A New Ecamsule-Containing SPF 40 Sunscreen Cream for the Prevention of Polymorphous Light Eruption: A Double-blind, Randomized, Controlled Study in Maximized Outdoor Conditions

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Adapalene–Benzoyl Peroxide Once-Daily, Fixed-Dose Combination Gel for the Treatment of Acne Vulgaris: A Randomized, Bilateral (Split-Face), Dose-Assessment Study of Cutaneous Tolerability in Healthy Participants

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Clobetasol Propionate Shampoo 0.05% in the Treatment of Seborrheic Dermatitis of the Scalp: Results of a Pilot Study

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Clobetasol Propionate Lotion in the Treatment of Moderate to Severe Plaque-Type Psoriasis

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Cumulative Irritancy Potential of Adapalene Cream 0.1% Compared With Adapalene Gel 0.1% and Several Tretinoin Formulations

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Cumulative Irritation Comparison of Adapalene Gel and Solution With 2 Tazarotene Gels and 3 Tretinoin Formulations

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Adapalene (Differin®) is a naphthoic-acid derivative with retinoid activity that is effective in the treatment of mild to moderate acne vulgaris.1-4 Adapalene, in both gel and cream formulations, at the marketed and approved concentration of 0.1%, is better tolerated than most tretinoin formulations, including tretinoin microsphere gel 0.1% (Retin-A Micro®) and tretinoin cream 0.025% (Avita®).5-10 The cumulative irritancy assay (patch test) is designed to assess the irritation potential of topically applied materials. Irritation results obtained from this type of assay are due to direct damage to the epidermal cells, and no immunologic (allergic) mechanism is involved. Results of this standard assay are widely accepted to be indicators of irritation. This study compared the irritation potential of adapalene gel and solution with several retinoid and retinoidlike products containing either tazarotene or tretinoin.back to top


METHODS This cumulative irritancy study was conducted as a single-center, randomized, controlled, investigator/evaluator, double-blind, intraindividual comparison involving healthy subjects meeting specific inclusion-exclusion criteria. The cumulative irritancy assay, a 21-day patch test, was designed to assess the irritation potential of topically applied dermatologic materials under stressful conditions (ie, occlusion).11 A total of 42 subjects (6 males and 36 females) ranging in age from 22.9 to 74.8 years were enrolled and evaluated. All subjects received adapalene gel 0.1%, adapalene solution 0.1%, tazarotene gel 0.1%, tazarotene gel 0.05%, tretinoin microsphere gel 0.1%, tretinoin cream 0.025%, tretinoin gel 0.025%, and white petrolatum (negative control). Approximately 0.2 g of each of the 7 test products and negative control was applied to 8 sites on the upper area of the back according to a predefined randomization list. Application was made under occlusive conditions for 24 hours (4 times per week) and 72 hours (once weekly) for 3 weeks. At each study visit, skin reactions (erythema scores±other local reactions) were assessed by the same trained board-certified physician evaluator during the study, 15 to 30 minutes after removal of the product, using the grading scale for erythema (Table 1).

View this table

Table 1. Erythema Grading Scale

In addition, other concomitant cutaneous reactions (eg, dryness, cracking, peeling) on test sites were noted, including adhesive reactions. The principal safety criterion was the mean cumulative irritancy index (MCII) assessed by clinical evaluation of the erythema at each test site. Evaluation of the test product application sites was conducted by the same investigator/evaluator throughout the study. The sites were scored at baseline (day 1) and at each study visit, week 1 (days 2 through 5, inclusively), week 2 (days 8 through 12, inclusively), week 3 (days 15 through 19, inclusively), and week 4 (day 22). The backs of the subjects were photographed before each reading. When an irritation reaction related to the product was graded 3 for any site, product application was discontinued for the incriminated sites. When an irritation reaction related to the adhesive prohibited the wearing of a patch at a particular site, all patch applications were discontinued for the subject. However, the subject was not discontinued from treatment unless, in the investigator’s/evaluator’s opinion, there was a safety concern. At that time, an adverse event form would have been completed. All subjects were informed in accordance with the International Conference on Harmonization guidelines and Good Clinical Practices. A written consent form, approved by the Institutional Review Board, was supplied by the investigator and was understood and signed by each subject before inclusion in the study. back to top


