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Lymphocyte priming in murine contact hypersensitivity is affected less by pimecrolimus than by tacrolimus1
P301
P303
CLINICAL IRRITATION PATCH TESTS OF RETINOID FORMULATIONS David C. Wilson, MD, Education & Research Foundation, Lynchburg, VA, United States, Victor Stevens, PhD, Ligand Pharmaceuticals, San Diego, CA, United States Five retinoid gels and some companion cream alternatives were evaluated for irritation in a double-blind, 21-day cumulative irritation patch-test at an independent, experienced test site. Two test panels were evaluated in these experiments; one panel comparing formulations under standard occlusion, and one panel evaluating selected formulations under both occlusive and semi-occlusive conditions. Each test panel consisted of 7 active topical retinoids plus a positive control. Commercially available formulations were evaluated under occlusion with standard patches loaded with 0.2 grams of test material. A semi-occlusive patch was achieved by cutting open two sides from these patches prior to loading with test formulation. Patches were applied to the back skin of 25 evaluable subjects in Panel 1 and 29 evaluable subjects in Panel 2. Irritation was evaluated once daily when the patches were changed, except for Sundays. The study continued for 21-days, with irritation scores noted on 18 of 21 days. Topical gel formulations of tretinoin, alitretinoin, adapalene, tazarotene, and bexarotene were evaluated. The positive control was 0.05% sodium lauryl sulphate (SLS). Vehicle gel for bexarotene or a cream formulation of tazarotene or of tretinoin permitted an assessment of the base formulation on the total irritation potential of each product. Irritation potentials in gel formulations by the patch test ranked the following retinoids from low to high: adapalene approx. ⫽ bexarotene ⬍⬍ tretinoin ⬍⬍ alitretinoin approx. ⫽ tazarotene. The positive control of 0.5% SLS was approximately 75% of the maximal possible sum of irritation scores (4 ⫻ 18 readings) under occlusion and 67% under semi-occlusion. Occlusion of the patch increased the irritation potential of formulations by only 2-4% of the maximum for formulations with low irritation scores, but this increased to 10-20% of the maximum for formulations that had high irritation scores. Gels were 10% more irritating than creams, thus formulation effects could account for about 10% of the maximum irritation potential.
ASSESSING POSSIBLE SYNERGY BETWEEN A MOISTURIZING BODY WASH AND LOTION Keith D Ertel, PhD, The Procter & Gamble Company, Cincinnati, OH, United States, Paula Hartwig, BS, The Procter & Gamble Company, Cincinnati, OH, United States, Robert Bacon, BS, The Procter & Gamble Company, Cincinnati, OH, United States, BS, The Procter & Gamble Company, Cincinnati, OH, United States Dry skin is a common complaint among dermatologic patients. Personal cleansing products are recognized as a potential source of drying, and dermatologists often recommend that their patients with dry skin use a mild cleansing product. Such recommendations have traditionally specified synthetic detergent (syndet) bars; however, some new personal cleanser technologies, such as moisturizing body washes, can go beyond simply minimizing skin drying potential to improving dry skin condition. In addition to minimizing potential sources of drying, dermatologists also recommend that their patients apply lotion to help alleviate the symptoms of dry skin. Given the expanded range of personal cleansing products that is now available, we asked whether patients might achieve a greater dry skin benefit by using lotion with a moisturizing body wash rather than a syndet bar. Twenty-four healthy females with dry leg skin were enrolled into a randomized study. Washes were conducted once daily over 5 days following a published leg wash protocol (LCAT) that is used to assess personal cleansers’ potential to improve dry skin. Sites were washed with a moisturizing body wash or a syndet bar. After washing, a moisturizing lotion was applied at a dose of 1 mg/cm2. This dose was chosen to be consistent with consumer experience and to not overwhelm any underlying skin effects due to the cleanser. Expert visual assessments and Corneometer measurements were made at baseline, 3 hours after the first wash, before final wash on day 5 (approximately 24 hours after the previous days’ wash), and 3 hours after the final wash. There is a consistent and significant visual and instrumental dry skin improvement advantage for the moisturizing body wash plus lotion combination compared to the syndet bar plus lotion combination. In addition, mean erythema scores for the moisturizing body wash regimen consistently ranked lower than those for the syndet bar regimen. This trend might reflect the lower skin irritation potential for the moisturizing body wash compared to the syndet bar shown when the products are tested under an irritation protocol (FCAT). The results of this work indicate that personal cleanser choice can impact the dry skin benefit achieved with lotion, and that dermatologists can help their patients achieve a greater dry skin benefit by recommending that they combine lotion with a personal cleanser, such as the moisturizing body wash, that is both mild to skin and provides a dry skin improvement benefit.
Dr Stevens is employed by Ligand Pharmaceuticals. 100% sponsored by Ligand Pharmaceuticals.
