous gland ac-
`tivity are major factors in acne lesion development.
`
`Dapsone is an anti-inflammatory agent that, in the 5% gel for-
`mulation, is an effective topical treatment for patients with acne
`
`vulgaris. 15 It has been studied and found to be effective for at
`least 12 months of treatment 16 and to reduce comedonal as well
`as papulopustular acne lesions when used as monotherapy 15 or
`in combination with a retinoid. 1718 During clinical trials of dap-
`sone 5% gel, some investigators observed a greater acceptance
`and efficacy of the product in female patients vs in male pa-
`tients. Given this observation, and previously reported gender
`differences in skin and acne," we explored whether gender im-
`pacts the efficacy and tolerability of dapsone 5% gel.
`
`Patients, Treatment, and Assessments
`The two 12-week, double-blind trials (DAP0203 and DAP0204) en-
`rolled patients 12 years and olderwith facial acne vulgaris. Patients
`had 20 to 50 papulopustular lesions and 20 to 100 comedones
`above the mandibular line at baseline. Other exclusion criteria
`and study design details are reported in the original study publica-
`tion. 15 Patients were randomized 1:1 to receive either dapsone 5%
`gel or vehicle gel. Assessments were performed at baseline and at
`weeks 2, 4, 6, 8, and 12. The following parameters were analyzed
`and compared in female vs male patients at all time points: the
`mean percentage reduction from baseline in acne lesion counts
`(papulopustular, comedonal, and total); the proportion of patients
`
`This matt! riaI wacped
`at the NLM and maybe
`Subjat USCopyright Laws
`
`AMN1035
`Amneal v. Almirall, LLC
`IPR2018-00608
`
`1
`
`

`

`JOURNAL OF DRUGS IN DERMATOLOGY (cid:9)
`Issue 12
`VOLUME 11
`DocuMuluf 2012
`
`(cid:149)
`
`E.Tanghetti,J. Harper, M . G. OefeIeuI
`
`1418
`
`FIGURE 1. Mean percentage reduction in lesion counts from baseline
`to 12 weeks. NS, not significant.
`
`a)PapulopustUlar lesions
`
`Statistical Analyses
`Data from 2,898 patients in both studies were combined for
`the statistical analyses, One hundred and twelve patients were
`excluded from the analysis because of an absence of posttreat-
`ment efficacy data.
`
`0
`
`10
`
`20
`
`30
`
`40
`
`50
`
`60
`
`70
`
`5
`
`0 (cid:9)
`
`2 (cid:9)
`
`4 (cid:9)
`
`6 (cid:9)
`
`8 (cid:9)
`
`10 (cid:9)
`
`12
`
`Duration of Treatment (weeks)
`
`Pvalues (dapsone vs vehicle)
`
`Female (cid:9)
`
`MOe (cid:9)
`
`OS (cid:9)
`
`002 (cid:9)
`
`OS (cid:9)
`
`.007 (cid:9)
`
`145 (cid:9)
`
`001 (cid:9)
`
`0003 (cid:9)
`
`.0003 (cid:9)
`
`P values (male vs female)
`
`Vehicle (cid:9)
`
`Oacsv’e (cid:9)
`
`c0001 (cid:9)
`
`’0001 (cid:9)
`
`’0007 (cid:9)
`
`v 0007 (cid:9)
`
`v 000 1 (cid:9)
`
`’0001 (cid:9)
`
`’.0001 (cid:9)
`
`v.0001 (cid:9)
`
`bI Comedonal lesions
`
`1
`
`ce
`
`5
`
`t
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`40
`
`-.--- Dapsove (mole)
`-0--- Vehicle (female)
`- fl
`- - Vehicle (male)
`
`0
`
`2 (cid:9)
`
`.01
`
`.0002
`
`’0001
`
`v.0001
`
`12
`
`Lesion reduction data were analyzed using a longitudinal mixed-
`710% net reduction; P’ 0002 (male) effect repeated-measures analysis of covariance model, which
`4.8% not reduction; P.0138(femvla) also established the suitability of pooling the data from the 2
`clinical trials. Data for GAAS and for local signs and symp-
`toms were analyzed based on a repeated-measures logistic
`reoressien mnrlwl. 15, modified Past observ ation carried forward
`(i) continu-
`(LOCF) approach was used to impute missing data:
`ous parameters-for week 2 missing data, the average between
`baseline and week 4 data were used; for all other weeks of mea-
`surement, LOCF was used; (ii) discrete parameters-LOCF was
`used for all weeks. For all analyses, outcomes were considered
`significant if P<.05.15
`
`00.7% 7011 reduction; P ’.0001 (male)
`
`i:’taJ1:iJ
`Patient Disposition and Baseline Characteristics
`Of the 2,898 patients included in the pooled analysis, 1,453 (753
`female, 700 male) received dapsone 5% gel twice daily, and
`1,445 patients (767 female, 678 male) received vehicle twice
`58% net reduction: P’ .0154 (female) daily. The treatment groups were similar with respect to the
`distribution of males and females (Table 2). Males had a high-
`er mean total lesion count at baseline than females (83.00 vs
`74.06 in the vehicle gel group, and 84.01 vs 74.25 in the dapsone
`gel group) and tended to have a higher baseline GAAS score
`(proportion of patients with GAAS score ~:2: 96.8% vs 92.8%
`[vehicle] and 95.4% vs 94.3% [dapsone]).