Statistical Methodology Sample Size, Design, and Randomization—A standard sample size for this type of cumulative irritancy clinical study is 25 subjects. To account for the multiplicity of comparisons, planned enrollment was estimated at 48 subjects. Enrollment was completed at 42 subjects, with the consent of the sponsor. On initiation, each of the 8 products was applied to one of the zones (Z1–Z8) according to the predefined randomization schedule. This randomization schedule was generated by the RANUNI routine of SAS using 8x8 Latin squares. Statistically Analyzed Variables—For evaluating the cutaneous tolerance, a cumulative irritancy index (CII) was calculated for each treatment and for each subject, as follows: CII=sum of irritation score/number of readings. The following conventions were applied for the CII calculation: baseline (day 1) score was excluded from the calculation. When the irritation reaction was rated 3 for any site, the product application was discontinued for the incriminated sites, and a score of 3 was assigned to the remaining readings (last observation carried forward). When a subject missed a scheduled visit, the scores of the sites from the next visit were assigned to the previously missed visit. Individual CII scores were averaged across subjects to obtain an MCII score for each treatment. MCII scores were submitted to an analysis of variance with effects for subject, zone, and formulation. To adjust for multiple comparisons, MCII score was compared, and formulations were classified using the Tukey multiple comparisons test performed at the 1% and 5% significance levels. According to MCII values, each test product could be classified into the irritation classes (Table 2).

 

 

View this table

Table 2. Irritation Classification*
back to top


results Of the 42 subjects enrolled, 38 subjects (90.5%) completed the study. Demographic data are presented in Table 3. Results are summarized in Table 4 and Figure 1. Figure 2 shows a clinical photograph of typical irritation observed during the study.

View this table

Table 3. Demographic Data
View this table

Table 4. Summary of Mean Cumulative Irritancy Index (MCII) Statistical Comparisons

In the study, the reasons for treatment discontinuation were not always due to an erythema score of 3 but also because of other clinical aspects of severe intolerance, such as epidermal peeling with subsequent superficial erosion (without severe erythema). Figure 3 shows the number of subjects who discontinued wearing the patches due to an irritation score of 3.
Adapalene gel and solution 0.1% were each significantly less irritating during sustained use than tazarotene gels 0.05% and 0.1%, tretinoin microsphere gel 0.1%, and tretinoin cream 0.025%. Although tretinoin gel 0.1% MCII was numerically superior to both adapalene gel and solution MCIIs, no statistically significant difference could be depicted between the 3 products. Repeated applications of adapalene gel or solution resulted in levels of irritation that were not significantly different from the white petrolatum control. back to top