All authors are employees of the Procter & Gamble Company 100% sponsored by the Procter & Gamble Company
P304
SIMPLE AND CONVENIENT DOSING IS POSSIBLE WITH ORAL TAZAROTENE Dale Yu, PhD, Allergan, Inc., Irvine, CA, United States, Edward Lee, Allergan, Inc., Irvine, CA, United States, Patricia S. Walker, MD, PhD, Allergan, Inc., Irvine, CA, United States, Diane Tang-Liu, PhD, Allergan, Inc., Irvine, CA, United States Background: An oral formulation of tazarotene is currently in development for the treatment of moderate to very severe plaque psoriasis and severe nodulocystic acne. Objectives: To assess the effects of food and body weight on the pharmacokinetics (PK) of oral tazarotene and its primary active metabolite, tazarotenic acid. Methods: A clinical study in healthy volunteers investigated the effects of food and body weight on the PK profile of oral tazarotene (single dose or seven consecutive daily doses ranging from 3 mg to 12 mg). Results: Taking 6 mg oral tazarotene with a high-fat meal did not affect the absorption of tazarotene—plasma tazarotenic acid AUC ratios in subjects who had taken tazarotene with a high-fat meal were completely within the 80-125% boundary (90% confidence interval) of those in fasted subjects. Cmax ratios were partially outside the 80-125% boundary but this divergence was most likely due to data variability and a small sample size. Comparisons of plasma tazarotenic acid Cmax and AUC values among subjects of differing body weights showed virtually no effect of body weight on systemic tazarotenic acid exposure (p ⬎ 0.05). Specifically, while there was a significant correlation of AUC with body weight on Day 0, there was no such correlation with Cmax and there was no correlation between Cmax or AUC and body weight on Day 9. Conclusion: The lack of influence of food and body weight on the PK profile of oral tazarotene should help facilitate simple and convenient dosing.
LYMPHOCYTE PRIMING IN MURINE CONTACT HYPERSENSITIVITY IS AFFECTED LESS BY PIMECROLIMUS THAN BY TACROLIMUS Josef G Meingassner, DVM, Novartis Research Institute, Vienna, Austria, Assadollah Bavandi, PhD, Novartis Research Institute, Vienna, Austria, Hermann Fahrngruber, Novartis Research Institute, Vienna, Austria, Frank Kalthoff, PhD, Novartis Research Institute, Vienna, Austria Contact hypersensitivity (CH) is a T-cell-mediated, antigen-specific dermatitis that is elicited in sensitized individuals by epicutaneous exposure to the antigen. Oral pimecrolimus and oral tacrolimus have been shown to inhibit the elicitation of CH with similar activity in mice sensitized against oxazolone. Interestingly, the induction phase (sensitization), which is associated with hyperplasia of local lymph nodes (LLN), was inhibited significantly by tacrolimus only, even at a third of the highest dose of pimecrolimus tested. This striking difference prompted analysis of the phenotypes and kinetics of activation-associated surface markers of lymphocytes of the LLN. BALB/c mice were treated orally with 30 mg/kg tacrolimus or 90 mg/kg pimecrolimus 2 hours before and 4, 24 and 48 hours after sensitization, and dissected 24, 48, 72 or 96 hours after sensitization. LLN cell samples were prepared and subjected to analysis by flow cytometry. LLN cells from placebo-treated sensitized mice (controls) and from non-sensitized mice were prepared similarly for comparison. At 72 hours (24 hours after the fourth dose), a higher proportion of LLN cells from controls expressed activation antigens such as CD25 (12.7%), CD69 (37.8%) and CD134 (19.7%), compared with non-sensitized mice. Tacrolimus significantly decreased the number of activated lymphocytes bearing these markers (5.7, 25.9 and 7.3%, respectively; p ⬍ 0.001), whereas pimecrolimus did not inhibit the up-regulation of CD25 and CD69 and only weakly (but significantly) inhibited CD134. At 96 hours (48 hours after the fourth dose), 42.0% of all LLN cells were B cells (CD19⫹) in controls, compared with 20.9% in non-sensitized mice. B cells showed an activated phenotype, as assessed by double staining for B220/CD95 (41.7%) and B220/CD40 (39.7%). In contrast to pimecrolimus, tacrolimus significantly reduced the number of activated B cells, as shown for B220/CD95 cells (30.6% vs 41.7%, respectively) and for B220/CD40 (29.3% vs 39.7%, respectively). These results indicate that treatment of mice with tacrolimus, in contrast to treatment with pimecrolimus, results in the potent inhibition of lymphocyte activation in LLN during sensitization.
All authors are employees of Allergan, Inc. 100% Sponsored by Allergan.
Disclosure not available at press time. This study was sponsored by Novartis Pharma AG.