`
`Lesion Counts
`The mean percentage reduction in all acne lesion counts from
`baseline to 12 weeks was significantly greater in females than
`males in both the dapsone-treatment and vehicle-treatment
`groups (Figure 1). In dapsone-treated patients, the mean per-
`centage reduction in total lesion counts was 46.6% in females
`g.1% net reduction; Pc 0001 (mele( and 35.8% in males (Psz.0001). Correspondingly, the percentage
`reduction of papulopustular lesions at 12 weeks was 56.8% in
`dapsone-treated females and 43.2% in dapsone-treated males
`)P<,0001). Reductions at 12 weeks in comedonal lesions were
`39.8% and 28.5% in females vs males, respectively, in the dap-
`sone-treatment group (P<.0001).
`
`bO% net reduction: P=. 0029 (female)
`
`In female patients at week 12, dapsone 5% gel elicited signifi-
`cantly greater reductions in papulopustular (4.83%, P=.0138),
`comedorial (5.90%, P=,0154), and total (5.51%, P00.0029) le-
`sion counts than vehicle gel. In male patients at week 12, the
`treatment differences also favored dapsone, but with greater
`(P<.0001), and 9.72%
`reductions of 7.56% (Pm,0002), 10.7%
`(P<.0001)
`in papulopustular, comedonal, and total lesion
`counts, respectively.
`
`.02
`
`’0001
`
`’0001
`
`v.0001
`
`10
`6 (cid:9)
`8 (cid:9)
`4
`Duration of Treatment (weeks)
`
`P values (dapsone vs vehicle)
`Fvivvlv
`
`40 (cid:9)
`
`OS
`
`Mile
`
`IS (cid:9)
`
`NO
`
`P values (male vs female)
`
`NS (cid:9)
`
`003 (cid:9)
`
`NO
`
`008
`
`Vahille. (cid:9)
`
`010,0101
`
`.0101
`
`55
`
`0003
`
`vOcO, (cid:9)
`
`’000’
`
`.0754
`
`.0014 (cid:9)
`
`.0002
`
`c) Total lesions
`
`10
`
`20
`
`30
`
`40
`
`50
`
`C
`5
`0.
`6 (cid:9)
`
`:i
`0 (cid:9)
`- -(cid:176) (cid:9)
`
`:::
`Vehicle )loivalo(
`Vehicle (male(
`
`0
`
`2
`
`6
`10
`8 (cid:9)
`4
`Duration of Treatment (weeks)
`
`12
`
`P valueS (dapsOfla vs vehicle)
`NO
`NO
`
`Femlv
`
`Mile.
`
`.02
`
`.00
`
`NO
`
`0002
`
`0’
`
`0001
`
`P values (male vs lernale(
`0,11,1,
`0101
`
`.0003.0001v.0001
`
`Oii,vilcv
`
`OS
`
`01004
`
`,000l
`
`c 11001
`
`.003
`
`v.0001
`
`’0001
`
`’0001
`
`achieving treatment success (Global Acne Assessment Scale
`[GAAS] score of 0 [none] or 1 [minimal];Table 1), and the pro-
`portion of patients without local signs and symptoms (erythema,
`
`oiliness, dryness, or peeling).