References

  1. Verschoore M, Langner A, Wolska H, et al. Vehicle controlled study of CD 271 lotion in the topical treatment of acne vulgaris. J Invest Dermatol. 1993;100:221A.
  2. Verschoore M, Langner A, Wolska H, et al. Efficacy and safety of CD 271 alcoholic gels in the topical treatment of acne vulgaris. Br J Dermatol. 1991;124:368-371.
  3. Bernard BA. Adapalene, a new chemical entity with retinoid activity. Skin Pharmacol. 1993;6(suppl 1):61-69.
  4. Shroot B, Michel S. Pharmacology and chemistry of adapalene. J Am Acad Dermatol. 1997;36:S96-S103.
  5. Verschoore M, Poncet M, Czernielewski J, et al. Adapalene 0.1% gel has low skin-irritation potential. J Am Acad Dermatol. 1997;36:S104-S109.
  6. Caron D, Sorba V, Kerrouche N, et al. Split-face comparison of adapalene 0.1% gel and tretinoin 0.025% gel in acne patients. J Am Acad Dermatol. 1997;36:S110-S112.
  7. Cunliffe WJ, Caputo R, Dreno B, et al. Clinical efficacy and safety comparison of adapalene gel and tretinoin gel in the treatment of acne vulgaris. Europe and U.S. multicenter trials. J Am Acad Dermatol. 1997;36:S126-S134.
  8. Shalita A, Weiss JS, Chalker DK, et al. A comparison of the efficacy and safety of adapalene gel 0.1% and tretinoin gel 0.025% in the treatment of acne vulgaris: a multicenter trial. J Am Acad Dermatol. 1996;34:482-485.
  9. Thiboutot D, Gold MH, Jarratt MT, et al. Randomized controlled trial of tolerability, safety, and efficacy of adapalene gel 0.1% and tretinoin microsphere gel 0.1% for the treatment of acne vulgaris. Cutis. 2001;68(suppl 4):10-19.
  10. Egan N, Loesche MC, Baker MM. Randomized, controlled, bilateral (split-face) comparison trial of the tolerability and patient preference of adapalene gel 0.1% and tretinoin microsphere gel 0.1% for the treatment of acne vulgaris. Cutis. 2001;68(suppl 4):20-24.
  11. Berger RS, Bowman JP. A reappraisal of the 21-day Cumulative Irritation Test in Man. J Toxicol Cutan Ocul Toxicol. 1982;1:109-115.
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Alan Greenspan, MD; Christian Loesche, MD; Nancy Vendetti; Kathleen Georgeian; Richard Gilbert, PhD; Michel Poncet, PhD; Michael D. Baker, BS; Pascale Soto, RPh

Accepted for publication March 19, 2003. Drs. Greenspan and Gilbert and Mss. Vendetti and Georgeian are with TKL Research, Inc, Paramus, New Jersey. Drs. Loesche and Poncet and Mr. Soto are with Galderma Research & Development, Sophia Antipolis, France. Mr. Baker is with Galderma Research & Development, Princeton, New Jersey. Dr. Greenspan is on the speakers bureau and is a paid consultant for Galderma Laboratories, LP. Mss. Vendetti and Georgeian and Dr. Gilbert report no conflict of interest.
This study was supported by Galderma Laboratories, LP.

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Alan Greenspan, MD; Christian Loesche, MD; Nancy Vendetti; Kathleen Georgeian; Richard Gilbert, PhD; Michel Poncet, PhD; Michael D. Baker, BS; Pascale Soto, RPh

Accepted for publication March 19, 2003. Drs. Greenspan and Gilbert and Mss. Vendetti and Georgeian are with TKL Research, Inc, Paramus, New Jersey. Drs. Loesche and Poncet and Mr. Soto are with Galderma Research & Development, Sophia Antipolis, France. Mr. Baker is with Galderma Research & Development, Princeton, New Jersey. Dr. Greenspan is on the speakers bureau and is a paid consultant for Galderma Laboratories, LP. Mss. Vendetti and Georgeian and Dr. Gilbert report no conflict of interest.
This study was supported by Galderma Laboratories, LP.

Author and Disclosure Information

Alan Greenspan, MD; Christian Loesche, MD; Nancy Vendetti; Kathleen Georgeian; Richard Gilbert, PhD; Michel Poncet, PhD; Michael D. Baker, BS; Pascale Soto, RPh

Accepted for publication March 19, 2003. Drs. Greenspan and Gilbert and Mss. Vendetti and Georgeian are with TKL Research, Inc, Paramus, New Jersey. Drs. Loesche and Poncet and Mr. Soto are with Galderma Research & Development, Sophia Antipolis, France. Mr. Baker is with Galderma Research & Development, Princeton, New Jersey. Dr. Greenspan is on the speakers bureau and is a paid consultant for Galderma Laboratories, LP. Mss. Vendetti and Georgeian and Dr. Gilbert report no conflict of interest.
This study was supported by Galderma Laboratories, LP.