P302
MARCH 2004
J AM ACAD DERMATOL
P79
P303
CLINICAL IRRITATION PATCH TESTS OF RETINOID FORMULATIONS David C. Wilson, MD, Education & Research Foundation, Lynchburg, VA, United States, Victor Stevens, PhD, Ligand Pharmaceuticals, San Diego, CA, United States Five retinoid gels and some companion cream alternatives were evaluated for irritation in a double-blind, 21-day cumulative irritation patch-test at an independent, experienced test site. Two test panels were evaluated in these experiments; one panel comparing formulations under standard occlusion, and one panel evaluating selected formulations under both occlusive and semi-occlusive conditions. Each test panel consisted of 7 active topical retinoids plus a positive control. Commercially available formulations were evaluated under occlusion with standard patches loaded with 0.2 grams of test material. A semi-occlusive patch was achieved by cutting open two sides from these patches prior to loading with test formulation. Patches were applied to the back skin of 25 evaluable subjects in Panel 1 and 29 evaluable subjects in Panel 2. Irritation was evaluated once daily when the patches were changed, except for Sundays. The study continued for 21-days, with irritation scores noted on 18 of 21 days. Topical gel formulations of tretinoin, alitretinoin, adapalene, tazarotene, and bexarotene were evaluated. The positive control was 0.05% sodium lauryl sulphate (SLS). Vehicle gel for bexarotene or a cream formulation of tazarotene or of tretinoin permitted an assessment of the base formulation on the total irritation potential of each product. Irritation potentials in gel formulations by the patch test ranked the following retinoids from low to high: adapalene approx. ⫽ bexarotene ⬍⬍ tretinoin ⬍⬍ alitretinoin approx. ⫽ tazarotene. The positive control of 0.5% SLS was approximately 75% of the maximal possible sum of irritation scores (4 ⫻ 18 readings) under occlusion and 67% under semi-occlusion. Occlusion of the patch increased the irritation potential of formulations by only 2-4% of the maximum for formulations with low irritation scores, but this increased to 10-20% of the maximum for formulations that had high irritation scores. Gels were 10% more irritating than creams, thus formulation effects could account for about 10% of the maximum irritation potential.
ASSESSING POSSIBLE SYNERGY BETWEEN A MOISTURIZING BODY WASH AND LOTION Keith D Ertel, PhD, The Procter & Gamble Company, Cincinnati, OH, United States, Paula Hartwig, BS, The Procter & Gamble Company, Cincinnati, OH, United States, Robert Bacon, BS, The Procter & Gamble Company, Cincinnati, OH, United States, BS, The Procter & Gamble Company, Cincinnati, OH, United States Dry skin is a common complaint among dermatologic patients. Personal cleansing products are recognized as a potential source of drying, and dermatologists often recommend that their patients with dry skin use a mild cleansing product. Such recommendations have traditionally specified synthetic detergent (syndet) bars; however, some new personal cleanser technologies, such as moisturizing body washes, can go beyond simply minimizing skin drying potential to improving dry skin condition. In addition to minimizing potential sources of drying, dermatologists also recommend that their patients apply lotion to help alleviate the symptoms of dry skin. Given the expanded range of personal cleansing products that is now available, we asked whether patients might achieve a greater dry skin benefit by using lotion with a moisturizing body wash rather than a syndet bar. Twenty-four healthy females with dry leg skin were enrolled into a randomized study. Washes were conducted once daily over 5 days following a published leg wash protocol (LCAT) that is used to assess personal cleansers’ potential to improve dry skin. Sites were washed with a moisturizing body wash or a syndet bar. After washing, a moisturizing lotion was applied at a dose of 1 mg/cm2. This dose was chosen to be consistent with consumer experience and to not overwhelm any underlying skin effects due to the cleanser. Expert visual assessments and Corneometer measurements were made at baseline, 3 hours after the first wash, before final wash on day 5 (approximately 24 hours after the previous days’ wash), and 3 hours after the final wash. There is a consistent and significant visual and instrumental dry skin improvement advantage for the moisturizing body wash plus lotion combination compared to the syndet bar plus lotion combination. In addition, mean erythema scores for the moisturizing body wash regimen consistently ranked lower than those for the syndet bar regimen. This trend might reflect the lower skin irritation potential for the moisturizing body wash compared to the syndet bar shown when the products are tested under an irritation protocol (FCAT). The results of this work indicate that personal cleanser choice can impact the dry skin benefit achieved with lotion, and that dermatologists can help their patients achieve a greater dry skin benefit by recommending that they combine lotion with a personal cleanser, such as the moisturizing body wash, that is both mild to skin and provides a dry skin improvement benefit.
Dr Stevens is employed by Ligand Pharmaceuticals. 100% sponsored by Ligand Pharmaceuticals.