`
`This materiel W3COhied
`atthe fILM and may be
`Subject USCapyr(ght Laws
`
`2
`
`(cid:9)
`(cid:9)
`

`

`JOURNAl. Oil Diwes IN DERMATOlOGY (cid:9)
`(cid:149) VoluME 11 (cid:149) ISSUE 12
`DECEMBER 2012
`
`E.Tanglietti,J, Harper, M.G. Oefelein
`
`1419
`
`GAAS Incidence of Treatment Success
`A significantly greater proportion of female patients achieved
`treatment success (as indicated by a GAAS score of 0 or 1) com-
`pared with male patients in both treatment arms (Figure 2).The
`treatment success rate in females and males, respectively, was
`48.6% vs 34.4% (P=.0003) with dapsone 5% gel and 39,4% vs
`28.0% (P=.0013) with vehicle gel.
`
`The within-gender treatment difference (dapsone gel - vehicle
`gel) in the proportion of patients achieving treatment success
`was 9.2% in females (P=.0001) and 6.4% in males (P=.0010).The
`odds ratio for treatment success in dapsone-treated vs vehicle-
`treated patients was 1.61 in females (96% confidence interval
`Id], 1.26-2.06) and 1.56 in males (95% Cl, 1.20-2.03).
`
`Tolerability
`The proportion of patients with erythema, dryness, peeling, or
`oiliness was low, regardless of gender or treatment group. Ery-
`thema and oiliness decreased from baseline over the 12 weeks
`of treatment in both treatment groups and for both female and
`male patients. The occurrence of erythema, dryness, peeling,
`or oiliness was similar between males and females and did not
`differ significantly by treatment arm, regardless of time point
`(F.05 at 12 weeks) (Figure 3).
`101 E19LIM[O]It1
`The findings of this pooled analysis indicate that females with
`acne responded better than males to dapsone 5% gel. Female
`patients experienced a significantly greater reduction from
`baseline in acne lesion counts and a significantly higher clinical
`success rate at 12 weeks compared with males. For all efficacy
`outcomes, the vehicle was also found to have a beneficial ef-
`fect, albeit to a significantly lesser degree than the dapsone 5%
`gel, again with females being more responsive than males.
`
`FIGURE 2. Treatment success rate (assessed by Global Acne As-
`U Male (cid:9) (cid:149) Female
`sessment Scale [GAAS]).
`
`P= .0001
`
`I
`
`P (cid:9)
`
`.0010
`
`I
`
`(cid:149).: J34.49/6
`
`Vehicle
`
`Dapsone
`
`a
`
`60 1
`I (cid:9)
`U 501
`
`.
`
`40
`
`II 0
`
`TABLE 1.
`
`I -
`itr4.i.
`
`Minimal (cid:9)
`
`Failure (cid:9)
`
`2 (cid:9)
`
`Mild (cid:9)
`
`3 (cid:9)
`
`Moderate (cid:9)
`
`4 (cid:9)
`
`Severe (cid:9)
`
`I
`"’facialI..-
`
`r-
`
`A few comedones are
`present; a few papulopustular
`lesions may be present
`
`Several/many comedones are
`present; a few papulopustular
`lesions are present
`
`Many comedones and
`papulopustular lesions are
`present; nodulocystic lesions
`are allowed
`
`Significant degree of
`noncomedonal disease;
`papules/pustules are a
`predominant feature; a few
`nodulocystic lesions may be
`present; many comedones
`may be present
`
`The reasons for the gender difference in response observed in this
`study are not clear, and there have been no previously published
`reports of gender-based analyses from other acne clinical trials
`to inform our interpretation of the findings. However, possible
`reasons for the gender difference in response include differences
`between men and women with respect to treatment adherence,
`differences in lesion scoring for men vs women, unknown/unchar-
`acterized dapsone-hormone interactions, differences in male and
`female physiology, and differences in acne pathology between
`men and women related to their physiological differences.
`
`Gender has been identified as a potential source of nonadher-
`20
`ence with treatment and may explain our current findings.