Article PDF
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Adapalene (Differin®) is a naphthoic-acid derivative with retinoid activity that is effective in the treatment of mild to moderate acne vulgaris.1-4 Adapalene, in both gel and cream formulations, at the marketed and approved concentration of 0.1%, is better tolerated than most tretinoin formulations, including tretinoin microsphere gel 0.1% (Retin-A Micro®) and tretinoin cream 0.025% (Avita®).5-10 The cumulative irritancy assay (patch test) is designed to assess the irritation potential of topically applied materials. Irritation results obtained from this type of assay are due to direct damage to the epidermal cells, and no immunologic (allergic) mechanism is involved. Results of this standard assay are widely accepted to be indicators of irritation. This study compared the irritation potential of adapalene gel and solution with several retinoid and retinoidlike products containing either tazarotene or tretinoin.back to top


METHODS This cumulative irritancy study was conducted as a single-center, randomized, controlled, investigator/evaluator, double-blind, intraindividual comparison involving healthy subjects meeting specific inclusion-exclusion criteria. The cumulative irritancy assay, a 21-day patch test, was designed to assess the irritation potential of topically applied dermatologic materials under stressful conditions (ie, occlusion).11 A total of 42 subjects (6 males and 36 females) ranging in age from 22.9 to 74.8 years were enrolled and evaluated. All subjects received adapalene gel 0.1%, adapalene solution 0.1%, tazarotene gel 0.1%, tazarotene gel 0.05%, tretinoin microsphere gel 0.1%, tretinoin cream 0.025%, tretinoin gel 0.025%, and white petrolatum (negative control). Approximately 0.2 g of each of the 7 test products and negative control was applied to 8 sites on the upper area of the back according to a predefined randomization list. Application was made under occlusive conditions for 24 hours (4 times per week) and 72 hours (once weekly) for 3 weeks. At each study visit, skin reactions (erythema scores±other local reactions) were assessed by the same trained board-certified physician evaluator during the study, 15 to 30 minutes after removal of the product, using the grading scale for erythema (Table 1).

View this table

Table 1. Erythema Grading Scale

In addition, other concomitant cutaneous reactions (eg, dryness, cracking, peeling) on test sites were noted, including adhesive reactions. The principal safety criterion was the mean cumulative irritancy index (MCII) assessed by clinical evaluation of the erythema at each test site. Evaluation of the test product application sites was conducted by the same investigator/evaluator throughout the study. The sites were scored at baseline (day 1) and at each study visit, week 1 (days 2 through 5, inclusively), week 2 (days 8 through 12, inclusively), week 3 (days 15 through 19, inclusively), and week 4 (day 22). The backs of the subjects were photographed before each reading. When an irritation reaction related to the product was graded 3 for any site, product application was discontinued for the incriminated sites. When an irritation reaction related to the adhesive prohibited the wearing of a patch at a particular site, all patch applications were discontinued for the subject. However, the subject was not discontinued from treatment unless, in the investigator’s/evaluator’s opinion, there was a safety concern. At that time, an adverse event form would have been completed. All subjects were informed in accordance with the International Conference on Harmonization guidelines and Good Clinical Practices. A written consent form, approved by the Institutional Review Board, was supplied by the investigator and was understood and signed by each subject before inclusion in the study. back to top


Statistical Methodology Sample Size, Design, and Randomization—A standard sample size for this type of cumulative irritancy clinical study is 25 subjects. To account for the multiplicity of comparisons, planned enrollment was estimated at 48 subjects. Enrollment was completed at 42 subjects, with the consent of the sponsor. On initiation, each of the 8 products was applied to one of the zones (Z1–Z8) according to the predefined randomization schedule. This randomization schedule was generated by the RANUNI routine of SAS using 8x8 Latin squares. Statistically Analyzed Variables—For evaluating the cutaneous tolerance, a cumulative irritancy index (CII) was calculated for each treatment and for each subject, as follows: CII=sum of irritation score/number of readings. The following conventions were applied for the CII calculation: baseline (day 1) score was excluded from the calculation. When the irritation reaction was rated 3 for any site, the product application was discontinued for the incriminated sites, and a score of 3 was assigned to the remaining readings (last observation carried forward). When a subject missed a scheduled visit, the scores of the sites from the next visit were assigned to the previously missed visit. Individual CII scores were averaged across subjects to obtain an MCII score for each treatment. MCII scores were submitted to an analysis of variance with effects for subject, zone, and formulation. To adjust for multiple comparisons, MCII score was compared, and formulations were classified using the Tukey multiple comparisons test performed at the 1% and 5% significance levels. According to MCII values, each test product could be classified into the irritation classes (Table 2).