All authors are employees of the Procter & Gamble Company 100% sponsored by the Procter & Gamble Company
P304
SIMPLE AND CONVENIENT DOSING IS POSSIBLE WITH ORAL TAZAROTENE Dale Yu, PhD, Allergan, Inc., Irvine, CA, United States, Edward Lee, Allergan, Inc., Irvine, CA, United States, Patricia S. Walker, MD, PhD, Allergan, Inc., Irvine, CA, United States, Diane Tang-Liu, PhD, Allergan, Inc., Irvine, CA, United States Background: An oral formulation of tazarotene is currently in development for the treatment of moderate to very severe plaque psoriasis and severe nodulocystic acne. Objectives: To assess the effects of food and body weight on the pharmacokinetics (PK) of oral tazarotene and its primary active metabolite, tazarotenic acid. Methods: A clinical study in healthy volunteers investigated the effects of food and body weight on the PK profile of oral tazarotene (single dose or seven consecutive daily doses ranging from 3 mg to 12 mg). Results: Taking 6 mg oral tazarotene with a high-fat meal did not affect the absorption of tazarotene—plasma tazarotenic acid AUC ratios in subjects who had taken tazarotene with a high-fat meal were completely within the 80-125% boundary (90% confidence interval) of those in fasted subjects. Cmax ratios were partially outside the 80-125% boundary but this divergence was most likely due to data variability and a small sample size. Comparisons of plasma tazarotenic acid Cmax and AUC values among subjects of differing body weights showed virtually no effect of body weight on systemic tazarotenic acid exposure (p ⬎ 0.05). Specifically, while there was a significant correlation of AUC with body weight on Day 0, there was no such correlation with Cmax and there was no correlation between Cmax or AUC and body weight on Day 9. Conclusion: The lack of influence of food and body weight on the PK profile of oral tazarotene should help facilitate simple and convenient dosing.
LYMPHOCYTE PRIMING IN MURINE CONTACT HYPERSENSITIVITY IS AFFECTED LESS BY PIMECROLIMUS THAN BY TACROLIMUS Josef G Meingassner, DVM, Novartis Research Institute, Vienna, Austria, Assadollah Bavandi, PhD, Novartis Research Institute, Vienna, Austria, Hermann Fahrngruber, Novartis Research Institute, Vienna, Austria, Frank Kalthoff, PhD, Novartis Research Institute, Vienna, Austria Contact hypersensitivity (CH) is a T-cell-mediated, antigen-specific dermatitis that is elicited in sensitized individuals by epicutaneous exposure to the antigen. Oral pimecrolimus and oral tacrolimus have been shown to inhibit the elicitation of CH with similar activity in mice sensitized against oxazolone. Interestingly, the induction phase (sensitization), which is associated with hyperplasia of local lymph nodes (LLN), was inhibited significantly by tacrolimus only, even at a third of the highest dose of pimecrolimus tested. This striking difference prompted analysis of the phenotypes and kinetics of activation-associated surface markers of lymphocytes of the LLN. BALB/c mice were treated orally with 30 mg/kg tacrolimus or 90 mg/kg pimecrolimus 2 hours before and 4, 24 and 48 hours after sensitization, and dissected 24, 48, 72 or 96 hours after sensitization. LLN cell samples were prepared and subjected to analysis by flow cytometry. LLN cells from placebo-treated sensitized mice (controls) and from non-sensitized mice were prepared similarly for comparison. At 72 hours (24 hours after the fourth dose), a higher proportion of LLN cells from controls expressed activation antigens such as CD25 (12.7%), CD69 (37.8%) and CD134 (19.7%), compared with non-sensitized mice. Tacrolimus significantly decreased the number of activated lymphocytes bearing these markers (5.7, 25.9 and 7.3%, respectively; p ⬍ 0.001), whereas pimecrolimus did not inhibit the up-regulation of CD25 and CD69 and only weakly (but significantly) inhibited CD134. At 96 hours (48 hours after the fourth dose), 42.0% of all LLN cells were B cells (CD19⫹) in controls, compared with 20.9% in non-sensitized mice. B cells showed an activated phenotype, as assessed by double staining for B220/CD95 (41.7%) and B220/CD40 (39.7%). In contrast to pimecrolimus, tacrolimus significantly reduced the number of activated B cells, as shown for B220/CD95 cells (30.6% vs 41.7%, respectively) and for B220/CD40 (29.3% vs 39.7%, respectively). These results indicate that treatment of mice with tacrolimus, in contrast to treatment with pimecrolimus, results in the potent inhibition of lymphocyte activation in LLN during sensitization.
All authors are employees of Allergan, Inc. 100% Sponsored by Allergan.
Disclosure not available at press time. This study was sponsored by Novartis Pharma AG.
P302
MARCH 2004
J AM ACAD DERMATOL
P79