`Some evidence suggests that female patients are more com-
`pliant with acne treatment than male patients . 2023 A recent
`literature review by Lott and colleague S 24 examined medication
`adherence in teenagers with acne and described a weak asso-
`ciation between poorer adherence and male gender.
`
`Adverse events are another source of flOnadherence. 25 Some
`authors have observed that local side effects of topical therapy,
`such as cutaneous irritation, erythema, dryness, peeling, and
`scaling, can lead to poor patient compliance .21,11 In the present
`analyses, the tolerability of dapsone 5% gel did not differ be-
`tween males and females.
`
`Differences in cleansing care practices between males and females
`also may have contributed to the differential response to treat-
`ment. Skin cleansing, perhaps as part of a cosmetic routine, may
`be more strictly followed by females than males. All patients in this
`study were required to wash daily with a standard noncomedo-
`genic, soap-free cleanser before application of study medication.
`
`An intriguing alternative explanation for the observed gen-
`der difference in response to dapsone 5% gel is the possibility
`of a difference between males and females in underlying acne
`
`This material was cGpied
`at the NLM and may be
`Subject USopyright Laws
`
`3
`
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`JOURNAL UI’ DRUGS IN 1)l;nr1A10LoGy (cid:9)
`1)Lc[;MIIRIf 2012 (cid:149) VOLUMI: 11 (cid:149) IssuE 12
`
`E.Tanghetti,J. Harper, MG. Oefeleitt
`
`1420
`
`TABLE 2.
`
`Sex, n (%)
`
`Female
`
`Male
`
`FIGURE 3. Incidence of adverse events at 12 weeks: dapsone 5%
`gel vs placebo,
`
`- (cid:9) ....................... ,.... (cid:9) .;;
`
`(cid:149) i.._I
`
`a)
`
`767 (53.1)
`
`678 (46.9)
`
`753 (51.8)
`
`700 (48.2)
`
`25 - (cid:9)
`
`20
`
`-.---. Dapsone (female) ---Dapsone (male)
`--- o- -- Vehicle (female) (cid:9)
`. . -. Vehicle (male)
`
`28.17 – 0.30
`
`32.95 – 0.43
`
`28.18 – 0.31
`
`33.61 – 0.41
`
`45.89 – 0.81
`
`50.06 – 0.93
`
`46.07 – 0.86
`
`50.40 – 0.94
`
`74.06 – 0.92
`
`83.00 – 1.10
`
`74.25 – 0.98
`
`84.01 – 1.08
`
`Cu
`CL
`
`b)
`
`C
`
`Duration of Treatment (weeks)
`
`25 (cid:9)
`
`-’-.---- Dapsone (female) -s--- Dapoone (male)
`-0---- Vehicle (female) _o - -- Vehicle (male)
`
`Lesion counts, mean – SE
`
`Papulopustular
`
`Female
`
`Male
`
`Comedonal
`
`Female
`
`Male
`
`Total
`
`Female
`
`Male
`
`GAAS scores, in 1%)
`
`0 or 1
`
`Female
`
`Male
`
`Female
`
`Male
`
`55 (7.2)
`
`22 (3.2)
`
`43 (5.7)
`
`32 (4.6)
`
`712 192,81
`
`656 (96.8)
`
`710 (94.3)
`
`668 (95.4)
`
`GAAS Global Acne Assessment Scale; SE, standard error.
`
`pathology. Dao and Kazinta suggested that hormonal interac-
`tions contribute substantially to the gender differences in acne,
`notably, sebum production, which plays a key role in the devel-
`opment of acne. It is increased by androgens and decreased
`by estrogens. Moreover, both components of sebum and their
`perox)dation products, as well as androgens, have putative
`immunomodulatory effects, 2830 which may impact the inflamma-
`tory component of acne pathology in males. Increased sebum
`production and a modified inflammatory response, in turn, may
`lead to the development of acne in males that is more severe and
`refractory to treatment. Interestingly, on average, the male pa-
`tients in this study did present at baseline with more comedonal
`and papulopustular acne lesions than their female counterparts.
`
`Notably, female patients in this study not only responded better
`than males to dapsone therapy, but also responded better to the
`vehicle gel.The reason for this unknown, but the findings suggest
`an action of the vehicle gel on skin that is more robust in females.