 

 

View this table

Table 2. Irritation Classification*
back to top


results Of the 42 subjects enrolled, 38 subjects (90.5%) completed the study. Demographic data are presented in Table 3. Results are summarized in Table 4 and Figure 1. Figure 2 shows a clinical photograph of typical irritation observed during the study.

View this table

Table 3. Demographic Data
View this table

Table 4. Summary of Mean Cumulative Irritancy Index (MCII) Statistical Comparisons

In the study, the reasons for treatment discontinuation were not always due to an erythema score of 3 but also because of other clinical aspects of severe intolerance, such as epidermal peeling with subsequent superficial erosion (without severe erythema). Figure 3 shows the number of subjects who discontinued wearing the patches due to an irritation score of 3.
Adapalene gel and solution 0.1% were each significantly less irritating during sustained use than tazarotene gels 0.05% and 0.1%, tretinoin microsphere gel 0.1%, and tretinoin cream 0.025%. Although tretinoin gel 0.1% MCII was numerically superior to both adapalene gel and solution MCIIs, no statistically significant difference could be depicted between the 3 products. Repeated applications of adapalene gel or solution resulted in levels of irritation that were not significantly different from the white petrolatum control. back to top


Adapalene (Differin®) is a naphthoic-acid derivative with retinoid activity that is effective in the treatment of mild to moderate acne vulgaris.1-4 Adapalene, in both gel and cream formulations, at the marketed and approved concentration of 0.1%, is better tolerated than most tretinoin formulations, including tretinoin microsphere gel 0.1% (Retin-A Micro®) and tretinoin cream 0.025% (Avita®).5-10 The cumulative irritancy assay (patch test) is designed to assess the irritation potential of topically applied materials. Irritation results obtained from this type of assay are due to direct damage to the epidermal cells, and no immunologic (allergic) mechanism is involved. Results of this standard assay are widely accepted to be indicators of irritation. This study compared the irritation potential of adapalene gel and solution with several retinoid and retinoidlike products containing either tazarotene or tretinoin.back to top


METHODS This cumulative irritancy study was conducted as a single-center, randomized, controlled, investigator/evaluator, double-blind, intraindividual comparison involving healthy subjects meeting specific inclusion-exclusion criteria. The cumulative irritancy assay, a 21-day patch test, was designed to assess the irritation potential of topically applied dermatologic materials under stressful conditions (ie, occlusion).11 A total of 42 subjects (6 males and 36 females) ranging in age from 22.9 to 74.8 years were enrolled and evaluated. All subjects received adapalene gel 0.1%, adapalene solution 0.1%, tazarotene gel 0.1%, tazarotene gel 0.05%, tretinoin microsphere gel 0.1%, tretinoin cream 0.025%, tretinoin gel 0.025%, and white petrolatum (negative control). Approximately 0.2 g of each of the 7 test products and negative control was applied to 8 sites on the upper area of the back according to a predefined randomization list. Application was made under occlusive conditions for 24 hours (4 times per week) and 72 hours (once weekly) for 3 weeks. At each study visit, skin reactions (erythema scores±other local reactions) were assessed by the same trained board-certified physician evaluator during the study, 15 to 30 minutes after removal of the product, using the grading scale for erythema (Table 1).