`The dapsone 5% gel vehicle contains diethylene glycol monoethyl
`ether (DGME), an organic solvent, which may favorably impact so-
`bum composition and oiliness. Indeed, DGME has been found to
`
`0246 (cid:9)
`8 (cid:9)
`Duration of Treatment (weeks)
`
`10 (cid:9)
`
`12
`
`---- Dapsone (female) (cid:9) (cid:149) Dapsone (male)
`Vehicle (female) (cid:9)
`Vehicle (male)
`
`Duration of Treatment (weeks)
`
`1012
`
`C)
`
`25 (cid:9)
`
`20
`
`Q_ 5, c 15
`W o
`i’.t: (cid:9)
`
`10
`
`5
`C.,
`Cu
`CL
`
`d)
`
`25 (cid:9)
`
`---- Dapsone (female) -.---Dapsone )male)
`Vehicle (female) (cid:9)
`_o... Vehicle (male)
`
` 20
`
`h
`
`5,0.
`
`10
`
`e
`
`CL
`
`0
`
`0 (cid:9)
`
`2 (cid:9)
`
`6 (cid:9)
`8 (cid:9)
`4 (cid:9)
`Duration of Treatment (weeks)
`
`10 (cid:9)
`
`12
`
`This material was copied
`at the NLM and may be
`Subject USCopyright Laws
`
`4
`
`(cid:9)
`

`

`JOURNAL OF l)itijcs IN 1)1/ItMA1OLOCY
`l)ticnsiirrir 2012 (cid:149) VOLUME 11 (cid:149) Issull 12
`
`E.Taiighettr,J. Harper, M.G. Oefclein
`
`1421
`
`increase the water solubility of waxy substances, such as polyoxy-
`ethYlene -2- stearyl ether 31 Hypothetically, a similar dissolution of
`sebum fatty acids in the skin may confer a clinical benefit in acne,
`the magnitude of which may be greater in females than in males.
`
`The results of this analysis are intriguing but must be consid-
`ered within the limitations of the analysis.The analysis was post
`hoc, Moreover, differences were apparent between males and
`females regarding the magnitude of the drug effect relative to
`the placebo effect, with a greater mean treatment difference re-
`ported for male patients. How these variations in response may
`have contributed to the findings of this analysis is not known.
`
`"Female patients experienced a
`significantly better response to dapsone
`5% gel than male patients."
`
`In conclusion, female patients experienced a significantly better
`response to dapsone 5% gel than male patients. Further as-
`sessment of skin differences between genders is necessary to
`more clearly understand varying treatment outcomes between
`males and females. Nonetheless, these data suggest that pa-
`tient gender may be a novel predictor of outcome that should
`be considered in acne clinical trial design as well as analysis.
`
`[ACKNOWLEDGMENTS]
`The authors gratefully acknowledge Drs. Steven Feldman and
`Guy Webster for their reviews and insightful evaluations of the
`rnanuscript.The authors also thank Bianca Ruzicka PhD ofApothe-
`Corn for her contributions to the development of this manuscript.
`rDIscIOsuREsII
`Dr. Tanghetti is an investigator and speaker for Allergen and Ste-
`ifel Laboratories and a consultant and speaker for Galderma
`Laboratories. Dr. Harper is a consultant, advisor, and speaker for
`Allergan; an advisor and speaker for Coria Laboratories and Gal-
`derma Laboratories; a speaker and investigator for lntendis an
`investigator for Medicis; and a consultant and speaker for Steifel
`Laboratories. Dr. Oefelein is a former employee of Allergan and
`was an employee at the time the analyses were performed.Third -
`party medical writing assistance, supported by Allergan, Inc, was
`used in the preparation of this paper. Allergan also funded the
`statistical analyses of this substudy. The pivotal trials on which
`this substudy was based were originally sponsored by Fujisawa
`Healthcare, Inc. and QLT USA, Inc. Laboratories.
`
`4.
`
`5.
`
`6.
`
`7 (cid:9)
`
`8. (cid:9)
`
`9,
`
`12.
`
`14.
`
`16.
`
`17 (cid:9)
`
`18,
`
`Blank IH. Measurement of pH on the skin surface, II. pH of the exposed sur -
`faces of adults with no apparent skin lesions. J Invest Dermatol, 1939:2:75-79.
`Jacobi U, Gautier J, Sterry W, Lademann J. Condor-related differences in the
`physiology of the stratum corneum. Dermatology. 2005;211 41:312-317
`Kim MK, Patel RA, Shinn AH, et at. Evaluation of gender difference in skin type
`and pH J Dermato( Sc!. 2006;41(2):153-156.
`Ehlers C, Ivens UI, Moller ML, SenderovitaT, Setup J. Females have lower
`skin surface pH than men. A study on the surface of gender, forearm Site
`variation, right/left difference and time of the day on the skin surface pH
`Skin Rex Techno/. 2001:7(2):90-94.
`Seidenari S. Pagnoni A, Di Nardo A, Giannetti A. Echographic evaluation with
`image analysis of normal skin: variations according to age and sex. Skin P/rat-
`macof. 1994:7141:201-209.
`Sjdstrdm L, Smith U. Krotkiewski M, Bjbrntorp P Cellularity in different regions of
`adipose tissue in young men and women. Metabolism. 1972:21(12):1143-1153.
`Rolognia JL. Aging skin, Am Med. 1995:98ltAt99S-103S.
`10,
`11. Denda M, Koyama J, Hori J, et al, Age- and sex-dependent change in stratum
`corneum sphingolipids. Arch Dermatol Res. 1993:285(7):415-417
`Strauss JS, Kligman AM, Pocfni PE. The effect of androgens and estrogens on
`human sebaceous glands. J Invest Dermatol. 1962:39:139-155.
`13, Guy R, Ridden C, KealeyT. The improved Organ maintenance of the human
`sebaceous gland modeling in vitro the effects of epidermal growth factor,
`androgens, estrogens, 13-cis-retinoic acid, and phenol red. J Invest Derma-
`tot. 1996:106131:454-460.
`Pool PE, Strauss JS, Downing DT Age-related changes in sebaceous gland
`activity. J Invest Dernratol. 1979,73(l):108-111.
`15. Draelos ZD, Caner E, Maloney JM, at at. Two randomized studies demonstrate
`the efficacy and safety of dapsone gel, 5% for the treatment of acne vulgaris. J
`Am Aced Dermatol. 2007:5613I:439.el-elO.
`Lucky AW, Maloney JM, Roberts J, at al. Dapsone gel 5% for the treatment
`of acne vulgaris: safety and efficacy of long-term (1 year) treatment. J Drugs
`Dermatol. 2007:6(10):981-987
`Fleischer AB Jr. Shalita A, Eichenfeld Ll et al. Dapsone gel 5% in combina-
`tion with adapalene gel 0.1$, benzoyl peroxide gel 4% or moisturizer for the
`treatment of acne vuigaris: a 12-week, randomized, double-blind study. J Drugs
`Dermatol. 2010:9111:3340.
`Tsnghetti B, Dhawan 5, Green L, et al. Clinical evidence for the role of a topical
`anti-inflammatory agent in cornedonal acne: findings from a randomized study
`of dapsone 5% gel in combination with tazarotene 0.1 ’/ cream in patients with
`acne vulgaris. J Drugs Dermatol, 2011:10171:783-792,
`19, Dao H Jr, Kazin RA. Gender differences in skin: a review of the literature. Gend
`Med. 2007:4141:308-328.
`Zaghloul SS, Cunliffe WJ, Goodfield MJ. Objective assessment of compliance
`with treatments in acne. Br J Dermatol. 2605:152151:1015-102 t.
`Rapp DA, Brenes GA, Feldman SR, et at. Anger and acne: implications for quality
`of Efe, patient satisfaction and clinical care. Br J Derrnatol. 2004:151(l):183-169.
`Jones-Caballero M. Pedrosa B, Penss PP Self-reported adherence to treatment
`and quality of life in mild to moderate acne. Dermatology. 2008:217141:309-314.
`Tan JK, Balagurusamy M, Fung K, et al. Effect of quality of life impact and
`clinical severity on adherence to topical acne treatment. J Cutan Med Surg.
`2009:13141:204-208.