View this table

Table 1. Erythema Grading Scale

In addition, other concomitant cutaneous reactions (eg, dryness, cracking, peeling) on test sites were noted, including adhesive reactions. The principal safety criterion was the mean cumulative irritancy index (MCII) assessed by clinical evaluation of the erythema at each test site. Evaluation of the test product application sites was conducted by the same investigator/evaluator throughout the study. The sites were scored at baseline (day 1) and at each study visit, week 1 (days 2 through 5, inclusively), week 2 (days 8 through 12, inclusively), week 3 (days 15 through 19, inclusively), and week 4 (day 22). The backs of the subjects were photographed before each reading. When an irritation reaction related to the product was graded 3 for any site, product application was discontinued for the incriminated sites. When an irritation reaction related to the adhesive prohibited the wearing of a patch at a particular site, all patch applications were discontinued for the subject. However, the subject was not discontinued from treatment unless, in the investigator’s/evaluator’s opinion, there was a safety concern. At that time, an adverse event form would have been completed. All subjects were informed in accordance with the International Conference on Harmonization guidelines and Good Clinical Practices. A written consent form, approved by the Institutional Review Board, was supplied by the investigator and was understood and signed by each subject before inclusion in the study. back to top


Statistical Methodology Sample Size, Design, and Randomization—A standard sample size for this type of cumulative irritancy clinical study is 25 subjects. To account for the multiplicity of comparisons, planned enrollment was estimated at 48 subjects. Enrollment was completed at 42 subjects, with the consent of the sponsor. On initiation, each of the 8 products was applied to one of the zones (Z1–Z8) according to the predefined randomization schedule. This randomization schedule was generated by the RANUNI routine of SAS using 8x8 Latin squares. Statistically Analyzed Variables—For evaluating the cutaneous tolerance, a cumulative irritancy index (CII) was calculated for each treatment and for each subject, as follows: CII=sum of irritation score/number of readings. The following conventions were applied for the CII calculation: baseline (day 1) score was excluded from the calculation. When the irritation reaction was rated 3 for any site, the product application was discontinued for the incriminated sites, and a score of 3 was assigned to the remaining readings (last observation carried forward). When a subject missed a scheduled visit, the scores of the sites from the next visit were assigned to the previously missed visit. Individual CII scores were averaged across subjects to obtain an MCII score for each treatment. MCII scores were submitted to an analysis of variance with effects for subject, zone, and formulation. To adjust for multiple comparisons, MCII score was compared, and formulations were classified using the Tukey multiple comparisons test performed at the 1% and 5% significance levels. According to MCII values, each test product could be classified into the irritation classes (Table 2).

 

 

View this table

Table 2. Irritation Classification*
back to top


results Of the 42 subjects enrolled, 38 subjects (90.5%) completed the study. Demographic data are presented in Table 3. Results are summarized in Table 4 and Figure 1. Figure 2 shows a clinical photograph of typical irritation observed during the study.

View this table

Table 3. Demographic Data
View this table

Table 4. Summary of Mean Cumulative Irritancy Index (MCII) Statistical Comparisons

In the study, the reasons for treatment discontinuation were not always due to an erythema score of 3 but also because of other clinical aspects of severe intolerance, such as epidermal peeling with subsequent superficial erosion (without severe erythema). Figure 3 shows the number of subjects who discontinued wearing the patches due to an irritation score of 3.
Adapalene gel and solution 0.1% were each significantly less irritating during sustained use than tazarotene gels 0.05% and 0.1%, tretinoin microsphere gel 0.1%, and tretinoin cream 0.025%. Although tretinoin gel 0.1% MCII was numerically superior to both adapalene gel and solution MCIIs, no statistically significant difference could be depicted between the 3 products. Repeated applications of adapalene gel or solution resulted in levels of irritation that were not significantly different from the white petrolatum control. back to top