`24, Lon R, Taylor SL, O’Neill JL, Krowchuk DIP Feldman SR. Medication adherence
`among acne patients: a review. J Cosniet Dermarol, 2010:9(2(:150-166
`Yan AC, Treat JR. Beyond first-line treatment: management strategies for main-
`taining acne improvement and compliance. Cuss. 2008:8212 suppl 11:18-25.
`Akomesh FK. Topical dermatological drug delivery: quo vsdis? Curt Drug Deliv
`2010:7(4):283-296.
`Castro GA, Ferreira LA. Novel vesicular and particulate drug delivery systems for
`topical treatment of acne, Expert Opin Drug Deliv. 2008;5l61:665.679
`28. Olsen NJ, Kovacs WJ. Gonadal Steroids and immunity. Endocr Rev
`1998:17(4).369-384.
`29. Ottaviani M, Alestes T, Flori 0, Mastrofranoesco A, Zouboulis CC, Picardo M.
`Peroxidated squelene induces the production of inflammatory mediators
`in HaCaT keratinocyles: a possible role in acne vulgeris. J Invest Dermatol
`2006:1281111:2430-2437.
`Georgel B Crozat K, Lauth X, et al. A toll-like receptor 2-responsive lipid effector
`pathway protects mammals against skin infections with gram-positive bacteria.
`Infect lmmurr. 2005;7318):4512-4521.
`31. Williams SO, Long S, Allen J, Wells ML. Scale-up of an oil/water cream contain-
`ing 40% diethylene glycol monoethyl ether. Drug Dev Ind Pdrarnr. 2000,26111:71-77
`
`20.
`
`21.
`
`22.
`
`23.
`
`25.
`
`26.
`
`27.
`
`30.
`
`Collier CN, Harper JC, Cafardi JA, et al. The prevalence of acne in adults 20 years
`and older. JAnrAcadDermatol. 2008:58111:56-59, (cid:9)
`Wilhelm KB Cua AR, Maibach HI. Skin aging. Effect on transepidermal wafer
`toss, stratum corneum hydration, skin surface pH, and casual sebum content.
`EmilTanghetti MD
`Arch Dermatol. 1991 : 127 1 12 (: 1806-180 9.
`Uhman H, Vahiquist A. In vivo studies concerning a pH gradient in human srra-
`Email’ .................................... et@dermatotogyandlasersurgery.com
`turn corneum and upper epidermis. Acta Derrrr Verrereol. 1994:74(5):375-379. (cid:9)
`This mate ria I s’as copied
`attha NLM and maybe
`Subject US Copyright Laws
`
`AUTI-JOR CORRF.SPONDENCE
`
`5
`
`

`

`DECEMBER 2012
`
`Coi’yiuct IT ' 2012 (cid:9)
`
`L
`
`1396
`t: (cid:9)
`
`VOLUME 11 (cid:149) ISSUE 12
`
`JOURNAL OF i)lw(,,s IN 1)ERMATOLOm’
`
`DEPARTMENTS (CONTD)
`1518 News, Views, & Reviews
`
`1521 Pipeline Previews
`
`1523 ClinicalTrial Review
`
`1526 Buyer’s Resource Guide
`
`JDD ONLINE available atJDDonline.com
`
`e76 A NewTreatment Regimen for Rosacea: OnabotuljnumtoxjnA
`Steven H. Dayan MD, Rachel N. Pritzker MD, and John P Arkins BS
`
`e80 Comparison of Two Techniques Using Hyaluronic Acid to Correct the Tear
`Trough Deformity
`M. Shane Ham man MD, Mitchel P Goldman MD, and Sabrina G. Fabi MD
`
`e85 Case Report: Acanthosis Nigricans Resulting From Repetitive Same-Site Insulin
`Injections
`James D. Brodell Jr MD, Jonathan D. Cannella MD, and Stephen E. Helms MD
`
`Journal of Drugs in Dermatology )JDD)
`is indexed in MEDLINE/PubMed and is published monthly by the
`Journal of Drugs in Dermatology
`377 Park Avenue South, 6th Floor, New York, NY 10016
`telephone. 212-213-5434 1 fax: 212-213-5435 I JDDonlino.corr
`
`Of Drugs
`No part of this publication may be reproduced, Stored in a retrieval system, or transmitted in electrical Or other forms or by any meant Without prior Written permission from the Journ
`for a ny
`in Dermatology JDD). This publication has been registered With the Library of Congress (ISSN: 154555161. The Publisher and the organizations appearing herein assume no espo55ib (cid:9)
`0
`the
`injury end/or damage to persons or property as a matter of product liability, negligence, or otherwise, or from any use o contaifle
`d
`15r
`Operation of any methods products. instructions, or ideas we r000m m the
`material herein. No suggested test or procedure should be carried Out unless, in the reader’s judgment, its risk is justified. Because of the rapid advances in the medical sciences, dosages"’
`that independent verification of diagnoses and drug dosages should be made. Discussions, views, and recommendations as to medical procedures, choice of drugs, and drug
`osuP(cid:176) (cid:176) 0
`ff
`responsibility of the authors. Statements and Opinions expressed in the articles and communications herein are those of the author(s) and not necessarily those of the editors, publisher
`
`The editors, publisher, and staff disclaim any responsibility for such material and do not guarantee, warrant, or endorse any product or service advertised in this publication nor dO they u 3t
`any claim made by the manufacturer of such product or service.
`
`I
`
`Although all advertising material is expected to conform to ethical and medical standards, inclusion in this publication does not constitute a guarantee or endorsement by the Journal or its staffof
`
`the quality or value of such products or of the claims of any manufacturer. The paper used in this publication meets the minimum requirements of the American National Standard for linforrflation
`Sciences Permanence of Paper for Printed Library Materials, ANSI Z39.43-1992.
`
`tB 2012 Journal of Drugs in Dermatology
`
`This material was
`
`6
`
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`ISsN. 1545 9616 (cid:9)
`
`December 2012
`
`i: W (cid:9)
`
`ie 12
`
`MUGS 1 DEVICES 1 METHODS _j $ 1Nkj
`
`a (cid:9)
`
`SPECIAL TOPIC’
`-i ACNE AND ROSACEA
`
`?. (cid:9)
`
`I
`
`l
`
`SlngIecenter , Open4ab& Study of a ProprIetary TopIcal 05% Salicylic Acid-Ba edreatment Regimen containIng
`Sandalwood Oil in Adolescents and Adults With Mild to Moderate Acne
`
`*nth1p
`
`Clindamycin Phosphate 1.2% and Tretinoin 0.025% Gel for Rosacea: Summary of a Placebo-Controlled, DoUble-Blind Trial
`The E ICacy and Tolerability of Dapeofle 5% Gel in Female vs Male Patients With Facial Acne Vulgaris: Gender as a Clinically Relevant Outcome Variable
`
`
`
`A DoubIegjn, Randomized, Bilateral Comparison of Skin Irritancy Following Application of the Combination Acne P
`ClindamycllVrretlflOin and Benzoyl Peroxlde/Adapatene (cid:9)
`
`roducts
`
`.
`
`Inflammatory Acne Management With a Novel Prescription Dietary Supplement
`
`In Vivo Antibacterial Effects of Tretinoin-Clindamycin and Clindamycin Alone on Propionibacteriurn acnes With Varying Clindamycin
`Minimum Inhibitory Concentration Levels
`
`Gender as a Clinically Relevant Outcome Variable in Acne: Benefits of a Fixed Combination Clindamycin Phosphate (1.2(cid:176)o)
`mx e 2.5%l Aqueous Gel
`
`A High (cid:9)
`
`rn~ (cid:9)
`Improvement in Signs and Sy
`
`OF
`The Pa! go (cid:9)
`MEDICINE
`NitrOsO glutathione Generating Nitric Oxide Nanoparticlos as an Improved Strategy for Combating at. .. ... (cid:9)
`
`L
`
`::::h1T1 J
`
`Jginosa-infected Wounds
`
`’ (cid:9)
`
`I (cid:9)
`
`Clinical Efficacy and Safety of a Multimodality Skin Brightener Composition Compared With 4% l4ydroqulnone
`
`’20 12 VOLUME 11 TSSUE 12
`SISAC (cid:9)
`
`Ic Therapy With Aminolevulinic Acid MCA 20% Topical $oltflton for
`Incubation Period
`of Occlusion (cid:9)
`
`n With Triple Antibiotic Ointment
`
`TRIAL REVIEW
`
`7
`
`(cid:9)
`