References

  1. Verschoore M, Langner A, Wolska H, et al. Vehicle controlled study of CD 271 lotion in the topical treatment of acne vulgaris. J Invest Dermatol. 1993;100:221A.
  2. Verschoore M, Langner A, Wolska H, et al. Efficacy and safety of CD 271 alcoholic gels in the topical treatment of acne vulgaris. Br J Dermatol. 1991;124:368-371.
  3. Bernard BA. Adapalene, a new chemical entity with retinoid activity. Skin Pharmacol. 1993;6(suppl 1):61-69.
  4. Shroot B, Michel S. Pharmacology and chemistry of adapalene. J Am Acad Dermatol. 1997;36:S96-S103.
  5. Verschoore M, Poncet M, Czernielewski J, et al. Adapalene 0.1% gel has low skin-irritation potential. J Am Acad Dermatol. 1997;36:S104-S109.
  6. Caron D, Sorba V, Kerrouche N, et al. Split-face comparison of adapalene 0.1% gel and tretinoin 0.025% gel in acne patients. J Am Acad Dermatol. 1997;36:S110-S112.
  7. Cunliffe WJ, Caputo R, Dreno B, et al. Clinical efficacy and safety comparison of adapalene gel and tretinoin gel in the treatment of acne vulgaris. Europe and U.S. multicenter trials. J Am Acad Dermatol. 1997;36:S126-S134.
  8. Shalita A, Weiss JS, Chalker DK, et al. A comparison of the efficacy and safety of adapalene gel 0.1% and tretinoin gel 0.025% in the treatment of acne vulgaris: a multicenter trial. J Am Acad Dermatol. 1996;34:482-485.
  9. Thiboutot D, Gold MH, Jarratt MT, et al. Randomized controlled trial of tolerability, safety, and efficacy of adapalene gel 0.1% and tretinoin microsphere gel 0.1% for the treatment of acne vulgaris. Cutis. 2001;68(suppl 4):10-19.
  10. Egan N, Loesche MC, Baker MM. Randomized, controlled, bilateral (split-face) comparison trial of the tolerability and patient preference of adapalene gel 0.1% and tretinoin microsphere gel 0.1% for the treatment of acne vulgaris. Cutis. 2001;68(suppl 4):20-24.
  11. Berger RS, Bowman JP. A reappraisal of the 21-day Cumulative Irritation Test in Man. J Toxicol Cutan Ocul Toxicol. 1982;1:109-115.
References

  1. Verschoore M, Langner A, Wolska H, et al. Vehicle controlled study of CD 271 lotion in the topical treatment of acne vulgaris. J Invest Dermatol. 1993;100:221A.
  2. Verschoore M, Langner A, Wolska H, et al. Efficacy and safety of CD 271 alcoholic gels in the topical treatment of acne vulgaris. Br J Dermatol. 1991;124:368-371.
  3. Bernard BA. Adapalene, a new chemical entity with retinoid activity. Skin Pharmacol. 1993;6(suppl 1):61-69.
  4. Shroot B, Michel S. Pharmacology and chemistry of adapalene. J Am Acad Dermatol. 1997;36:S96-S103.
  5. Verschoore M, Poncet M, Czernielewski J, et al. Adapalene 0.1% gel has low skin-irritation potential. J Am Acad Dermatol. 1997;36:S104-S109.
  6. Caron D, Sorba V, Kerrouche N, et al. Split-face comparison of adapalene 0.1% gel and tretinoin 0.025% gel in acne patients. J Am Acad Dermatol. 1997;36:S110-S112.
  7. Cunliffe WJ, Caputo R, Dreno B, et al. Clinical efficacy and safety comparison of adapalene gel and tretinoin gel in the treatment of acne vulgaris. Europe and U.S. multicenter trials. J Am Acad Dermatol. 1997;36:S126-S134.
  8. Shalita A, Weiss JS, Chalker DK, et al. A comparison of the efficacy and safety of adapalene gel 0.1% and tretinoin gel 0.025% in the treatment of acne vulgaris: a multicenter trial. J Am Acad Dermatol. 1996;34:482-485.
  9. Thiboutot D, Gold MH, Jarratt MT, et al. Randomized controlled trial of tolerability, safety, and efficacy of adapalene gel 0.1% and tretinoin microsphere gel 0.1% for the treatment of acne vulgaris. Cutis. 2001;68(suppl 4):10-19.
  10. Egan N, Loesche MC, Baker MM. Randomized, controlled, bilateral (split-face) comparison trial of the tolerability and patient preference of adapalene gel 0.1% and tretinoin microsphere gel 0.1% for the treatment of acne vulgaris. Cutis. 2001;68(suppl 4):20-24.
  11. Berger RS, Bowman JP. A reappraisal of the 21-day Cumulative Irritation Test in Man. J Toxicol Cutan Ocul Toxicol. 1982;1:109-115.
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